Job crafting, an employee-initiated job design/redesign, has become important for employees’ well-being such as work engagement. This study examined the effectiveness of a newly developed job crafting intervention program on work engagement (as primary outcome), as well as job crafting and psychological distress (as secondary outcomes), using a pretest-posttest study design among Japanese employees.Participants were managers of a private company and a private psychiatric hospital in Japan. The job crafting intervention program consisted of two 120-min sessions with a two-week interval between them. Outcomes were assessed at baseline (Time 1), post-intervention (Time 2), and a one-month follow-up (Time 3). The mixed growth model analyses were conducted using time  as an indicator of intervention effect. Effect sizes were calculated using Cohen’s d.p = 0.03) in the mixed growth model analyses, but with only small effect sizes (Cohen’s d = 0.33 at Time 2 and 0.26 at Time 3). The program also significantly improved job crafting  and reduced psychological distress .The program showed a significant positive effect on work engagement (t = 2.20, The study indicated that the newly developed job crafting intervention program was effective in increasing work engagement, as well as in improving job crafting and decreasing psychological distress, among Japanese managers.UMIN000024062. Retrospectively registered 15 September 2016.UMIN Clinical Trials Registry  Today’s organizations require their employees to be motivated, proactive, responsible, and involved. In other words, modern work organizations need engaged employees , 2.TableWork engagement is defined as an active, positive, work-related state of mind characterized by vigor, dedication, and absorption , 4. AccoThe number of intervention studies aimed at improving work engagement is increasing. Although seven randomized controlled trials (RCTs) have been conducted since 2012, only two studies showed an improvement of work engagement at follow-up.For instance, Coffeng et al. (2014) conducted an intervention to change the physical work environment  and found a significant improvement of absorption, a component of work engagement . HoweverOne possible reason why previous studies failed to find an intervention effect on work engagement  is that they did not employ strategies to simultaneously improve the two resources of work engagement – that is, job resources and personal resources , 8. SpecJob resources include physical, social, or organizational aspects of the job that help individuals to achieve their working goals; stimulate personal growth, learning, and development; or reduce job demands or associated physical or psychological costs, such as support from colleagues and opportunity for development . PersonaJob crafting – that is, employee-initiated design/redesign of work characteristics – can be conceptualized as a personal resource. According to Wrzesniewski and Dutton 2001), job crafting is defined as “the physical and cognitive change individuals make in the task or relational boundaries of their work” 01, job c. BecauseTo date, there have been only three non-randomized controlled trials of job crafting program, which composed of two or three group sessions –28. For The aim of this study was to investigate the effectiveness of a newly developed job crafting intervention program on work engagement among Japanese employees with a pretest-posttest study design. We expect that the scores of job crafting (for manipulation check) and work engagement (primary outcome) will increase at Time 2 (post-intervention) and at Time 3 (one-month follow-up) than compared to Time 1 (baseline). In addition, the score of psychological distress (secondary outcome) will decrease at Time 2 and Time 3 compared to Time 1. The strong point of this program is that it focuses on three types of job crafting  based on the concept of Wrzesniewski and Dutton , which mA pre- and post-intervention study was conducted. There was no control group because it was difficult to set due to the condition of the participant organizations. Therefore, we put this study as a pilot study to investigate the effectiveness of our job crafting intervention preliminarily. The study protocol was registered retrospectively at the UMIN Clinical Trials Registry (UMIN-CTR) (ID = UMIN000024062). The ethics review board of The University of Tokyo Graduate School of Medicine/Faculty of Medicine approved the procedures before the start of the study (the reference number: 10749). This manuscript was reported according to the TREND statement checklist .n = 54) and managers who belonged to seven selected departments at a private psychiatric hospital (n = 25). Participants were approached by a contact person in their own company or hospital using an e-mail invitation or a poster. The inclusion criterion for participants was regular (full time) employment; workers with non- regular (part time) employment and reemployment in a temporary position were excluded.This study was carried out from August to November 2015 at two private companies in Japan. We recruited all full-time managers in a manufacturing company , department 2 , and department 3 . The sessions were conducted outside of working hours in the hospital . In the first session, following the introduction of the idea of job crafting including task, relational or cognitive crafting, by the researcher, participants learned the concept of job crafting from a case study (30 min), shared their personal crafting stories in their own working lives (30 min), and made their own individual job crafting plans  for the next two weeks (30 min). They were also provided with a homework booklet for a job crafting exercise. During the two weeks between the first and second sessions, they were encouraged to implement their job crafting plans. In the second session, each participant reviewed his/her own job crafting plan individually (15 min); the participants then shared their reflections as a group (30 min), discussed what job crafting would be feasible and sustainable to practice (30 min), and, finally, made a modified job crafting plan (30 min). Participants who could not attend first session were distributed the material of the session and asked to make their job crafting plan and practice it before they attend the second session. Thus, they could attend the second session. There was no incentive offered for participation in the program.The intervention program, which was based on the job crafting theory of Wrzesniewski and Dutton 2001) [01 [20], All data were collected using a web-based self-report questionnaire at baseline, post-intervention, and one-month follow-up.Work engagement was assessed using the Japanese version of the Utrecht Work Engagement Scale (UWES), which has been reported to be reliable and valid . It compPsychological distress was measured using the Brief Job Stress Questionnaire (BJSQ) , comprisJob crafting was assessed using a scale developed by Sekiguchi and his colleagues  based onDemographic variables included age, gender , marital status , educational attainment , and working hours per week were collected. These variables could be possibly confounded in the association between work-related variables and employee well-being , 32, 33.d) of 0.35 or greater for work engagement, at an alpha error rate of 0.05 (two-tailed) and a beta error rate of 0.20 using the G*Power 3 program [d) for self-efficacy and job-related affective well-being, it seemed reasonable to set 0.35 as an expected effect size in our job crafting intervention program.The estimated sample size was 66 participants to detect an effect size  was conducted to test the effect of the intervention. The mixed model is useful to understand changes in human behavior over time because of higher-level clustering unit  , 37. Firrop-outs , 39. ValThe participant flowchart is shown in Fig. p < .05 and p < .01, respectively); no significant difference was observed in other variables between the two groups (p > .05). There were also no significant differences in demographic characteristics at baseline between those who completed surveys (n = 39) and those who did not complete all surveys (n = 11) (p > .05).Demographic characteristics of participants in subgroups and total are presented in Table Table t = 2.23, p = 0.03; t = 2.20, p = 0.03). The effect sizes were small and significant at post-intervention (Time 2): Cohen’s d = 0.33 , but not significant at one-month follow-up (Time 3) Cohen’s d = 0.26 .Table t = −2.07, p = 0.04; t = −2.06, p = 0.04). The effect sizes were small and non-significant at post-intervention (Time 2): Cohen’s d = −0.15 , but significant at one-month follow-up (Time 3): Cohen’s d = −0.31 .The program showed a significantly favorable effect on psychological distress before and after adjusting the covariates , with small effect sizes at post-intervention (Time 2)  and at one-month follow-up (Time 3) . For the subscales, the program also showed a significant effect on cognitive crafting before and after adjustment of covariates , with small effect sizes at post-intervention (Time 2)  and at one-month follow-up (Time 3) . On the other hand, the program did not show significant effects on task crafting or relational crafting (p > .05); in addition, effect sizes were small and not significant, excepting for task crafting at one-month follow-up (Time 3) .The program showed a significantly positive effect on job crafting before and after adjusting the covariates  among Japanese employees. The novel aspect of the current program is that it contains three factors of job crafting, such as task, relational, and cognitive crafting, which focuses on improving two preceding factors of work engagement  . The stuThe program significantly increased work engagement. Only two previous studies , 28 inveThe present study also found that the program effectively improved job crafting of participants, and particularly cognitive job crafting. We can assume that the current program promoted work engagement through job crafting, especially cognitive crafting. According to the extended Job Demands-Resources model , work enHowever, the effect sizes for work engagement were small, and the favorable effect at post-intervention survey (Time 2) disappeared at one-month follow-up (Time 3). One possible reason for this is that the program did not improve all aspects of job crafting. This speculation seems to be supported by the results that the program did not significantly improve task crafting and relational crafting. As mentioned above, compared to cognitive crafting, it seems difficult for participants to acquire skills to improve task and relational crafting, because the latter focus on changing the actual job and relational boundaries. The program may have needed a session focusing on enhancing the application of the acquired skills in the participants’ daily working lives. For instance, in a previous job crafting training program for police officers , particiIn addition, the interval period between the sessions may have been too short for participants to practice their job crafting plans. The current job crafting intervention program had a two-week interval between the sessions, which is shorter than a previous job crafting program with a four-week interval . In our p = 0.04). This result is in accordance with previous findings from observational studies of the association of job crafting with negative psychological outcomes [The program significantly decreased the psychological distress of participants  design.N = 50) was modest, compared to the planned number of 66 to detect an effect size of 0.35 or greater for work engagement. Thus, the study had lower statistical power due to the small sample size than that with the planned sample size.Second, the sample size of this study  but became significant at one-month follow-up , longer follow-up will be needed to detect the effect of the program on outcomes such as task crafting or relational crafting in future studies.Fourth, the follow-up period was relatively short compared with previous studies that focused on work engagement . BecauseFifth, the current study did not assess job or personal resources, which were predictors of work engagement in Job Demands-Resources model , becauseThis single group pre- and post-intervention study demonstrated that the newly developed job crafting program was effective in improving work engagement, as well as in improving job crafting and decreasing psychological distress, among Japanese managers.


Over the past generation, limb preservation programs and diabetic foot services have begun to proliferate within academic health science centers as well as within health-care systems in general. We describe four key components for a successful program that, developed sequentially with temporal overlap, can allow the program to scale. The first component includes establishment of a ‘hot foot line’ for urgent emergency department/inpatient referral. The second includes development of a wound-healing clinic to address outpatient care through to remission. The third component focuses on the diabetic foot in remission to maximize ulcer-free days following healing. The fourth and final component focuses on implementation of local and widespread screening clinics to identify and triage patients into appropriate therapeutic and surveillance programs for healing, remission, and primary prevention. Along with developing each of these components, we describe discrete methods to quantify success. The population of people affected by diabetes is rising. It has increased by nearly 400% in the last generation within the USA alone . It is eTo combat the increasing complications of the diabetic foot and resulting morbidity, limb preservation programs have begun to proliferate. Limb preservation programs consists of interdisciplinary teams that work synergistically to exchange information, discuss assessment, and create joint plans to achieve the goal of limb salvage in an integrated model. This model often incorporates podiatric and vascular surgeons (‘Toe and Flow’ model) as the core of an interdisciplinary team but which may include a diverse group of health professionals –8. We haThe assembly of a motivated interdisciplinary team is an essential initial element to establishing a limb salvage team and successful limb preservation program. There are four additional components which we and others have found to be important in creating a truly comprehensive local, regional, or national initiative. These components include initiating a ‘hot foot line’, having access to or establishing a wound-healing clinic, a remission clinic, and a screening clinic. In addition to these four components, a limb preservation program should monitor measurable outcomes to assess and demonstrate the validity, efficacy, and long-term outcomes of these specialized programs. The purpose of this manuscript is to outline these four components and measurable outcomes.In the acute setting, diabetic foot complications presenting to the emergency room or on the inpatient wards should be reported to a single ‘hot foot line’ . Once enFor example, if the patient presents with tissue loss, infection, and palpable pulses, the podiatric surgeon will be the primary consult to address the lower extremity wound and infection . The podIf a patient presents with non-palpable pulses and a concomitant infection is present, vascular surgery will be the primary managing surgeon for the treatment of ischemia and infection. The vascular team may internally consult with podiatric surgery for initial debridement and infection control in an effort to preserve the limb. After the nidus of infection is removed or concomitant with the debridement, the vascular members of the team will perform revascularization.If a patient is to present with ischemia without signs of acute infection, the initial primary consultant within the team would be the vascular surgeon. If revascularization is performed by the vascular surgeon with established arterial outflow to the extremities, the podiatric surgeon may be consulted to perform appropriate reconstructive surgery or partial-foot amputations as needed ,9,10. OnA wound clinic should be established to evaluate and treat active tissue loss. The primary focus of the clinic is to determine the etiology of the lower extremity wound and employ appropriate modalities to rapidly accelerate wound closure, moving patients into remission . NeuropaIdeally, this should be an interdisciplinary clinic that includes specialists trained in the reconstruction of the foot and ankle, as well as those trained in vascular reconstruction. It is preferable to have both specialists available concurrently for the evaluation of complex cases where the expertise of both specialties is needed for planning and intervention. If this is not feasible, then a close-knit working relationship is required of the two specialists to synergistically improve patient outcomes . PhysicaAfter resolution of sequelae from wounds and complete healing is obtained, the patient should be referred to a remission clinic ,18. RegaThe final component of a comprehensive limb preservation program is development and dissemination of screening services. Ideally, every person with diabetes will be screened at least annually for risk factors for lower extremity complications. This would include a detailed examination of the lower extremity in regard to the cardiovascular, neurological, dermatological, and musculoskeletal systems. This examination has been codified as part of the American Diabetes Association Comprehensive Diabetic Foot Examination . It was The implementation of continuous prospective data collection is essential to the limb preservation program . The datA successful limb preservation program begins and ends with an enthusiastic, cohesive, interdisciplinary team. With this foundation in place, the four steps to building a scalable single site, regional or national limb preservation program should include (in order): implementation of a hot foot line, wound-healing clinic, remission clinic, and screening clinics. The measured outcomes from each of these components will contribute to an audit that will ensure quality improvement through assessment and review, as well as establish benchmarks for quality of care.


All of them provided written informed consent to participate in this study.The participants underwent body composition, flexibility, and blood pressure measurements before and after the intervention. The exercise groups participated in a dance and yoga program for 12 wk, respectively. The dance group participated in a dance program for 2 h once a week, for 12 wk, modified based on exercise . The yogThe muscle mass, percent body fat, visceral fat area, and basal metabolic rate were measured using Inbody 720 equipment . Flexibility (sit-and-reach) and resting heart rate were measured based on the book recommendations . Blood pP<0.05.All data are presented as mean±standard deviation. Paired t-tests were used to analyze differences between the dependent variables before and after the dance and yoga program, respectively. All analyses were performed using SPSS ver. 18.0 . Statistical significance was set at P<0.001) compared to that before the program. While after the yoga program, significant improvements were seen in both the sit-and-reach movement (P<0.001) and systolic blood pressure (P=0.003)  . Thus, 1


PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas. In this study, we sought to define a threshold value for positive PRAME expression (PRAME+) in a large dataset, identify factors associated with PRAME expression, evaluate the prognostic value of PRAME in Class 2 uveal melanomas, and determine whether PRAME expression is associated with aberrant hypomethylation of the PRAME promoter.We previously identified P < 0.0001). PRAME expression was associated with shorter time to metastasis and melanoma specific mortality in Class 2 tumors . In Class 1 tumors, PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004). PRAME expression was strongly associated with hypomethylation at 12 CpG sites near the PRAME promoter.Among 678 samples analyzed by qPCR, 498 (73.5%) were PRAME- and 180 (26.5%) were PRAME+. Class 1 tumors were more likely to be PRAME-, whereas Class 2 tumors were more likely to be PRAME+ (PRAME mRNA expression, Class 1 versus Class 2 status, chromosomal copy number, mutation status of BAP1, EIF1AX, GNA11, GNAQ and SF3B1, and genomic DNA methylation status. Analyses were performed on 555 de-identified samples from Castle Biosciences, 123 samples from our center, and 80 samples from the TCGA.Analyses included PRAME is aberrantly hypomethylated and activated in Class 1 and Class 2 uveal melanomas and is associated with increased metastatic risk in both classes. Since PRAME has been successfully targeted for immunotherapy, it may prove to be a companion prognostic biomarker. Due to a high rate of metastasis, much research has focused on the development of biomarkers to predict metastatic risk. Previously, we described a gene expression profile that could be performed on a fine needle biopsy of the primary tumor that accurately predicted metastasis . Tumors alidated  and is walidated .CDH1 and RAB31) could be used to identify Class 1 tumors that may have increased metastatic risk. Class 1 tumors with low expression of these genes and very low predicted metastatic risk were called Class “1A,” whereas those with high expression and higher predicted metastatic risk were called Class “1B.” In our efforts to further improve the prognostic accuracy of the gene array platform, we conducted a genome wide search for new biomarkers and found that mRNA expression of the cancer-testis antigen Preferentially Expressed Antigen in Melanoma (PRAME) was an accurate biomarker for metastasis in Class 1 tumors [PRAME above baseline was associated with increased metastatic risk. Limitations of that study included a relatively small number of tumor samples that were biased towards larger tumor size.While the vast majority of metastatic events in uveal melanoma arise from Class 2 tumors, a small subset of Class 1 tumors also give rise to metastasis. We found that the expression of two of the 12 discriminating genes on the array , compare PRAME expression to the 1A/1B designation in Class 1 tumors, identify clinical and molecular factors associated with PRAME expression, evaluate the prognostic value of PRAME expression in Class 2 tumors, and determine whether PRAME expression in uveal melanoma is correlated with promoter hypomethylation.The purpose of the present study was to study PRAME mRNA expression and to establish a threshold for positive PRAME expression in primary uveal melanoma, we analyzed qPCR data from 678 tumor samples, including 123 of our samples and 555 de-identified samples submitted from a large number of ocular oncology centers to Castle Biosciences. These samples included 454 (67.0%) Class 1 tumors and 224 (33.0%) Class 2 tumors. Class 1 tumors included 317 (69.8%) Class 1A tumors, 131 (28.9%) Class 1B tumors, and 6 (1.3%) tumors for which 1A/1B information was not available. Whereas most samples showed negligible PRAME expression, a subset of samples showed a broad range of PRAME expression  [To evaluate the spectrum of P < 0.0001)   tumors were PRAME− and 180 (26.5%) were PRAME+. Class 1 tumors were more likely to be PRAME−, whereas Class 2 tumors were more likely to be PRAME+  Figure . Among C) Figure . Among CPRAME expression were available for 123 of our uveal melanoma samples . To expand this analysis, we examined the TCGA Research Network dataset which consists of an independent cohort of 80 primary uveal melanoma samples (http://cancergenome.nih.gov/) . In both datasets, well-known risk factors for metastasis such as increased patient age, ciliary body involvement, and extrascleral tumor extension were not associated with PRAME expression status.Clinical annotations and  samples . The onlih.gov/) . Since Pa Figure . ConsistPRAME expression was associated with increased metastatic risk in Class 1 uveal melanomas [PRAME expression is also a biomarker for metastasis in Class 2 tumors. For this analysis, we combined our 123 cases with the 80 cases from the TCGA. Using Kaplan-Meier survival analysis, PRAME+ status was associated with shorter time to metastasis for both Class 1 and Class 2 tumors together  and for Class 2 tumors alone  and for Class 2 tumors alone  Figure . Similar) Figure .PRAME expression, we analyzed 26 of our cases and 80 TCGA cases for which chromosomal copy number and PRAME expression data were available (P < 0.0001), 8p loss (P = 0.04), 8q gain (P < 0.0001) and 16q loss (P < 0.0001) , the chromosomal alteration most strongly associated with metastasis in uveal melanoma, highlighting the potential benefit of including PRAME expression status in a prognostic test.To identify chromosomal copy number changes that may be associated with vailable . Overalls P = 0.0, 8q gainP = 0.04), 6p gain (P = 0.01), 6q loss (P < 0.0001), 8q gain (P < 0.0001), and 16q loss (P = 0.004). PRAME+ status in Class 2 tumors was associated with 6p gain (P = 0.04), 6q loss (P = 0.0001), 8p loss (P = 0.05), 8q gain (P = 0.02) and 16q loss (P = 0.003). PRAME expression was not associated with monosomy 3 in either comparison . However, this association is likely due to BAP1 mutations occurring almost exclusively in Class 2 tumors [PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004). There were no mutations associated with PRAME expression in Class 2 tumors when analyzed separately.To identify common driver mutations that may be associated with PRAME+ status, we analyzed 59 of our cases for which mutation data were available, as well as the 80 TCGA cases, for mutations in nd SF3B1 . When ClPRAME mRNA at appreciable levels  in PRAME+ tumors compared to PRAME− tumors   Figure . The mos) Figure . These dPRAME mRNA expression is a significant risk factor for metastasis in Class 1 uveal melanomas, and we developed a general method for establishing a PRAME+ threshold in various datasets [PRAME expression is strongly associated with larger tumor size, a study composed primarily of large tumors may not accurately reflect the true range of PRAME expression. To pursue the development of PRAME as a clinical biomarker, we sought here to rigorously establish a standard method for defining the PRAME+ expression threshold using a standardized and widely used qPCR platform. To achieve a widely applicable threshold and avoid potential systematic biases arising from a single center study, we analyzed a large number of samples obtained from many different ocular oncology centers representing a wide range of tumor sizes and both Class 1 and Class 2 tumors in proportions representative of actual clinical practice. From this analysis, we established a PRAME+ threshold and used it to identify clinical, chromosomal and mutational features associated with PRAME expression. We also established a PRAME+ threshold for RNA-Seq using the TCGA dataset, but this threshold must be considered provisional since that dataset was composed primarily of very large tumors treated by enucleation. Indeed, 43% of the TCGA samples were PRAME+, compared to only 27% of our samples.We previously reported that datasets . In thatPRAME becomes transcriptionally activated later during tumor progression. Interestingly, even though PRAME+ status was a stronger predictor of metastasis in Class 1 tumors, it was also associated with metastasis in Class 2 tumors. In our earlier study that was much smaller and biased towards larger tumors treated by enucleation, we did not find a correlation between PRAME expression status and the “1A/1B” system that the clinical test currently uses to indicate low (1A) versus moderate (1B) metastatic risk [PRAME expression status versus the 1A/1B designation in Class 1 tumors in order to determine the optimal biomarker for increased metastatic risk in Class 1 tumors. A limitation of this analysis is the limited follow-up, particularly from the TCGA dataset, which results in a large number of censored data points. Our planned prospective multicenter study with long follow-up is the appropriate study design to validate these findings. Since we found that PRAME+ correlates significantly with tumor size, this multi-center study will also evaluate whether there is a minimum threshold tumor size at which point PRAME becomes prognostic.Across all samples, larger tumor size was the only clinical feature that correlated with PRAME+ status, suggesting that tic risk . In the PRAME expression was associated with specific chromosomal gains and losses, some of which were specific to either Class 1 or Class 2 tumors. Changes that were associated with PRAME+ status in both Class 1 and Class 2 tumors included 6p gain, 6q loss, 8q gain and 16q loss. 6p gain and 6q loss were frequently found in the same tumor samples, likely representing the formation of an isochromosome 6p [PRAME expression and isochromosome formation on chromosomes 6 and 8 is of interest and may provide new insight into uveal melanoma tumorigenesis. We previously showed that genes which become aberrantly up-regulated in PRAME+ tumors are enriched for functions related to chromosome maintenance, meiotic recombination and telomere maintenance [PRAME may predispose tumor cells to isochromosome formation, as well as other forms of aneuploidy that promote tumor progression.osome 6p , 14. A posome 6p , but ourosome 6p . The comntenance , which intenance . Hence, PRAME becomes aberrantly hypomethylated and transcriptionally activated during uveal melanoma progression is similar to findings in other cancers [PRAME is not normally expressed in most normal adult tissues, targeted molecular inhibition of the PRAME protein or immunotherapy directed against PRAME−expressing tumor cells may be well tolerated. Indeed, there is growing evidence that PRAME may be a good target for immunotherapy [300–309 peptide presented by HLA*A02:01 on the cell surface [PRAME expression of two matched primary and metastatic UM samples analyzed by the Illumina HumanRef-8 v1.0 expression microarray in our previously published dataset (GEO accession number GSE39717) [Our finding that  cancers , 21 and otherapy –25. Sinc surface . Others  surface , 27. Fur surface . InteresSE39717) , and we PRAME expression as a biomarker for increased metastatic risk in Class 1 tumors [PRAME expression is also associated with worse prognosis among Class 2 tumors. We demonstrated that specific chromosomal gains and losses, as well as specific driver mutations, are found preferentially in PRAME+ tumors. Finally, we showed that specific CpG sites around the PRAME promoter are differentially hypomethylated in PRAME+ tumors, suggesting that the aberrant transcriptional activation of PRAME in uveal melanoma is the result of epigenetic reprogramming during tumor progression. In addition to its prognostic value, PRAME expression status may potentially be useful in the future for guiding the use of PRAME-directed immunotherapy, which would make PRAME the first true “companion prognostic” biomarker in uveal melanoma.In summary, we have provided a threshold for PRAME+ expression from qPCR data for primary uveal melanomas across a wide spectrum of tumor sizes and in both tumor classes representative of actual clinical practice. We previously identified 1 tumors , and herPRAME expression and GEP Class data were obtained from 555 uveal melanoma samples from Castle Biosciences that had been collected between July 21, 2015, and March 2, 2016, as part of internal PRAME qPCR method development. These samples were obtained as formalin-fixed paraffin-embedded tissue from enucleations in 55 (9.9%) cases and as fresh-frozen samples from fine needle aspirate biopsies in 500 (90.1%) cases. The data available for these cases included GEP class, 1A versus 1B subtype for Class 1 tumors, and PRAME mRNA expression. Additionally we analyzed clinical, whole exome sequencing, RNA sequencing, SNP 6.0 array data, and DNA methylation data from 80 uveal melanoma samples generated by the TCGA Research Network: http://cancergenome.nih.gov/.The sources of all uveal melanoma samples used in this study are summarized in PRAME mRNA expression was analyzed by qPCR using the Applied Biosystems 7900 HT Real-Time PCR System with TaqMan primers and Gene Expression Master Mix following the manufacturer's protocol as previously described [PRAME, as previously described [PRAME mRNA expression in normal tissues, RNA-Seq data was obtained from the Genotype-Tissue Expression (GTEx) project [For the RNA samples from our center and from Castle Biosciences, escribed . Ct valuescribed . Relativescribed , which wescribed . Next-ge project .For research purposes of this study, we estimated the gene expression profile class assignment for the 80 TCGA samples, which were analyzed by RNA-Seq. Raw RNA-Seq datasets were prepared using the pipeline described in the previous section. The top 20% most variable genes were selected, analyzed by principal component analysis, and plotted using the stats, matrixstats, and rgl packages, respectively, in R (version 3.2.3). This analysis grouped the samples into two clusters, as we have previously described for Class 1 and Class 2 tumors . The idePRAME expression, respectively, and each was plotted with a line representing the best-fitting LOESS model   Figure . Based o) Figure  and the ) Figure  to repre) Figure .Whole-exome sequencing was conducted on 24 of our primary uveal melanomas and matched blood using NimbleGen SeqCap EZ Human Exome Library v2.0 (Roche Nimblegen) and run on the Illumina Genome Analyzer II. Exome sequencing data on 80 primary uveal melanoma TCGA samples were downloaded from CGHub and aligned to the hg19 reference genome using Novoalign. Variant calling was conducted using Mutect2  and VarsPRAME locus using the GViz package in R. All 12 methylation probes targeting PRAME that are included in the Methyl450K array were significantly hypomethylated in the TCGA PRAME+ samples.The 80 TCGA uveal melanoma tumors samples were assayed for global DNA methylation status with the Infinium HumanMethylation450K BeadChip (Illumina). This kit interrogates ∼450,000 methylation sites at single-nucleotide resolution, including at CpG sites within promoter, 5′UTR, first exon, gene body, and 3′UTR regions. Methylation data underwent quality control, normalization, and differential analysis of PRAME+ and PRAME− samples using the ChAMP methylation pipeline in R . CpG sitPRAME promoter were designed with the Bisulfite Primer Seeker (http://www.zymoresearch.com/tools/bisulfite-primer-seeker). Forward Primer: GAAGGATTTCGTGTTTAAGGTTTTTTAAGG. Reverse Primer: GTGTTTTTATTTTGGAAATAGAGATTTAGT TTTTTTT. The PRAME promoter region was amplified with the EpiMark Hot Start Taq polymerase (New England Biolabs) at Tm = 54.5°C, and the PCR product purified by agarose gel separation/elution before Sanger sequencing. The status of the PRAME methylation site detected by Infinium HumanMethylation450K BeadChip probe cg27303185 in normal tissues was obtained from Marmal-aid [For validation, primers were designed against a region containing 3 of these 12 probes and validated in 4 PRAME+ and 3 PRAME− samples. This validation study was small due to limited sample availability. For primer design, 500 ng of tumor DNA was bisulfite converted using the EZ Methylation-Lightning Kit (Zymo Research). Primers for PCR amplification of the rmal-aid  and plot® version 14.10.2. Fisher's exact test was used to evaluate discrete dichotomous variables, the Mann-Whitney test for comparison of continuous variables, Spearman's rho for correlation analyses of continuous variables, and Kaplan-Meier survival analysis for determining the association of PRAME expression status with patient outcomes.Statistical analysis was performed using Medcalc


A significant increase in atmospheric radon concentration was observed in the area around the epicentre before and after the occurrence of the shallow inland earthquake in the northern Wakayama Prefecture on 5 July 2011  in Japan. The seismic activity in the sampling site was evaluated to identify that this earthquake was the largest near the sampling site during the observation period. To determine whether this was an anomalous change, the atmospheric daily minimum radon concentration measured for a 13-year period was analysed. When the residual radon concentration values without the seasonal radon variation and the linear trend was > 3 standard deviations of the residual radon variation corresponding to the normal period, the values were deemed as anomalous. As a result, an anomalous increase in radon concentration was determined before and after the earthquake. In conclusion, anomalous change related to earthquakes with at least Mj 5.5 can be detected by monitoring atmospheric radon near the epicentre. Radon concentration in soil is ~1000 times higher than that in the atmosphere. Radon generated from soil, rocks and ground water is released into soil pore air. Depending on the interconnected porosity, diffusion length, the presence of fractures and pressure gradient, radon can migrate to the Earth's surface. Groundwater and underground air are closely linked to the migration of radon in bedrock. In other words, radon present in voids relatively close to the Earth's surface  move to the Earth's surface.Radon (–7. The exhaust monitors (airflow ionisation chamber with an effective volume of 1.4 × 10−2 to 1.8 × 10−2 m3) have ~10 times higher sensitivity than general continuous radon monitors such as AlphaGUARD .As a noble gas, radon is chemically stable and can be detected with highly sensitive methods. In Japan, atmospheric radon concentrations have been estimated using ionisation currents recorded as exhaust monitoring measurements by some radioisotope (RI) institutes, 3. Magnitude Mj is calculated only for large and shallow (depth ≤ 60 km) earthquakes using acceleration data of the seismic intensity metres at the Local Meteorological Observatories in Japan. The temporal change in the atmospheric radon concentration was compared with the crustal strain, the groundwater radon concentration and the groundwater discharge rate prior to the earthquake. A previous study had reported that crustal strain fluctuations in the order of 10−8 could be linked to pre-seismic phenomena. Therefore, our previous studies concluded that there is a correlation between atmospheric radon concentration and crustal strain in earthquakes of magnitudes smaller than the 1995 Kobe earthquake. The present article aims to investigate the atmospheric radon concentration's variability before and after the shallow inland earthquake at the northern Wakayama Prefecture on 5 July 2011 ).The measurements performed from January 1984 until February 1996 at the RI institute of Kobe Pharmaceutical University  recorded a significant increase in the atmospheric radon concentration from October 1994 until the 1995 Southern Hyogo Prefecture (Kobe) Earthquake The radon data were obtained from one monitoring site Figure  for a pe. The area is the most seismically active region in the Kii Peninsula and is characterised by anomalously shallow swarm activity, crustal uplift and dilation. The 2011 northern Wakayama Earthquake with magnitude Mj 5.5 occurred on 5 July 2011, and its epicentre  was located in the southern part of the area along the BTL. The focal depth of the earthquake was 7 km and its hypocentral distance from the monitoring site was 22 km. The 2013 Awaji Island Earthquake Mj 6.3  also occurred on 13 April 2013.The monitoring site is located at the Wakayama Medical University N34.2°, E135.2°) in Wakayama City, Japan  was used at the monitoring site to monitor RI leakage in exhaust air from the RI institute .A gas-flow ionisation chamber  were linearly interpolated.In this article, we investigate the variation in radon concentration before and after the earthquake. For the atmospheric radon level, the gas-flow ionisation chamber can detect the atmospheric radon with high precision. However, knowledge of the background atmospheric radon level is necessary to determine the absolute radon concentration values accurately. Therefore, absolute values of radon concentration were not determined in this article., when air flowed through forced draught fans at an exchange rate of 4.9 h–1. Therefore, we considered that an air-exchange rate of 26 h–1 was enough to measure atmospheric radon. In addition, we confirmed that the effects of RIs used in this RI institute can be ignored.A previous study provided evidence that variations in outdoor radon concentration could be determined using gas-flow ionisation chambers for RI monitoring systems131I and other radionuclides from Fukushima. However, the monitoring site  was located in the west part of Japan and >600 km west–southwest of the Fukushima Daiichi nuclear power station . Air mass is generally carried by the wind to the east around Japan. Therefore, the monitoring site was located out of the transport area of gaseous 131I. Consequently, we disregarded the effect of gaseous 131I.The validation period included the nuclear accident at the Fukushima Daiichi nuclear power station on 11 March 2011. Because of the accident, there was significant long-range transport of gaseous . Figure 90Sr with the ionisation chamber. The daily minimum data were divided into two periods: the normal period (from 1 January 2000 to 31 December 2010) and the validation period (1 January 2011 to 21 June 2013). The seasonal variation and decreasing trend were calculated using the data for the normal period as shown below.The daily minimum radon concentration can be used when examining seismic anomalous radon variationsSi  from the detrended level was calculated on the detrended data  was obtained in Figure Rn was calculated by subtracting Si from Ri in Figure Next, using the daily minimum values of the measured ionisation current data during the entire observation period, the time series of the residual radon variation . AppRi and Si, where Ri is divided into the variation during the normal period (grey line) and the variation during the validation period (black line). The anomalous increase in the radon concentration is determined by the values > ± 3σ of the residual radon variation during the normal period. Figure Rn during the entire observation period and the ± 3σ lines, the grey line of Rn indicates the variation during the normal period, and the black line of Rn indicates the variation during the validation period. Anomalous increases in the radon concentration > ± 3σ are observed before and after the 2011 northern Wakayama Earthquake (Mj 5.5), which occurred on 5 July 2011.Figure . Figure . As shown in Figure Figure Rn values before and after the 2013 Awaji Island Earthquake (Mj 6.3) were within the normal variation range  shown in Table (16), which were proposed for radon variation in soil and ground water–20.We discuss the relationship between radon changes and the 2013 Awaji earthquake, and other events occurred outside of the region of Figure  Figures  and 8. MAnomalous variations in the daily minimum atmospheric radon concentration were recorded at the Wakayama Medical University from 9 February 2011 to 3 September 2011. The period of the anomalous variations includes the 2011 northern Wakayama Earthquake. This phenomenon might be an indication of changes in the radon concentration, due to exhalation by the seismic anomaly around the monitoring site, where the active earthquake swarm occurred.An anomalous change related to earthquakes with at least Mj 5.5 can be detected by monitoring atmospheric radon near the epicentre. These anomalies are higher than ± 3σ, and are calculated using the normal period data. It was supported by our demonstrations that the temporal change in the atmospheric radon concentration retain a potential to occur with that in the crustal strain of not only a shallow inland earthquake of Mj 7.3 (1995 Kobe earthquake) but also a shallow inland earthquake of the smaller magnitude. A seismic radon response is anticipated for Mj 5.5 level earthquakes. Therefore, the present study reveals the importance of monitoring atmospheric radon in order to investigate the possible earthquake mechanisms.


Eating disorders are serious psychiatric illnesses that are often associated with poor quality of life and low long-term recovery rates. Peer mentor programs have been found to improve psychiatric symptoms and quality of life in other mental illnesses, and a small number of studies have suggested that eating disorder patients may benefit from such programs. The aim of this study is to assess the efficacy of a peer mentor program for individuals with eating disorders in terms of improving symptomatology and quality of life.Up to 30 individuals with a past history of an eating disorder will be recruited to mentor 30 individuals with a current eating disorder. Mentoring will involve 13 sessions (held approximately every 2 weeks), of up to 3 h each, over 6 months.This pilot proof-of-concept feasibility study will inform the efficacy of a peer mentoring program on improving eating disorder symptomatology and quality of life, and will inform future randomised controlled trials.ACTRN12617001412325. The date of registration (retrospective): 05/10/2017.Australian and New Zealand Clinical Trials Registration Number: The online version of this article (10.1186/s40814-018-0268-6) contains supplementary material, which is available to authorized users. Eating disorders are serious psychiatric conditions with high rates of morbidity and mortality. They are associated with a staggering socioeconomic cost of almost $70 billion per year in Australia alone . AnorexiPeer support is based on the belief that people who have faced, endured and overcome adversity can offer useful support, encouragement, hope and mentorship to others facing similar situations . In broaMental health peer work is a relatively new approach to service delivery. Evaluation has lagged behind implementation of peer workforce roles; however, a number of randomised controlled trial findings are available, and although the evidence base is a developing one, there is a strong indication that a substantial peer workforce in a psychiatric service will improve patient outcomes . Peer meN = 270) [n = 58) compared to unmatched (n = 49) mentees. In another study, an 8-week mentoring pilot program for undiagnosed  adolescent girls (n = 31) demonstrated a significant reduction in disordered eating by the conclusion of the program [A recent systematic review and synthesis of the impact of peer support on eating disorders yielded only four eligible studies N = 270) . One suc0 . One s program . In a qu program , mentees program  identifi program , and the program . Indeed, program .Potential benefits to the mentees’ recovery process notwithstanding, the feasibility of the current peer mentoring program relies on the delivery of mentoring that is sustainable and non-maleficent from the point of view of the mentors. It is therefore important to examine and analyse the likely risks and benefits associated with the provision of mentoring from this perspective, as these individuals are likely to have vulnerabilities associated with their previous diagnosis . The peeThere is little available research on the evaluation of risks to recovered individuals working in a mental health peer support role. In the literature that does exist, boundary issues and transgressions are cited as common challenges encountered by mentors –25. SpecThe examination of potential risks and benefits to mentors in this particular pilot program through both qualitative and quantitative data collection methods will attempt to assess whether the recruitment, training and support currently in place are effective and sufficient to ensure the wellbeing of the mentors, which is of paramount importance when considering the long-term feasibility of the program.Previous peer mentoring programs in Victoria, Australia, have focused on a range of mental illnesses, though none have focused on people with eating disorders to date. In this context, we describe here a peer support program for people with an eating disorder, aimed at addressing a service gap in Victoria, Australia, for those who require additional support to sustain recovery while living independently.The aim of this study is to determine the efficacy of a peer mentor program for people who have received eating disorder treatment in a specialist hospital setting or equivalent, in improving eating disorder symptomatology and quality of life, to inform future randomised controlled trials. An additional aim is to determine the feasibility of the study by assessing participants’ capability to complete the mentoring sessions and the program. The study’s feasibility will be measured in terms of having a sufficient number of participants sign up, participate and be retained until the end of the study and also that they tolerate and accept the intervention, that the intervention can be delivered as per protocol and that there are no concerning adverse events related to the study. The current program is a new program that combines peer support principles with documented evidence, balanced against available resource and organisational risk constraints. The program is designed to harness the experience of people who have recovered from eating disorders and combine it with regular de-briefing and supervision. This project aims to ensure eating disorder patients leaving hospital can better sustain their recovery outcomes in the long term. This is the first time such a program has been offered in Victoria, Australia. Thus, the primary aim of the study is to evaluate the effectiveness of the peer mentor program on eating disorder patient outcomes. A secondary, exploratory aim of the program is to evaluate the effects of the program on peer mentors in terms of eating disorder symptomatology and quality of life.Participation in the peer mentor program is hypothesised to improve eating disorder symptomatology and quality of life, and reduce relapse rates in eating disorder participants .The study is a multi-site collaborative trial conducted at Eating Disorders Victoria (EDV), The Melbourne Clinic (TMC),  and the Body Image and Eating Disorders Treatment and Recovery Service (BETRS) at the Austin Hospital (inpatient unit) and St Vincent’s Hospital (intensive day patient program), all in Melbourne, Victoria, Australia. Up to 30 mentees with an eating disorder  will be matched with up to 30 mentors with a past history of an eating disorder. Participation will involve a longitudinal study assessing the efficacy of a peer mentor program for individuals with eating disorders. All mentees and mentors will be over the age of 18 years.As this is a pilot proof-of-concept feasibility study, a randomised controlled trial will not be undertaken, but the program will be evaluated with a within-group design. Participation will involve a series of 13 mentoring sessions of up to 3 h each  over 6 months, following the mentee’s discharge from the BETRS/TMC inpatient unit or transition to/from the BETRS/TMC intensive eating disorders day program. The peer mentoring program will be delivered in a variety of community settings, i.e. local shopping centres, parks and cafes. Mentees and mentors will not be permitted to meet in either person’s home.Mentors will be employed as ‘casual’ employees of EDV  and intensive day program , collectively known as the BETRS; and TMC. A member of the research team at BETRS/TMC will identify potential mentees and approach them with the study information form. Mentors will be recruited by EDV according to EDV policy and procedures. Mentors will be employed explicitly for this role and will be invited to participate in the research component of the program by one of the research staff. Participation will be voluntary. The suitability of mentors will be assessed during the interview process for their employment and by one of the researchers when approached for participation in the research component of the project. A minimum of 2 years in recovery will be required as indicated by the clinical measures that will be used to assess current or recovered eating disorder stages .Written informed consent will be obtained from all participants (mentees and mentors) prior to the commencement of the peer mentor program, by a member of the research team.mentees include:Transitioning out of the BETRS inpatient program at the Austin Hospital or TMC, or transition in/out of the BETRS/TMC outpatient/day patient programCurrent diagnosis of an eating disorder  according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)Currently actively receiving treatment for their eating disorder for the duration of the program. . The wellness criteria are evidenced by self-reported absence of eating disorder symptoms (indexed by the EDE-Q), being weight-restored, not receiving treatment for eating disorders symptoms and use of a personal Wellness Plan/self-care activities to maintain their recovery. The Wellness Plan also outlines signs that indicate a mentor is struggling and how to best support them during these times.Successful recruitment as a staff member at EDV, including referee checks and agreement code of conductInclusion criteria for Exclusion criteria for mentors and mentees include anyone who is at serious risk of harm to oneself or another, as determined by the clinical team, for example, individuals at high risk of suicide.Mentors will attend a 3-day training and induction program prior to the program rollout to ensure that mentors are prepared in their role. EDV staff and external trainers deliver different elements of the training dependent on their experience. As the mentors are EDV staff, the training starts with inducting them as employees and going through the procedures and policies outlined for all EDV staff members.An overview of the Intentional Peer Support (IPS) model is given to all mentors as a framework to base all interactions. This model states that peer support is intentional, in that we come to the relationship with a specific purpose in mind—with the program, this is maintaining recovery. The four core elements of IPS are connection—between the mentor and mentee, holding a worldview and understanding how we have come to know what we know and mutuality—learning and growing together and moving towards identified goals (recorded in the mentee’s Wellness Plans) .Training also covers off the challenging situations mentors might be faced with when supporting their mentee. Information about the program’s aims and objectives are made clear so the mentors know what they are working towards. As there is a high possibility of self-harm and thoughts of suicide, all mentors complete an internationally recognised safeTALK suicide alertness workshop which covers hands-on skills to be able to respond to someone who has the thoughts of suicide . The EDVThe program will involve 13 mentoring sessions of up to 3 h each, ideally completed every 2 weeks, over 6 months. Mentoring activities will include peer support activities such as providing information, emotional support and sharing of their own recovery experience. Mentoring activities are guided by each individualised mentee’s Wellness Plan , at 3-month (mid-program) and 6-month (end-of-program) time points, and at 12-month follow-up for both mentees and mentors  will be recorded.Eating Disorders Examination Questionnaire (EDE-Q) : The EDEDepression Anxiety Stress Scale (DASS-21) : The DASBrief Disability Questionnaire (BDQ) : The BDQAssessment of Quality of Life (AQoL) : The AQoFeedback questionnaire (not at baseline): General feedback on the program will be sought.The following quantitative measures will be collected at each time point to determine the efficacy of the peer mentor program for reducing eating disorder symptoms and quality of life:Mentees and mentors will also complete a qualitative online reflection exercise  and enable detailed exploration of the most important and relevant themes associated with participating in this program. The qualitative interviews will also cover areas A–C  and under lock-and-key (hard copy data) at EDV in the short term, prior to long-term storage at St Vincent’s Hospital.Participants (mentees or mentors) are free to withdraw from the study without explanation. Data collected will be retained, unless otherwise specified by the participant. If agreed by the participant, they will also be afforded the opportunity to complete relevant follow-up assessments.If a mentee or a mentor withdraws from the program, replacement participants will be sought. This will ensure that mentees will not be significantly affected by their partner’s (mentor) withdrawal and that the study has sufficient statistical power to identify efficacy of the program. Debriefing will be offered by program staff to the remaining participant, and mentees will be re-matched with another suitable mentor.Thirty mentors and a minimum of 30 mentees will be recruited. This minimum sample size of 60 participants will enable differences to be identified between time points in a pilot evaluation . Sample size has been determined using the qualitative principle of data saturation, which provides an estimate of sample size based upon the comprehensiveness of the data set to identify all of the issues affecting the population under study. As Fusch and Ness  highlighQuantitative analyses will include within-group analyses of variance (ANOVAs) and non-parametric assessments between time points, for mentees and mentors separately. Multiple imputation procedures that utilise the expectation-maximisation (EM) algorithm with bootstrap estimates of standard errors will be used for missing data. Using the six-stage approach described by Braun and Clarke , thematiEating disorders are disabling and often long-term conditions. The efficacy of available treatments is limited, resulting in high relapse rates and significant morbidity and mortality. The current trial aims to assess the efficacy and feasibility of a peer mentor program (as a supplement to standard treatment) for patients with eating disorders, in terms of improvements in both eating disorder symptomatology and quality of life, as well as relapse rates. A unique aspect of this research is to assess the impact of this program on mentors to identify the positive and/or negative impact that engaging with current eating disorder patients has on someone who has recovered from an eating disorder. This study will assess any adverse effects on mentees or mentors and glean information that will inform refinement of the intervention for a full-scale randomised controlled trial. The findings of this pilot program will inform larger randomised controlled trials assessing the efficacy of peer mentoring for individuals with eating disorders, by providing preliminary data on the need of the program .Protocol version: 1.5, 12/12/2017. Date recruitment began: 20/01/2017. Estimated date recruitment will be completed: 30/06/2018.Findings will be published in peer-reviewed journals and presented in national and international conferences. No restrictions are placed on the publication of results. Author eligibility will be based on ICMJE criteria.Additional file 1:Appendix A: Excerpt from peer mentor position description. Appendix B: Wellness plan. Appendix C: Online mentor questionnaire. Appendix D: Program summary. Appendix E: Online reflection exercise. Appendix F: Qualitative interview themes. (DOCX 1383 kb)


Carvedilol is a non-selective, third-generation beta-blocker and is one of the cornerstones for treatment for patients with heart failure and reduced ejection fraction (HFrEF). However, due to its short half-life, immediate-release carvedilol (IR) needs to be prescribed twice a day. Recently, slow-release carvedilol (SR) has been developed. The aim of this study is to evaluate whether carvedilol-SR is non-inferior to standard carvedilol-IR in terms of its clinical efficacy in patients with HFrEF.Patients with stable HFrEF will be randomly assigned in a 1:1 ratio to the carvedilol-SR group (160 patients) and the carvedilol-IR group (160 patients). Patients aged ≥ 20 years, with a left ventricular ejection fraction ≤ 40%, N-terminal pro B-natriuretic peptide (NT-proBNP) ≥ 125 pg/ml or BNP ≥ 35 pg/ml, who are clinically stable and have no evidence of congestion or volume retention, will be eligible. After randomization, patients will be followed up for 6 months. The primary endpoint is the change in NT-proBNP level from baseline to the study end. The secondary endpoints include the proportion of patients with NT-proBNP increment > 10% from baseline, composite of all-cause mortality and readmission, mortality rate, readmission rate, changes in blood pressure, quality of life, and drug compliance.The SLOW-HF trial is a prospective, randomized, open-label, phase-IV, multicenter study to evaluate the therapeutic efficacy of carvedilol-SR compared to carvedilol-IR in HFrEF patients. If carvedilol-SR proves to be non-inferior to carvedilol-IR, a once-daily prescription of carvedilol may be recommended for patients with HFrEF.NCT03209180. Registered on 6 July 2017.ClinicalTrials.gov, ID: The online version of this article (10.1186/s13063-018-2470-5) contains supplementary material, which is available to authorized users. Heart failure (HF) is a clinical syndrome characterized by typical symptoms and signs that result from abnormal cardiac structure or function . It is gNeuro-humoral activation plays a crucial role in development and progression of HF . Beta-blCurrent HF guidelines recommend the administration of carvedilol twice daily , 11. ThiIn the “Assessment of clinical effect and treatment quality of immediate-release carvedilol-IR versus SLOW-release carvedilol-SR in Heart Failure patients (SLOW-HF): a prospective, randomized, open-label, multicenter study,” we aim to evaluate the clinical efficacies of immediate-release carvedilol (IR) and slow-release carvedilol (SR) forms of carvedilol in Asian HFrEF patients.The study flow is presented in Fig. Patients who are at aged 20 years or older and with a confirmed diagnosis of HFrEF (left ventricular ejection fraction (LVEF) ≤ 40%) within the pre-analytical 6 months will be included in this study. Transthoracic echocardiography was operated at each institute according to the recommendations of the American Society of Echocardiography using commercially available systems . In addiThe primary endpoint is the change in N-terminal pro B-natriuretic peptide (NT-proBNP) level from baseline to 6 months after randomization. The secondary endpoints include the proportion of patients with NT-proBNP increment > 10% from baseline, composite of all-cause mortality and readmission, mortality rate, readmission rate, change in systolic and diastolic blood pressure at sitting position, control rate and response rate of blood pressure among patients with elevated blood pressure at baseline, quality of life assessed by the Minnesota Living with Heart Failure Questionnaire and Visual Analog Scale, and drug compliance. Table Subjects who meet the inclusion and exclusion criteria will be randomly assigned to the carvedilol-SR or carvedilol-IR groups, respectively. The randomization table will be generated by an independent statistician using the SAS system’s randomization program. Restricted block randomization is applied in order to ensure that the subjects are assigned to each group in a balanced manner. At this time, the size of the block will be set by a multiple of 2  and it will be implemented using the uniform random-number generator in SAS version 9.2. Web-based randomization will be used and all investigators will be masked to this process until the allocation has been determined.In this study, we will use carvedilol (trade name: Dilatrend®) which is manufactured and distributed by Chong Kun Dang Pharmaceutical Corporation in the Republic of Korea. After randomization, patients will receive either carvedilol-IR twice a day or carvedilol-SR once a day for 6 months. Patients in the carvedilol-IR group will receive carvedilol-IR 3.125-mg, 6.25-mg, 12.5-mg, and 25-mg tablets twice a day, while patients in the carvedilol-SR group will receive carvedilol-SR 8-mg, 16-mg, 32-mg, and 64-mg tablets once a day. If the patients were taking beta-blockers other than carvedilol, their dose will be calculated into the equivalent dose of carvedilol . Drug compliance, adverse effects, and additional concomitant drugs will also be checked. Any unscheduled visit will be recorded. The detailed process is described in Table Drug compliance will be assessed by “pill count,” by comparing the number of doses remaining with the number of doses that should remain. All patients will be educated to bring the remaining tablets of carvedilol-IR or -SR to each scheduled visits during the clinical follow-up period. Examiners will count the number of returned pills and calculate the drug compliance as follows:If any discrepancy is present, examiners should record the reason for the difference. Overall medication compliance should be at least 80% or more during the trial. Subjects who do not satisfy this criterion will be excluded from the per-protocol (PP) analysis.The aim of the study is to evaluate whether the clinical efficacy of carvedilol-SR is non-inferior to carvedilol-IR in terms of NT-proBNP reduction in stable Asian HFrEF patients. Therefore, the sample size was calculated based on the primary endpoint, i.e., the change in NT-proBNP level from baseline to 6 months. Olsson et al.  showed aχ2 test or Fisher’s exact test will be used for categorical variables, and the unpaired Student t test will be used for continuous variables, as appropriate. Fisher’s exact test will be used when the expected frequencies are less than 5. The change in NT-proBNP level from baseline to 6 months after randomization will be analyzed with the paired t test. In addition, analysis of covariance (ANCOVA) will be also conducted to analyze the change of NT-proBNP. The outcomes of chronological trend, such as mortality and readmission rate, will be assessed using Kaplan-Meier estimates. The log-rank test will be used to compare differences in clinical outcomes between the groups. A multivariable Cox proportional hazard regression model will be used to adjust for significant covariates. The data will be primarily analyzed according to the intention-to-treat rule including all randomized subjects. We also plan a PP analysis for patients with drug compliance of 80% or less. One-sided p values < 0.05 will be considered statistically significant. The analyses will be performed by a professional statistician.Data will be presented as numbers and frequencies for categorical variables, and as means ± standard deviations or median with interquartile range for continuous variables. For comparisons between the carvedilol-IR group and carvedilol-SR group, the The Executive Committee will be composed of the study chairperson and the principal investigators of the investigating centers. This committee will approve the final trial design and protocol issued to the Data and Safety Monitoring Board (DSMB) and the clinical sites. This committee will also be responsible for reviewing the final results, determining the methods of presentation and publication, and the selection of secondary projects and publications by members of the Steering Committee.An independent DSMB will be composed of cardiologists and a biostatistician, all of whom did not participate in the trial, following the applicable regulatory guidelines. The DSMB will review the safety data from this study and will make recommendations based on safety analyses of unanticipated device effects (UADEs), serious adverse events (SAEs), protocol deviations, and follow-up reports. In addition to the scheduled DSMB meetings (which will be determined prior to the initiation of the study) the board will convene a meeting at any time if safety problems become an issue. The DSMB is responsible for recommending to the Executive Committee to modify or stop the study if there are any safety or compliance issues. However, the final decision regarding study modifications will rest with the Executive Committee. Cumulative safety data will be reported to the DSMB and will be reviewed on an ongoing basis throughout enrollment and follow-up to ensure patient safety. Every effort will be made to allow the DSMB to conduct an unbiased review of the patients’ safety information. All DSMB reports will be made available to the appropriate agencies upon request but otherwise will remain strictly confidential. Prior to the DSMB’s first review of the data, the DSMB charter will be drafted. This plan defines the stopping rules for stopping the trial for safety. The first meeting of the DSMB will be requested for discussion of the protocol and an understanding of all the protocol elements. The DSMB will develop a consensus understanding of all trial endpoints and definitions used in the event adjudication process.The Clinical Events Adjudication Committee (CEAC) consists of cardiologists who do not participate in this study. The CEAC has responsibility to develop specific criteria used for the categorization of clinical events and clinical endpoints in the study, which are based on protocol. At the onset of the trial, the CEAC establishes regulations mentioning the minimum amount of data required and the algorithm followed in order to classify a clinical event. All members of the CEAC are blinded to the primary results of the study and meet regularly to review and adjudicate all clinical events in which the required minimum data is available. The CEAC also reviews and rules on all deaths that may occur during the trial.Data coordination and site management services are performed by the Clinical Trials Center at Seoul National University Bundang Hospital.This clinical trial was approved by the Institutional Review Board or Ethics Committee at each of the 13 participating hospitals; they are: Seoul National University Bundang Hospital, Seoul National University Hospital, Yonsei University Severance Hospital, Wonju Severance Christian Hospital, Samsung Medical Center, Sejong General Hospital, Ajou University Hospital, Boramae Medical Center, Hallym University Medical Center, Korea University Guro Hospital, Korea University Anam Hospital, Seoul Medical Center, and Asan Medical Center. The investigation will conform to the principles outlined in the Declaration of Helsinki. The study protocol has been registered at ClinicalTrials.gov (NCT03209180). All authors are responsible for the study design, data acquisition, data analysis, manuscript writing and editing.After an initial cardiac injury, there is an increase in neuro-humoral activity, i.e., the sympathetic nervous system and renin-angiotensin-aldosterone system . This reCarvedilol has been extensively evaluated in HFrEF patients with mild-to-severe LV dysfunction , 9, 24 aCarvedilol-SR meets the basic criteria for a controlled release agent: (1) it maintains an effective plasma concentration throughout the day and (2) does not exceed the critical value above which side effects often develop . In addiThe SLOW-HF study is a randomized, open-label. phase-IV clinical trial that investigates the clinical benefit and safety of carvedilol-SR compared to carvedilol-IR in patients with HFrEF. If carvedilol-SR is not inferior to carvedilol-IR in terms of clinical efficacy and safety, it would be a useful therapeutic option to improve medication complexity and compliance in managing HFrEF patients.There are several limitations. First, the primary endpoint of our study is the change in NT-proBNP level from baseline to the study end. Although NT-proBNP is a well-validated marker for risk stratification and used as a surrogate marker for clinical outcomes, clinical endpoints, such as mortality and rehospitalization for worsening HF, would be more definitive. Second, there exists a possibility that patients with more advanced HF may be under-represented in this study because they often have fluid volume retention. However, similar findings have been observed in other clinical trials which investigated the effect of beta-blocker management in HF patients , 10, 21.The trial is currently in the recruitment phase (recruitment began on 27 October 2016 and is expected to finish on 31 December 2018).Additional file 1:SPIRIT 2013 Checklist. (DOC 124 kb)


On November 12, 2017 at 21:48 local time, an earthquake with a moment magnitude of 7.3 struck Ezgeleh, Kermanshah Province, Iran. It is estimated that 600 to 700 people were killed, and more than 10,000 injured. This unfortunate event gives us pause to re-examine, and thereby improve, Iran’s disaster planning, preparedness, mitigation, and program responses.Computer-mediated technologies such as Telegram messaging service were highly beneficial. They helped mobilized local, national, and global support for victims of this disaster. Not only did social media facilitate immediate assistance for thousands of people post-earthquake, it enabled victims, friends and families to share valuable and timely information. This proved to be of immense help in rescue and relief efforts for those affected by this event. 1It is clear, however, that computers and technology alone cannot prevent or reduce injury or fatalities. In December 2003, Bam, a city in the southeast region of Iran, experienced an earthquake with a magnitude of 6.6. This destroyed nearly 90% of the city, and left approximately 40,000 dead. Post-quake assessments revealed the lack of comprehensive disaster management plans, and an inadequate emergency medical service system. Local hospitals and health facilities were found to be structurally deficient. Poor communication between and across disaster relief organizations is also blamed for the high number of casualties.It is unfortunate that what should have been learned from the Bam disaster was not actualized in the Kermanshah earthquake. Many government agencies were not well coordinated, agile, and did not have current technology and up-to-date information about the area that needed relief efforts. Perhaps as a result, earthquake victims tended to rely on those in their own family and social networks for rescue and relief, rather than on government agencies and services. This may be due in part to their distrust of, and lack of confidence in, the wisdom and efficacy of government officials in disaster response and management. The substantial damage to the newly-built Islamabad and Sar-e-Pol-e Zahab Hospitals, for example, reveals perhaps non-compliance with the “Iranian code of practice for seismic resistant design of buildings (standard no. 2800),” as well as serious deficiencies in Iranian disaster prevention and mitigation plans and measures. From a humanitarian perspective, we must first express our gratitude to every individual, group, organization and nation that responded so swiftly to the Kermanshah disaster, and provided generous relief and assistance. We must next consider the power and impact of technology, and what we see as infrastructure, communication and administrative shortcomings. These lead us to several important conclusions and recommendations. 4It is critical for those affected by disasters such as a major earthquake to have immediate and accurate information as to where to find shelter, and where to obtain medical and social services, food and clean water, and other essentials. A cloud-hosted, emergency information website with mapping capabilities can inform residents about the extent of damage in their area, of road closures, open petrol stations, distribution centers of essential supplies, as well as of medical and shelter sites. The recent Nepal, Haiti, and Christchurch  earthquakes show that combining open-source and propriety software and maps, as well as secure data-sharing and free electronic tools and apps, are quick and cost-effective responses in times of crisis. In addition, reliable and accurate electronic databases of property and structures allow for rapid information retrieval, repair and rebuilding. Such systems can also help volunteers and first-responders in locating and assisting victims immediately after a catastrophic event, as well as facilitate longer-term recovery efforts by monitoring and coordinating activities to avoid waste, redundancy, bottlenecks and traffic congestion. Natural disasters such as major earthquakes are tragic and unfortunate. However, out of crisis emerge opportunities for innovation and improvement. The ideas and proposals that result, are often bold and novel, and less constrained and shackled by policy, rules, regulations and norms. The Ezgeleh earthquake provides us with an opportunity to overcome shortcomings, learn more about crowdsourcing as a means of collecting information during a crisis, with the goal of reducing injury and mortality from future disasters in Iran.