Web-based cognitive behavioral therapy (wCBT) has been proposed as a possible treatment for patients with heart failure and depressive symptoms. Depressive symptoms are common in patients with heart failure and such symptoms are known to significantly worsen their health. Although there are promising results on the effect of wCBT, there is a knowledge gap regarding how persons with chronic heart failure and depressive symptoms experience wCBT.The aim of this study was to explore and describe the experiences of participating and receiving health care through a wCBT intervention among persons with heart failure and depressive symptoms.Qualitative Research & Evaluation Methods: Integrating Theory and Practice. After coding each interview, codes were formed into categories.In this qualitative, inductive, exploratory, and descriptive study, participants with experiences of a wCBT program were interviewed. The participants were included through purposeful sampling among participants previously included in a quantitative study on wCBT. Overall, 13 participants consented to take part in this study and were interviewed via telephone using an interview guide. Verbatim transcripts from the interviews were qualitatively analyzed following the recommendations discussed by Patton in Overall, six categories were identified during the analysis process. They were as follows: “Something other than usual health care,” “Relevance and recognition,” “Flexible, understandable, and safe,” “Technical problems,” “Improvements by real-time contact,” and “Managing my life better.” One central and common pattern in the findings was that participants experienced the wCBT program as something they did themselves and many participants described the program as a form of self-care.Persons with heart failure and depressive symptoms described wCBT as challenging. This was due to participants balancing the urge for real-time contact with perceived anonymity and not postponing the work with the program. wCBT appears to be a valuable tool for managing depressive symptoms. Approximately 20% of the heart failure population suffers from depressive symptoms ,2. DepreGuidelines on heart failure from the European Society of Cardiology (ESC)  and the At a conceptual level, wCBT can be described as a form of telehealth, that is, a system that enables patients to access health education and support for self-care usually through the internet . In lineOur research group has recently developed and pilot-tested a 9-week guided wCBT program  aimed atThis was a qualitative, inductive, exploratory, and descriptive interview study  using daThe participants were persons with heart failure and depressive symptoms who were recruited after their participation in a wCBT program for depressive symptoms, hereafter called the wCBT program . The wCBTo ensure that participants had experience of wCBT, purposive sampling was used . All parSemistructured telephone interviews ,52 usingThe interviews lasted between 36-72 minutes (median 50 minutes) and were performed by JL (9 interviews) and AKK (4 interviews). Both interviewers were registered nurses. JL performed the interviews in his role as a PhD student and AKK in her role as a lecturer. Both had a good contextual understanding of the program. JL had some previous experience and AKK had extensive experience of qualitative interviewing. JL had previous contact (emails and writing feedback) with the participants during the program. All 13 interviews were digitally recorded and transcribed verbatim, 7 by a professional secretary with experience and 6 by JL.First, all transcripts were checked for accuracy against the recordings. Second, all transcripts were read as a whole to become familiar with the data. Third, a coding scheme was developed by JL and AKK. JL and AKK read and independently coded one interview. Anonymized parts of 3 transcripts were then used to generate tentative codes during a data workshop with PhD students from the disciplines of nursing and occupational therapy. The tentative codes generated by JL, AKK, and the workshop participants were then discussed by JL and AKK and a refined coding scheme was developed. Based on the developed coding scheme, JL then systematically coded all transcripts. At the end of the coding process, one more transcript was selected and coded by both JL and AKK to ensure a fair and neutral application of the coding scheme . Fourth,All participants were informed about the study and gave informed consent. To protect their confidentiality, published data were scrutinized to prevent the identification of the participants. The study conformed to the principles for medical research, as described in the World Medical Association’s Declaration of Helsinki , and wasOverall, 6 categories were identified during the analysis process. The categories, as well as the included subcategories, are listed in The participants described wCBT as a multifaceted experience. A common pattern was the experience of actively doing something to feel better or gain health. wCBT was described as a good way to treat depressive symptoms. Most participants described their experiences of wCBT in relation to other types of health care interventions they had encountered. Two subcategories were identified.My new self-help meant that wCBT assisted with self-help or self-care that helped participants to actively learn new ways to take responsibility for their health. Some participants stressed that wCBT was about learning and described the program as a course. Other participants said that wCBT could be similar to health care because professional health care personnel were accessible through the program but that wCBT was different from what they generally thought of as health care. However, most participants were hesitant about using words such as “health care.” This was due to their experience of having to be very active. wCBT was experienced as something one did in contrast to health care, which was seen as something one received.Yes, it is, kind of, a good reason to make, or maybe get help to make these changes that...And maybe I can get some advice that I hadn’t thought of myself...Kind of like someone taking one’s hand and saying: Let’s do it this way.Participant 10Helping other people meant that the program was experienced as a research project with the purpose of helping people with heart failure. Codes in this subcategory often came from participants describing the wCBT program as a treatment that was not mainly focused on them as individuals but an experience of contributing to other people’s well-being was conveyed.I think that it’s the right thing to do to give one’s support. If I can contribute in any way to research then I’ll do so willingly.Participant 3Most participants experienced the program as relevant and useful, at least to some degree. However, a few participants experienced no benefits from the program. An important factor related to finding the program useful was to recognize oneself in the program.Mainly useful meant that some participants experienced the program as highly relevant. A few participants described no experience of any shortcomings in the content of the program. However, most participants generally described the content of the program as helpful but with some disadvantages, such as describing the behavioral activation as hard to grasp or experiencing that the content of the program did not address areas and topics that they thought important for their health, such as management of health problems other than heart failure and stress management.Then I thought that it [the program] would probably contain a little bit more when it came to tools for stress too [...] There was a little but it didn’t give me those...I would have really liked a pure exercise program [to handle stress] there.Participant 9Mainly useful, in No use, a few participants reported that the program had not been of any benefit for them.In contrast to No, I don’t really think I got anything that I considered a cure if I can put it like this. [...] No, I might as well say that it was not of any benefit.Participant 7Different levels of recognition meant that experiences of recognition in and relevance of the program were commonly described by the participants. Examples and problems addressed were found to be realistic and similar to their everyday life. Furthermore, if participants described CBT components in the program as helpful, this contributed to their experiences of the program being recognizable and relevant.That’s the way it is, and I’m the one who is most positive about the program because it’s worked for me from start to finish.Participant 8However, in contrast, some participants did not recognize themselves in the program. The reasons for this were described as feeling too well or too ill compared with the presented examples. Another reason was described as having health problems not addressed in the program.That is to say some of the examples that you gave there [in the program] didn’t seem relevant to me.Participant 7The participants experienced working through the internet as positive and flexible. There were also challenges and some barriers connected to the use of the internet; 8 different subcategories were identified in this category.Working at home meant that most participants positively described working with the program at home because the home environment was peaceful and quiet. Working at home reduced the barriers to participating in a treatment program because one did not have to travel. This was important because getting started with different activities was experienced as difficult when suffering from depressive symptoms.Let’s put it this way, it was really nice to be able to be at home and do it in peace and quiet.Participant 4When I want and have time meant that the format and medium of the program provided a positive opportunity to work when the participants wanted to. Feeling motivated was described as important when choosing when to work with the program. In addition, the ability to increase or decrease the work tempo and repeat parts of the program were experienced as positive aspects. Contributing to the flexibility was the opportunity to make adjustments to when and where to work with the program, for example, if participants made a trip.If I wanted to sit down and do it at two in the night or five in the morning or in the middle of the day then this was fine I could choose when to carry out my exercises [...] it is an advantage to be able to do it at a time of my choice.Participant 6Adapting the content meant that participants described choosing to focus on the parts of the program that they experienced as meaningful and putting less effort into parts experienced as less important. The parts of the wCBT program that participants chose not to work with concerned things they already knew or did.I located and picked those small components, now what were they called? Little gems, [...] Oh, they were part of the internet program and they worked for me and were great.Participant 8Challenging format and medium meant that the format and medium made it easy to postpone the work on the program. Some participants therefore thought of setting fixed times to work on the program despite it reducing the flexibility. The experience of the program requiring self-discipline was common. The work was often experienced as lonely, especially if participants encountered problems with the program. The participants experienced a need to be active and take the initiative to solve some problems by themselves to gain a positive effect from the program.I’m a bit like, I’ll do this later and this bit I’ll postpone. And this is exactly what happens, and then things get difficult [...] It was not always a good thing that it was Internet-based and things got postponed.Participant 4Other challenges described were that the program required a lot of time and that there was a lot of text and assignments that needed to be completed during the program, which was experienced as stressful. In contrast, some participants described the program as timesaving owing to the medium and format. This was because the wCBT program gave the participants the opportunity to focus on the parts they felt important and because they did not have to travel to receive health care.The participants also said that they were not used to working with treatment through the internet, but they did not clearly assess the medium as negative or positive—rather, most participants described it as unusual. Another aspect experienced as valuable was the possibility to read the content of the program in printouts or on screen. Commonly, participants said that they were not used to reading long texts on the screen. Being presented with a number of different choices on how to perform the tasks in the program was sometimes experienced as hard, especially if the participants were not used to working with information technology and computers. Participants also said that the medium and format made them feel tied to the computer and vulnerable if the technology did not work. In contrast to the challenges experienced above, some participants mentioned no challenges with the medium and format.Everyday life affecting the treatment meant that factors or events not directly related to the program, heart failure, or depressive symptoms were important for how wCBT was experienced. These factors sometimes made it harder to work with the program, for example, if there was a demanding situation at work or if they had to handle other health problems.Just when one starts to establish a routine, things crop up which get a higher priority, and then these objectives and reviews get put on the back burner.Participant 9Integrity is protected meant that no experiences were identified of integrity being insufficiently protected in the program. The security system used in the program made them feel safe in regard to how information about them was handled. The organization behind the program was also important for creating experiences of safety. Universities and other public institutions were described as more reliable compared with private companies. Some participants experienced that integrity generally received too much attention when information technology systems were discussed.Look here, I’m 75 and have a number of medical problems and I don’t give a damn about confidentiality just as long as I receive decent health care.Participant 2However, among all the participants there was a limit to how, where, and by whom the information should be accessed; for example, some participants said that they would not be comfortable if such information was spread through social media. The participants said a number of times that it was important that health-related information was accessible for health care personnel, even if this came at the price of unauthorized persons being able to access the information. Close relatives such as spouses were also described as persons one may want to protect personal information from, something that was described as complicated when working at home with the program....it is worse if one is writing something that one doesn’t want the family to see...it can be a negative aspect of such a course of treatment if one has an inquisitive partner, indeed then things can get quite difficult.Participant 8Written format, the experiences differed in that the program mainly consisted of written information and depended on written communication. Some described the texts and feedback as well thought out and easy to read and understand. Furthermore, it was experienced to be easier to write about some types of health problems compared with talking about them. The written format was described as facilitating and clarifying what the participants were expected to do when working with the program. In contrast, some experiences suggested that the written format was a barrier to communication, and descriptions revealed that oral communication between participant and feedback provider was preferred.In Exactly, one gets a question which one starts to answer [...] one understands exactly what they’re after [...] it’s the way I am [...] it can be difficult to express oneself [verbally].Participant 4Anonymous and honest meant that working through the internet created conditions for a positive experience of anonymity. The participants thought that they could write exactly what they thought about things and be more honest in their communication. They were also positive about not feeling observed or analyzed. A requisite for this was that the communication took place without personal encounters. Furthermore, written delayed communication led to experiences of the feedback provider as a neutral medium or an unknown person. Both perceived anonymity and written delayed communication contributed to the experience of being protected or doing something behind a screen.Yes, this I would recommend, namely that one can be completely open there is no need to feel observed or analyzed or monitored in any way–instead it all takes place behind a screen, so to speak.Participant 6A number of technical problems were reported during participants’ work with the program. However, not everyone described such problems, and most participants experienced that they had been able to manage the problems they came across.Various problems were encountered and experienced in 4 different ways. First, problems were associated with participants’ computer equipment, such as old computers and problems with viruses. Second, the technique used in the program was demanding and complicated. Third, the interface of the program was sometimes confusing, creating insecurity regarding how to perform different tasks; for example, there was lack of automated feedback to know if assignments had been submitted.[...] when one had submitted something then one was uncertain as to whether it had arrived.Participant 12Various strategies meant that technical problems were managed in different ways. One strategy was to postpone the work if a technical problem was encountered, assuming that the problem would have been solved the next time one tried doing a task. Support was sought from relatives, friends, or the feedback provider. One participant said that she chose to get a new computer of the same model as a relative to get support that way. Another strategy was to read the instructions and test different solutions on one´s own.Fourth, technical problems during the log-in and authorization process were described. The log-in process could be complicated and some stated that they would have preferred to be able to set a less complicated password. Yes, I had to wait, repeat and try again. Yes, now and then I contacted [name of feedback provider] for assistance. [...] I sat there and explored the software by myself.Participant 10Most participants were less used to indirect contact with health care personnel. This was sometimes experienced as challenging and demanding. Participants described this as having to learn a new way of communicating with health care personnel. Several participants stated that they would have preferred more real-time contact, that is, direct verbal communication via telephone or video-telephony. Real-time communication through sound and picture (not necessarily only face-to-face) was described to make communication more dynamic and was thought to facilitate relationship building better than indirect communication. These experiences were described regardless of whether participants described the feedback in the program as positive and supportive or not.Depending on the circumstances meant that the experiences of the need for real-time communication were described as more important in some situations and less important in other situations. The purpose of an intervention or interaction was crucial for how important real-time communication was; for example, real-time communication was important for feeling cared for. Some participants said that delayed and indirect contact made them feel anonymous or reduced to a number. In contrast, when the experience of the program was described to be about learning, which was common, the delayed and indirect contact was experienced as suitable and sufficient.Oh yes, the obvious way is a face-to-face meeting with a person. But the thing with CBT and the like, and learning generally...Obviously things go really well with the Internet perhaps it is even an advantage.Participant 11Preferred situations meant that more real-time contact would have been preferred to allow for check-ups of the progress in the work and how the participant was doing. The use of real-time communication as a back-up if something did not work was also stressed.For example suppose that you gave feedback via phone in a different way. Then one can explain a bit more and other things too.Participant 5The participants described that they had generally become better at managing their lives. This was expressed in different ways among the participants. Some participants had learned to stop activities perceived as negative and had started to do things that balanced their activities in daily life. Others said that they had started to take the initiative to perform more positive activities and that they had begun to appreciate life again.Feedback is confirming and motivating and Reflection and new understanding.The participants experienced that problems could be solved and tasks could be performed differently compared with before they participated in the program. A prominent pattern was the experience of the program as stimulating them to take a greater responsibility for their health, for example, by seeking information about health problems and discussing health problems with their close relatives. This behavior change made them feel safer, reduced their feelings of hopelessness, and helped them to gain greater acceptance of their own health problems. The following 2 subcategories were identified: Feedback is confirming and motivating meant that the feedback participants received from the feedback provider was important because it facilitated the work process. One divergent finding was that a few participants described the feedback as not powerful enough to create a change in behavior. However, the feedback mostly was described as good and sometimes as prompt.But no, I think it would give a little more I mean you need some pressure, you need a carrot and stick you know.Participant 2The feedback was described as answering questions and providing new perspectives on the health problems that the participants worked with. Participants said that the feedback helped them to continue working in the program even if it felt cumbersome at times. Adding to this, the following 3 different experiences of good feedback were identified: confirmatory, coaching, and motivating.And receive an answer, an answer of concern to me alone. One doesn’t get standard answers.Participant 2Reflection and new understanding meant that the program gave rise to increased reflection, leading to new understanding and perspectives on their health and life situation. Descriptions showed that it could be painful to accept that heart failure comes with a poor long-term prognosis. On the other hand, experiences of being more prepared to manage worsening in heart failure were expressed. Participants described it as important that they had understood that depressive symptoms could be associated with heart failure and that it was common among patients with heart failure to experience depressive symptoms. Furthermore, participants said that the program had contributed to the experience of having gained new tools to manage problems and it had thereby affected their situation and well-being. They had learned to think in new ways and the program gave them new perspectives on everyday life. A common pattern was that participants started to challenge their old inward thinking. New thoughts were mostly positively expressed, including metaphors such as “the program was an eye opener” or “I see things from new angles.” However, one participant said that the program made him identify his health problems but that he could not take advantage of the program. Instead, he had sought other types of health care.However, I noted the following: well, I never, that was interesting. One hadn’t seen the connection and context of the two things, but when one got these two questions the penny dropped and one started to think in new ways.Participant 1The main finding of this study was that persons with depressive symptoms and heart failure described wCBT as a form of self-care for their health problems. Overall, the program was experienced as a new way to create self-care by active reflection on relevant and recognizable situations and support from a trustworthy person that was confirmative and motivating. The program was described as safe without any major challenges to integrity, except from their partners.The primary target of the wCBT intervention was to decrease depressive symptoms. However, the participants’ narratives most often referred to the program as something they experienced to help them take care of their own health problems, including both physical and psychological health problems. We interpret this as a holistic perspective on health among the participants. It is important to realize that the findings of this study are what the participants experienced and described and not primarily a qualitative evaluation of the wCBT program’s effect on depressive symptoms.Participants experienced that wCBT required them to be active participants in the treatment process and that the program helped them to focus on what they could do to improve their health. This is consistent with meta-analyses reporting data in studies of cancer survivors  and in tThe above-mentioned findings can be said to have general implications for health care interventions, regardless of how they are delivered. In our findings, there are also some aspects specifically related to wCBT as a telehealth intervention.Telehealth interventions are often seen as a practical and cost-effective way to face increased demands on a health care system . A wide Anonymous and honest and Written format with the category Improvements by real-time contact reveal a complex relationship between the possibility of being anonymous and a wish to have real-time contact. Anonymity is experienced as an easy way to address sensitive topics and to be honest but at the same time, it also led to an experience of being reduced to a number. Moreover, both positive and negative experiences regarding the use of written material and feedback and the need for more real-time communication were described in our findings. The contradicting findings regarding the written format and real-time communication can be seen as illustrating a dialectic relationship, similar to that described by Knowles et al [The findings described in the subcategories es et al , with paes et al , the nurThere are several limitations to this study. The authors’ involvement in designing the program may have affected their preunderstanding in regard to the analysis and presentation of findings . BecauseThe use of 2 different interviewers was important to counterbalance the risk of informant or researcher bias. No considerable differences were detected between the interviews conducted by JL and those conducted by AKK.We performed 13 interviews, which may be considered a small number. However, there are no clear guidelines for an appropriate sample size in qualitative descriptive studies . BecauseInterviews conducted via telephone may have rendered less rich data than those conducted face-to-face. However, face-to-face interviews were assessed as less beneficial because they required restrictions in the sampling process given the geographical spread of the participants. The median interview time was 50 minutes, which is similar to that often seen in other qualitative studies using face-to-face interviews . DespitePersons with heart failure and depressive symptoms experienced the wCBT intervention as challenging. This was because of participants balancing the urge for real-time contact with perceived anonymity, not postponing the work with the program, and learning a new way of communicating with health care personnel. Important advantages of the program were learning by reflection to gain new understanding of health problems and managing self-care to improve health. Being able to choose the time and place for the work was another advantage. wCBT appears to be experienced by persons with heart failure as a valuable tool to manage depressive symptoms. However, more research is needed to identify the circumstances in which anonymity is beneficial for the patients and how wCBT programs should be designed to balance the challenges experienced by persons receiving health care through wCBT.


The purpose of this study was to describe the centralized, cost-sharing design of the Independent Investigator Incubator .In September 2014, the I3 mentees indicated common “perceive deficits” including navigating the organizational and institutional culture, clear direction in achieving promotion and tenure, among others. When baseline mentee survey responses were compared to 12-month responses, we identified strong “perceived growth” in categories, such as Research and Interpersonal Skills and Career Development Skills. Further, productivity metrics at 12-months revealed that roughly 80% of I3 mentees successfully published a manuscript(s). The I3 program has helped generate roughly $12.1 million dollars in investigator-initiated funding after two years in the program.Results of the baseline mentee self-assessment survey found that the I3 program allows for shared costs between institutions and increased availability of successful subject matter experts. Study results imply that the I3 mentoring program provides transformative mentorship for junior faculty. Using our findings, we developed courses and an annual “snapshot” of mentee performance for mentors.The IThe online version of this article (10.1186/s12909-018-1290-3) contains supplementary material, which is available to authorized users. Mentoring in academic medicine provides an important mechanism for faculty to develop the necessary skillsets to succeed in a highly competitive environment by improving faculty career satisfaction, retention, research productivity, and professional success –6. WhileEffective mentorship is an essential element to supplement a research faculty’s personal and professional development by providing guidance through the mentor’s expertise, sponsorship, and institutional knowledge. Thereby, the mentee develops professional competency in career planning, communication skills, research and scholarship skills, managerial and leadership skills, negotiating and networking skills, and navigating the institutional culture , 8, 9. AFor research faculty, success is often defined by the ability to transition from trainee to early career awardee to independent investigator . The urghttps://report.nih.gov/index.aspx). In a 2015 article, Yin and colleagues reasoned that the decreasing pipeline of clinician-scientists in clinical and translational research is due in large part to the mounting challenges in transitioning from early career (K-type) to independent (R-type) funding, citing mentoring as “the single most important factor” in transition from K to R [As National Institutes of Health (NIH) budgets have been markedly reduced over the past decades, faculty have faced decreasing success rates in securing independent funding. For instance, the success rate for obtaining an R01-equivalent grant has fallen steadily from 33% in 1976, to 27% in 1996, to 20% in 2016  program both at administrative level and to provide more targeted mentoring. We report the 24-month pilot outcomes of the Independent Investigator Incubator (I3) Program focused on short-term and medium goals. Measures of effectiveness included mentee self-assessments, acquisition of professional skills, evaluation of the mentoring relationship, and productivity metrics . This research identified quantitative variables  provided administrative insight for program improvement and was employed to develop a novel tool for more “targeted mentoring”.The purpose of this study was to describe the cost-sharing, centralized design of the I3) Program. Indiana CTSI is a “hub” of the Clinical and Translational Science Awards (CTSA) Program. CTSA supports a national network of medical research institutions that work together to improve the translational research process to get more treatments to more patients more quickly. The hubs collaborate locally and regionally to catalyze innovation in training, research tools and processes. The primary goal of the I3 Mentoring Program is to facilitate the transition of high potential junior faculty researchers into independent investigators by removing as many barriers as possible and ultimately increasing their grant funding success. The I3 Mentoring Program employs a cost-sharing, centralized design that concentrated one-on-one mentorship from a senior faculty “super mentor,” feedback from a “super mentor” committee, mentoring resources, career development workshops, a professional grant writer and biostatistical support  Transforming Research Initiative (TRI) in collaboration with the Indiana Clinical and Translational Sciences Institute (CTSI) established the Independent Investigator Incubator  for each mentee, up to 15% FTE. “Super mentors” were provided with professional development opportunities including online CTSI mentoring training modules [“Super mentors” were identified and recruited from across the institution by the Associate Dean of Research Affairs based on their successful track records of mentorship, sustained funding, and productive research careers. These “super mentors” agreed to serve on an oversight committee to screen mentee applicants, mentor individual mentees in the program, and meet on a regular basis to review the progress of the program. Unlike many mentorship programs, I modules , the ins modules , and exp3 Mentees were recruited from across the institution via institutional newsletters, email alerts, and online departmental communications. Mentee applications were accepted on a rolling enrollment basis. Junior faculty applicants were screened and selected by the “super mentor” committee based on their academic achievements, area of research, and potential to become an independent investigator. The screening criteria targeted junior faculty during the crucial first three years of their research careers  or during their transition from career development award to investigator initialed funding. The I3 program required that the applicants had a departmental commitment to protected time for research, typically 50–75% FTE. This requirement is important to address the concern that clinical faculty require adequate protected time from their respective department to conduct research. I3 mentees were then matched to a specific “super mentor” with expertise in either basic science or clinical research.I3 pairs also were provided with structured expectations . The present study was accepted as Exempt (1) Category 1: Educational Research Conducted in Educational Settings; therefore, informed consent has been waived by the Indiana University Institutional Review Board (IRB) for this research (Study #: 1601639726).Mentees were provided with comprehensive support including: (1) robust one-on-one mentorship and targeted feedback from the “super mentor” review committee. (2) assistance from “super mentor” to set up a mentorship panel, (3) career development workshops through the CTSI and IUSM on a variety of topics , (4) mentoring resources and training including the Mentee Toolkit from the IUSM Faculty Mentoring Portal. The I3 program. Mentees were required to complete a Mentee Self-Assessment Survey and an electronic I3 Mentoring Program Survey. The Mentee Self-Assessment Survey was designed and adapted via expert opinion from University of California, San Francisco Faculty Mentoring Program. This 40 item self-evaluation tool was initially implemented at IUSM to assist the junior faculty mentee in assessing their professional strengths and weaknesses  and 12 months as measures of “Perceived Deficits” and “Perceived Growth” as an indicator of short-term outcomes  and funding at 24 months (medium). The logic model , satisfaction with the I3 Mentoring Program and the mentoring relationship, academic productivity measures , and career status and advancement . In addition, we collected data on grant funding awarded at 12 and 24 months to better address funded grants that had been largely conceived or written prior to the start of the program.The IP < 0.05).Data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at Indiana University, which is a secure, web-based application for electronic surveys and databases . Data an3 Mentoring Program Surveys collected at baseline (time zero) and 12 months. The I3 mentees represented a diverse group of research faculty based on sex, ethnicity, terminal degree, academic track, and discipline. For instance, the I3 Mentoring Program recruited a similar number of males (54%) and females (46%)  Fig.  and cons6%) Fig. . Notablyram Fig. .Fig. 3De3 mentee indicated deficits in “negotiating skills,” “dossier preparation skills” and “navigating the institutional culture.” In addition, over 30% indicated deficits in “creating and managing a budget”, “clear direction in achieving tenure,” and “enhancing professional visibility,”  Mentee Self-assessment Survey, mentees identified six professional skills as “Perceived Deficits”. Most notably, over 40% of I3 Mentoring Program, including “Research Skills,” “Communication Skills” and “Career Development Skills” .Three categories were identified as areas of “perceived growth” by mentees during the first year of the Ils” Fig. . Notably3 Mentoring Program Survey, I3 mentees expressed that they benefited from multiple career development tools and mentoring advice. In addition, all mentees were satisfied with their mentor pairing based on the mentor’s “availability” and “valuable feedback,” and all mentees wanted the mentoring relationship to continue. During the first year, all of the mentees were actively engaged with the majority of mentees meeting with their mentor either weekly or biweekly. In terms of productivity outcome measures, the majority of I3 mentees reported scholarship outcomes and dissemination of their research via manuscript submission (88%), manuscript publication (80%), poster presentation (73%), and oral presentation (69%)  and “grant funding” (69%). The initial funding status of I3 mentees is shown in Fig. 3 funding status. I3 mentees were awarded roughly $6.9 million dollars after one year in the program and $12.1 million after 2 years  and 12 months as an indicator for short-term outcomes / learning  Fig. . The I3 ars Fig. . Notably3 mentoring program recruited a diverse group of junior faculty based on sex, ethnicity, academic degree, and discipline. Notably, using mentee self-assessments (at baseline and 12 months), we identified important mentee perceptions of their skills for a variety of important domains where I3 mentees indicated “perceived deficits,” all of which improved after one year. In addition, we found that the I3 program positively impacted the mentees’ self-perceived professional growth and competence in domains, such as research and career development. Moreover, we found that the mentees are satisfied with their mentor pairing and desire the mentoring relationship to continue. Finally, we report productivity outcomes, such as publications and grant funding.In this manuscript, we report the pilot outcome data for the program that was utilized for initial program evaluation and improvement. During its first year, the I3 program utilizes a unique centralized mentorship assignment process for “super mentors” that allows for shared costs and increased availability of successful subject matter experts. The I3 program was designed to provide intensive mentoring and other support that synergizes with and promoted pre-existing departmental mentoring in a large medical research environment, such as IUSM. Unlike the centralized mentoring programs that targeted junior research faculty at the University of Utah and Duke University [3 program was designed as a three-year program with the possibility of extension based on mentee engagement, productivity, and career development needs. This is important because the ultimate goal of the I3 program is to espouse “independent investigators” with R01-type funding, and junior faculty with pre-K or K-type funding may require additional support. In addition, the cost-sharing model of I3 program is unique in that administrative and mentoring resources are shared between Indiana CTSI and IUSM  Mentor Panel (former KL2s giving advice), (ii) Work-Life Balance, (iii) Conflict Management, (iv) Scientific Writing (v) Keeping Tabs on your grant budget, (vi) Factors predicting success and failure for K to R transitions, (vii) Team Science, and (viii) Individual Development Plans. The program also provides writing workshops. Thereby, the I3 program recruited a core group of accomplished research mentors and compensated them with financial salary support. Freel et al. employed a similar method. This element attempts to mitigate a potential cost-benefit issue facing the mentoring relationship by incorporating a means by which to fund our mentors, thus tangibly recognizing and rewarding their time and expertise. For example, unlike graduate and postdoctoral trainees where the mentor-mentee relationship is often mutually beneficial, the mentoring relationship following the transition from trainee to junior faculty changes based on the cost-benefit ratio [The Iit ratio . There ait ratio . This in3 program. As the program is intended to be a three year process for junior faculty development, this study examined a variety of important domains , as well as products such as papers, grants and other measures of productivity . The 12-month mentee survey consisted of (i) mentor evaluation, (ii) mentee outcomes evaluation and (iii) self-assessment survey. Outcomes and self-assessment were used to gain insight regarding whether this intervention was effective in spurring a variety of important domains, as well as products such as papers and grants. In addition, this study was conducted to “evaluate” quantitative outcomes specially focused on mentee input that could be utilized to improve the I3 program both at administrative level and to provide more evidence-based, targeted mentoring.Next, we asked the following program evaluation question. “Can mentee outcomes and self-assessment be utilized to identify quantitative outcomes to evaluate the program at the administrative level and to provide more targeted mentoring?” The logic model Fig.  provides3 mentoring program to strategically target these deficits with additional seminars, workshops and courses. Indeed, a grant writing course is now being developed for junior faculty at IUSM. Similar to grant writing, the mentee can be explicitly taught how to create and manage a budget.Using mentee self-assessment surveys, we identified six “perceived deficits” in skillsets related to “career development” and “leadership and management” skills, all of which improved after 12 months in the program. However, many still noted deficits in procedural skillsets, such as “dossier preparation” and “creating and managing a budget.” This information provides administrative insight for the development of novel interventions, specifically targeting introspective input from the mentees themselves. Identifying these global deficits has enabled the I3 mentoring program fostered growth and development in key areas essential for building professional competence for research faculty. When evaluating “perceived growth” at 12 months, the greatest percentage of individuals indicated improvements in areas related to research and communication skills as well as career development skills. Some examples included grant writing, IRB submission, budget preparation, and curriculum vitae (CV) preparation. Others included communicating in conversation and writing, understanding authorship and publication, as well as designing and conducting research.In addition to identifying deficits, we found that the IWhile the academic procedural skillsets are necessary, the progression from junior investigator to independent investigator is dependent on the mentee’s ability to navigate the academic environment and integrate into the fabric of the academic institution. For instance, the ability to negotiate is critical for collaborative work with other scientists. Further, understanding promotion and tenure is more than developing a timeline and checklist of independent achievements. It requires a longitudinal plan that encompasses individual goals in context with a broad understanding of the needs and opportunities at the departmental and institutional levels along with keen insight into the people and processes that identify those needs. Self-assessment findings were used to gain administrative insight regarding whether this mentoring intervention was effective in spurring a variety of important domains for administrative program improvement specifically short-term goals related to learning Fig. .3 program impacted other key outcome measures including scholarship, research dissemination and acquisition of funding. Indeed, roughly 80% of the mentees indicated that they successfully published a manuscript(s) during their first year in the program, and roughly the same percentage of individuals presented their work . Notably, I3 mentees were awarded roughly $6.9 million dollars after one year in the program and $11.85 million after 2 years with a median funding level change from $40,000 to $268,000, respectively. While many of the faculty have a substantial trajectory coming into the program . We found that the Iram Fig. , all of 3 program has limited resources, it is important to identify and address any obstacles that might hinder the mentoring process and overall success of the program.Based on publications and funded grants , four mentees were identified who did not seem to benefit from the program. Interestingly, all of these individuals experienced life changing events that were likely associated with their gaps in research productivity, including impending relocation and family leave. Since the inception of the I3 program, another factor that has also emerged as a potential obstacle for success includes limited program engagement due to distance . We are currently working on strategies to improve engagement for individuals from satellite campuses by increasing mentor- and program-initiated contact and promoting the establishment of recurring meetings between the mentee and mentor. Because the IAnother goal of this research was to develop a supplemental tool for more targeted mentoring. The concept was to develop a short report (1 page) that provides the mentors with a “snapshot” of assessment of mentee performance, mentee indicators of success , and mentee changes in career-related perception over time. This snapshot is intended to supplement mentor impressions of the mentee and to identify perceived deficits that can be addressed. An example of this report is provided in the Additional files . In addition, it is impossible to isolate the effects of the program from other resources that are provided by IUSM. IUSM provides many resources to spur junior faculty development at this institution. These include, but are not limited to, internal funding mechanisms, seminars, workshops, etc. It is very possible that these resources also contributed to the success of junior faculty. Further, the program elements were not systematically evaluated to determine their relative value. Therefore, mentee input regarding the impact of specific elements of the program would be interesting to include for future program evaluation.While more complex multifactorial analyses might identify specific components/activities that contribute to outcomes, this study focused on self-report and outcomes as a potential indicator of the effectiveness of the I3 Mentoring Program demonstrated indicators of success based on the mentee’s satisfaction with their mentoring relationship, perceived professional growth, and productivity outcome measures, such as manuscript publication and funding acquisition. In addition, this study provided important information for program improvement focusing on more global interventions  as well as the creation of a novel mentor-specific tool . Ultimately, the cost-sharing, centralized design of the I3 mentoring program might serve as an effective, cross disciplinary mentorship for other academic institutions to utilize in order to jumpstart productive research careers for their junior faculty.The IAdditional file 1:Figure S1. The Mentee Self-Assessment Survey. The Mentee Self-Assessment Survey was designed and adapted via expert opinion from University of California, San Francisco Faculty Mentoring Program. This 40 item self-evaluation tool was implemented at IUSM to assist the junior faculty mentee in assessing their professional strengths and weaknesses. (PDF 2981 kb)Additional file 2:Figure S2. Snapshot of mentee performance for I3 mentors. A short report (1 page) was developed to provide the mentors with a “snapshot” of assessment of mentee performance over time in order to supplement mentor impressions of the mentee and to identify perceived deficits that can be addressed. (PDF 6781 kb)


Carvedilol is a nonselective beta-blocker used to reduce portal hypertension. This study investigated the effects and potential mechanisms of carvedilol in angiotensin II- (Ang II-) induced hepatic stellate cell (HSC) proliferation and contraction. α-smooth muscle actin (α-SMA), Ang II type I receptor (AT1R), RhoA, Rho-kinase 2 (ROCK2), and others.  The effect of carvedilol on HSC proliferation was measured by Cell Counting Kit-8 (CCK-8). Cell cycle progression and apoptosis in HSCs were determined by flow cytometry. A collagen gel assay was used to confirm HSC contraction. The extent of liver fibrosis in mice was evaluated by hematoxylin-eosin (H&E) and Sirius Red staining. Western blot analyses were performed to detect the expression of collagen I, collagen III, α-SMA expression and collagen deposition and attenuated liver fibrosis in carbon tetrachloride (CCl4)-treated mice. The in vivo data further confirmed that carvedilol inhibited the expression of angiotensin-converting enzyme (ACE), AT1R, RhoA, and ROCK2.  The results showed that carvedilol inhibited HSC proliferation and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Carvedilol also modulated Bcl-2 family proteins and increased apoptosis in Ang II-treated HSCs. Furthermore, carvedilol inhibited HSC contraction induced by Ang II, an effect that was associated with AT1R-mediated RhoA/ROCK2 pathway interference. In addition, carvedilol reduced  The results indicated that carvedilol dose-dependently inhibited Ang II-induced HSC proliferation by impeding cell cycle progression, thus alleviating hepatic fibrosis. Furthermore, carvedilol could inhibit Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway. Liver fibrosis and cirrhosis are worldwide public health problems with severe complications including portal hypertension and hepatic failure . They arStudies have suggested that the renin-angiotensin system (RAS) is important in the pathogenesis of liver fibrosis , 8. AngiCarvedilol is an adrenergic receptor blocker that can effectively reduce portal pressure and is used to prevent esophageal variceal bleeding. As a relatively new nonselective beta blocker (NSBB), carvedilol is more effective than propranolol at reducing portal hypertension in patients with cirrhosis . In addi2.Human LX-2 HSCs were obtained from the ATCC  and cultured in DMEM  supplemented with 10% fetal bovine serum  at 37°C with 5% CO3 cells/well) were seeded in 96-well plates and cultured overnight in DMEM with 10% fetal bovine serum. The concentrations of carvedilol were determined according to our previous experiments [μL of CCK-8  reagent was added to each well. The plates were incubated at 37°C for 1 hour, and spectro-photometric absorbance was measured at 450 nm using a scanning multiwell spectrophotometer . The results are based on triplicate experiments.HSCs  according to the manufacturer's protocol. The percentages of cells in each phase of the cell cycle were determined and analyzed with a Muse Cell Analyzer . The results are based on triplicate experiments.HSCs were seeded in 6-well plates at a density of 5 × 104 cells/well) were seeded in 6-well plates, cultured overnight, and then treated with Ang II and various concentrations of carvedilol for 24 hours. A PE Annexin V Apoptosis Detection Kit I  was used for analysis according to the manufacturer's protocol. The percentages of apoptotic cells were determined by flow cytometry . The data were analyzed with the FACSDiva 7.0 software. The results are based on triplicate experiments.HSCs  according to the manufacturer's protocol. Apoptotic HSCs were observed under a fluorescence microscope .HSCs were seeded in 6-well plates at a density of 2 × 104 cells/well) were cultured on the collagen gels for 24 hours. Then, Ang II and various concentrations of carvedilol/ROCK inhibitor (Y-27632) were added into each well. The diameters of the collagen lattices were monitored until 24 hours after stimulant addition. The results are based on triplicate experiments.Hydrated collagen gels were prepared in 24-well plates using type I rat tail tendon collagen according to the manufacturer's protocol . HSCs (3 × 104 cells/well) were seeded in the plates and cultured for 24 hours. After the cells adhered to the coverslips, Ang II and different concentrations of carvedilol were added. When the cells contracted, the coverslips were washed with PBS and immobilized immediately in electron microscopy fixative  for 1 hour. After the coverslips were fixed, serially dehydrated, and dried, they were observed under a scanning electron microscope .Aseptic coverslips were placed in 6-well plates, and HSCs . The mice were kept at a constant temperature and given laboratory chow and water 4 (25% CCl4 in olive oil) twice a week for 6 weeks, and mice in the carvedilol group were treated with carvedilol at the same time . Mice in the control group were injected intraperitoneally with olive oil alone. The survival rate of the mice was 80% until the end of the experiment.The experiment was performed according to our previous method for constructing a mouse model of liver fibrosis . The livLiver tissues were fixed with 4% formaldehyde and sectioned for H&E and Sirius Red staining. Liver fibrosis was assessed according to the METAVIR scale  . After bProteins were extracted for Western blot analysis, and concentrations were detected by the bicinchoninic acid (BCA) protein determination method. The proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene fluoride (PVDF) membranes, which were incubated in 5% nonfat milk for 1 hour and then with primary antibodies overnight at 4°C. After secondary antibody incubation and membrane washing, the bands were detected using enhanced chemiluminescence . The results were analyzed with ImageJ software.t-test or one-way ANOVA were used for statistical significance analysis. Values of P < 0.05 were considered statistically significant.All data are expressed as the mean ± standard deviation. Student's 3.1. Carvedilol Inhibited Proliferation and Cell Cycle Progression in HSCs Treated with Ang II. The effect of Ang II on HSC proliferation was evaluated by the CCK-8 assay. The results showed that Ang II enhanced HSC proliferation in a dose-dependent manner and produced a significant effect at 1 μM (μM) group and the Ang II (1 μM) + DMSO group (P < 0.05 vs. the control and Ang II groups). The results demonstrated that carvedilol might arrest cell cycle progression to inhibit HSC proliferation. Cyclins and cyclin-dependent kinases (CDKs) are known to play important regulatory roles in cell cycle progression. Cyclin D, cyclin E, CDK2, and CDK4 are crucial regulatory proteins of the G1 phase. The Western blot results showed that the expression of these proteins was increased in the Ang II group, while carvedilol notably inhibited this Ang II-mediated upregulation . The diameters of the gels were measured to evaluate the contraction effect, and we found that carvedilol impeded the gel contraction induced by Ang II in a dose-dependent manner  effectively inhibited AT1R protein expression and collagen synthesis (µM) group, and more significant inhibition of the expression of these proteins was observed after treatment with the combination of olmesartan and carvedilol  showed increased inflammatory cell infiltration and fibrous tissue hyperplasia compared to those in the carvedilol treatment group (METAVIR ≤ F2)  . Sirius nt group . In addint group . α-SMA iincrease . Moreoveincrease . The dat4-induced liver fibrosis was assessed by immunohistochemistry and Western blot analysis . The prolonged G0/G1 phase of the cell cycle showed that carvedilol impeded cell cycle progression in Ang II-treated HSCs, which might be the mechanism by which carvedilol inhibits HSC proliferation. CDK/cyclin complexes play critical roles in cell cycle control: cyclins are considered to aid in the transitions between cell cycle phases, and CDKs drive cell cycle progression [α-SMA, collagen I and III are considered markers of HSC activation, proliferation and fibrogenesis, and we found that the expression of α-SMA and collagen I and III was downregulated after carvedilol treatment. Both in vitro and in vivo experiments confirmed that carvedilol inhibited HSC proliferation and collagen deposition, attenuating liver fibrogenesis.HSCs are the major fibrogenic cell type in the liver , and thegression , 29. Stugression –32. In tgression . The resin vitro study showed that cellular morphology, as observed under SEM, changed when HSC contraction was induced by Ang II and that carvedilol effectively inhibited this response. This finding suggests that carvedilol may further reduce portal hypertension by inhibiting HSC contraction, and this may constitute a molecular mechanism by which carvedilol decreases portal hypertension. Activated HSCs can express AT1R, which in turn plays an important role in HSC activation and fibrogenesis [in vitro experiments demonstrated that the RhoA/ROCK2 pathway was inhibited by carvedilol in a dose-dependent manner and that this effect was associated with AT1R inhibition in Ang II-treated HSCs. The results also suggest that carvedilol may inhibit HSC contraction through the RhoA/ROCK2 pathway. In the gel contraction experiment, Y-27632 could inhibit Ang II-induced HSC contraction, which indicated that ROCK was a downstream effector of carvedilol's effects on HSCs. We also established a mouse liver fibrosis model by intraperitoneally injecting mice with CCl4 for 6 weeks, and in vivo experiments further verified the effect of carvedilol on the AT1R-mediated RhoA/Rho-kinase pathway, which might affect cell contraction and fibrogenesis.When liver injury occurs, HSCs are activated and become contractile, which increases intrahepatic vascular resistance and plays an important role in the development of portal hypertension . HSC conogenesis –38. Studogenesis , 8, 22. ogenesis , 14. OurThe RAS plays crucial roles in regulating blood pressure and maintaining electrolyte balance . Inhibitin vitro experiments demonstrated that carvedilol inhibited Ang II-induced HSC proliferation, impeded cell cycle progression, and induced HSC apoptosis. In vivo experiments further confirmed that carvedilol inhibited HSC activation and proliferation to attenuate liver fibrosis. Carvedilol also influenced elements of the intrahepatic RAS and markedly decreased the expression of ACE in fibrotic liver tissue. Moreover, carvedilol inhibited Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway, which may be one of its molecular mechanisms for reducing portal hypertension.In conclusion,


Radial endobronchial ultrasound (R-EBUS)-guided transbronchial biopsy (TBB) is a common diagnostic modality for peripheral pulmonary lesions; however, there is uncertainty about the optimal sequence of TBB and bronchial brushing during the procedure. Thus, we aimed to investigate whether a biopsy-first or brushing-first strategy confers a better diagnostic yield and safety signal for R-EBUS-guided procedures for peripheral pulmonary malignancy.From January 2017 to June 2018, consecutive patients referred for R-EBUS-guided TBB and bronchial brushing of peripheral pulmonary lesions and with a final malignant diagnosis were included. Patients were placed in a biopsy-first (biopsy followed by brushing) or a brushing-first (brushing followed by biopsy) group. The outcomes of interest were the diagnostic yield and complication profile of the procedures. Multivariate logistic regression and subgroup analysis were used to assess the impact of the procedure strategy.A total of 438 patients were included and the diagnostic yield of R-EBUS-guided TBB plus brushing for peripheral pulmonary malignancy was 73%. The diagnostic yield was associated with the solid lesion appearance  and R-EBUS probe position within the lesion , and the yield rates were comparable between the biopsy-first and brushing-first strategies. Moreover, the safety signal did not differ between the two groups.The two procedure strategies were indistinguishable in terms of diagnostic efficacy and adverse events for patients with peripheral pulmonary malignancy. Current evidence indicates that in patients with peripheral pulmonary lesions suspected of being malignant, either biopsy-first or brushing-first is a viable and acceptable diagnostic strategy during R-EBUS-guided procedures. Diagnosis of peripheral pulmonary malignancy can be attained via a variety of modalities, such as bronchoscopy, computed tomography (CT)-guided transthoracic needle biopsy and surgery. In the past two decades, advances in bronchoscopic procedures, such as radial endobronchial ultrasound (R-EBUS), virtual bronchoscopic navigation and electromagnetic navigation have made transbronchial biopsy (TBB) a more appealing and favorable approach , 2. Of tBesides the diagnostic modalities and tools, the details of the bronchoscopic procedures may affect their diagnostic yield. For instance, in bronchoscopically visible lesions, a brushing-first strategy provided a significantly higher diagnostic yield for lung cancer than a biopsy-first strategy . In a siTherefore, the aims of this study were to investigate whether a biopsy-first or brushing-first strategy confers a better diagnostic yield and safety signal for R-EBUS-guided TBB of peripheral pulmonary malignancy.This study was conducted at National Taiwan University Hospital, a tertiary-care referral center in Taiwan. Consecutive adult patients who underwent R-EBUS-guided TBB of peripheral pulmonary lesions from January 2017 to June 2018 were screened for eligibility. A peripheral pulmonary lesion was defined as a lesion circumscribed by lung parenchyma and invisible through conventional bronchoscopy . CriteriThe bronchoscopic exam was primarily conducted by pulmonary fellows, as previously described, under the supervision of eight rotating pulmonary faculty in attendance , 14. In The biopsy was taken with a cup forceps , and was repeated until adequate tissue samples were collected. Bronchial brushing was performed with a 2-mm brush  and a few back-and-forth movements were used to retrieve the samples. The biopsy specimens were put in 10% formalin and transported to the histopathology laboratory for analysis. Tissue samples obtained by bronchial brushing were smeared onto glass slides, air-dried at room temperature and sent for cytology exam. During the study period, fluoroscopic guidance and rapid on-site evaluation (ROSE) were not utilized at our institution, and biopsy and brushing specimens were read independently by the pathologist and cytopathologist, respectively. A biopsy-first strategy (biopsy followed by brushing) or a brushing-first strategy (brushing followed by biopsy) was chosen by the in-charge faculty based on the day of the week on which the procedure was conducted. On Monday and Thursday, it would be a biopsy-first strategy, and on Tuesday and Wednesday, a brushing-first strategy.The primary outcome was the diagnostic yield of R-EBUS-guided TBB plus brushing for peripheral pulmonary malignancy; another outcome of interest was the incidence of procedure-related complications. Patient records and images were reviewed to obtain the following information: demographics, lesion size, location and appearance, absence or presence of a CT bronchus sign, probe position, procedure-related complications, and histopathologic and cytologic diagnosis. Lesion size was measured as the largest diameter on axial CT films. Lesion location was divided into five anatomic lobes. Lesion appearance was categorized as solid or non-solid . A CT bronchus sign was present if one or more bronchi leading directly to the peripheral pulmonary malignancy were identified on CT . Probe pP values < 0.05 were considered statistically significant and all tests were two-sided. All statistical analyses were performed using SPSS  or Stata .Between-group comparisons were performed using χ2 or Fisher’s exact test for categorical variables and independent samples t-test for numerical variables. A multivariate logistic regression model was constructed with the diagnostic yield of TBB plus brushing as the outcome variable predicted by the procedure strategy (biopsy-first vs. brushing-first), using all relevant covariates without model selection. To explore possible effect modification by lesion appearance, size and location, and probe position based on biologic plausibility, we used stratified analysis to estimate the diagnostic odds in each subgroup. N = 239, 55%). The mean diameter of the peripheral pulmonary malignancy was 37 ± 16 mm. An approximately equal number of malignant lesions were distributed between the upper lobes  and the middle/lower lobes , and the majority  of them appeared solid on CT scans. Under most circumstances, the R-EBUS probe can be positioned within the malignant lesions . The leading pathologic diagnoses in our study cohort were lung adenocarcinoma , non-small cell lung cancer  and lung squamous cell carcinoma .During the study period, a total of 438 patients with peripheral pulmonary malignancy were included for analysis. The average age of the study population was 66 ± 12 years, and slightly more than half of the subjects were male (P = 0.004).Table The overall diagnostic yield of TBB plus brushing for peripheral pulmonary malignancy was 73%. The diagnostic yield was associated with the CT appearance of the malignancy and probe location Table . The diaN = 21, 4.8%), which was treated with instillation of topical epinephrine (N = 17) or bronchoscope wedge (N = 4). Other complications included pneumothorax (N = 6), unstable hemodynamics (N = 2) and bronchospasm (N = 1). Two R-EBUS-guided procedures were prematurely terminated due to the development of complications. The incidence of overall or individual complications was similar in both groups.No procedure-related mortality was observed in this study. Overall, complications occurred in 30 (6.8%) of the 438 patients  the overall diagnostic yield of TBB plus brushing of peripheral pulmonary malignancy was 73%; (b) a biopsy-first strategy provided diagnostic sensitivity for malignancy similar to a brushing-first strategy; (c) solid lesion appearance and position of the R-EBUS probe within the lesion were two features significantly associated with the diagnostic yield of TBB plus brushing; (d) the overall complication rate was 6.8%, with hemorrhage being the most common complication; (e) the safety signal did not differ between the biopsy-first and brushing-first groups.The most important finding in this study is that the two strategies resulted in a comparable diagnostic yield for R-EBUS-guided procedures for peripheral pulmonary malignancy. In fact, most of the previous reports regarding TBB and bronchial brushing with the assistance of R-EBUS did not specify the sequence of the procedures , 16–18. Our diagnostic sensitivity for peripheral pulmonary malignancy using TBB was consistent with that of previous studies of R-EBUS for malignant lesions, in which the diagnostic yield of R-EBUS ranged from 47 to 81% , 19–22. In a recent study by Chen, et al. , the diaSafety is certainly a concern when choosing a modality or procedure. Consistent with prior studies , 26, a fIn line with previous studies , 17, 18,A couple of caveats pertaining to this study should be mentioned. First, the study findings represent a single-center experience with R-EBUS-guided TBB for peripheral pulmonary malignancy carried out by a well-developed bronchoscopy team; thus, the results may not be generalized to other settings, such as a less-experienced institution or a lower-level healthcare facility. Nonetheless, as the first study to deal with this issue, we hope our report will encourage more large-scale and elaborate studies in this field. Second, our study was retrospective, and as such, the choice of procedure strategy was at the discretion of the in-charge pulmonary faculty. In this regard, a selection bias may exist; however, baseline features of the participants were nearly balanced between the biopsy-first and brushing-first groups, and further statistical adjustment did not identify any significant differences in the study outcomes between the two groups.In summary, the timing of bronchial brushing, either before or after biopsy, for peripheral pulmonary malignancy, at least in experienced hands, did not influence the diagnostic yield of R-EBUS-guided TBB plus brushing. Moreover, a similarly favorable safety signal was observed between the two strategies. Therefore, current evidence indicates that in patients with peripheral pulmonary lesions suspected of being malignant, either biopsy-first or brushing-first would be a viable and acceptable strategy with respect to diagnostic sensitivity and safety during R-EBUS-guided procedures.


Rubella infection in early pregnancy can lead to miscarriages, fetal death, or birth of an infant with congenital rubella syndrome (CRS). In Cameroon, like in many developing countries, rubella surveillance is not well-established. The aim of this study was to determine the prevalence of rubella virus specific antibodies among pregnant Cameroonians. We conducted a cross-sectional study for rubella infection among pregnant women attending antenatal clinics in the Center and South-West regions of Cameroon. Demographic data and blood were collected and tested for rubella specific antibodies (IgG and IgM), and for the IgM positive cases, IgG avidity and real time PCR was done. From December 2015 to July 2017, 522 serum samples were collected and tested from pregnant women. The seroprevalence of rubella specific IgG was 94.4%, presumably due to immunity induced by wild-type rubella virus. The seroprevalence of rubella specific IgM was 5.0%, possibly indicating rubella infection. However, IgG avidity testing of the IgM positive cases detected high avidity IgGs, ranging from 52.37% to 87.70%, indicating past rubella infection. 5.6% (29/522) of the participants had negative results for IgG to rubella virus, indicating susceptibility to rubella infection. None of the participants had received a rubella containing vaccine (RCV), but 51% (266/522) of the pregnant women lived in a house with a child with records of at least one dose of RCV. Rubella virus RNA was not detected in the urine of any IgM positive case. Findings from this study show that rubella infection is significant in Cameroon. Some pregnant women are still susceptible to rubella infection. For a better management of rubella infection in pregnancy in Cameroon, consideration should be taken to investigate for IgG-avidity test in cases with positive rubella IgM result to distinguish between recent from past rubella infection. Rubella virus infection is transmitted by respiratory droplets and causes a generally mild disease characterized by a rash and fever, primarily in children . AlthougRubivirus genus in the Togaviridae family, is a positive-polarity ribonucleic acid virus. Both vaccination and natural infection result in life long immunity. This vaccine-preventable disease is among the small number of viral diseases considered to be potentially eradicable ) and a reverse primer (RV251R [5′-CGT GGA GTG CTG GGT GAT-3′]). RNA samples were also tested using RNase P forward primer (HURNASE-P-F): 5’-AGA TTT GGA CCT GCG AGC G-3’ and a reverse primer (HURNASE-P-R): 5’-GAG CGG CTG TCT CCA CAA GT-3’ [A real-time  was calculated for the Odd ratio (OR), and values of p<0.05 were considered statistically significant. Logistic regression analysis was used to estimate OR of IgG and IgM seropositivity as outcome variable with age, sex, setting, pregnancy, region, presence of child who has taken RCV, number of children living in same house and tribe as explanatory variable.The study protocol was approved by Cameroon National Ethics Committee N0 2017/11/957/CE/CNERSH/SP. It also received approval from other institutional review boards such as the Institutional Review Board of the Cameroon Baptist Convention Health Board, the Yaoundé Gyneco-Obstetric and Pediatric Hospital, the Centre Hospitalier Essos and the St Elizabeth General Catholic Hospital Shisong. Research authorizations were obtained from each hospital and health districts where participants were recruited. Consent was also obtained from parents or guardians of the minors included in the study. Informed consent was obtained from all study participants.Five hundred and twenty-two (522) pregnant women  were enrThe overall seroprevalence of rubella specific IgG antibodies at the time of data collection was 94.4% (493/522). The overall seroprevalence of rubella specific IgM was 5.0% (26/522). According to the present study, 5.5% (29/522) of the total participants had no indication of immunity to rubella virus and tested negative for both IgG and IgM antibodies .Among the pregnant participants, 94.4% (493/522) were IgG positive with the South-West region having the higher prevalence of 59.6% (294/493). 5.0% (26/522) of the pregnant participants were IgM positive within the Center region having the higher prevalence of 65.4% (17/26) and the South-west the lower with 34.6% (9/26). 5.6% (29/522) of the pregnant participants were IgG and IgM negative. Pregnant participants from the Center region were two times more likely to have a positive IgG . The relationship between rubella IgG and the other sociodemographic characteristics  did not show any statistically significant association. However, rubella IgG was statistically associated to having any child with RCV in the same house during pregnancy .In this study, all the IgM positive cases had past rubella infection. Of 26 serum samples tested for rubella IgG avidity, all samples had high avidity rubella IgG antibodies which varied from 52.37% to 87.70% with an average of 69.87% (± 8.19%).In this study, 19% (99/522) of the pregnant participants presented with rubella clinical signs. 7.5% (37/493) of the IgG positive pregnant women had fever, 4.1% (20/493) had rash, 7.5% (37/493) had conjunctivitis and 0.2% (1/493) had lymphadenopathy. There was no statistically significant association between rubella IgG positivity and the presence or absence of any clinical presentation. Among the pregnant women presenting with rubella clinical signs, 7.7% (2/26) of the IgM positive participants presented with fever; 7.7% (2/26) presented with rash; 11.5% (3/26) presented with conjunctivitis and no participant positive to rubella IgM presented with lymphadenopathy. However, the number of IgM positive cases was too few for any significant statistical analyses between IgM positivity and rubella clinical signs.RNA was extracted from a total of 14 urine samples from the pregnant participants with positive IgM results. No rubella virus was detected from any of these samples using real time PCR.This study investigated the seroprevalence of rubella among Cameroonian pregnant women attending ANC in the Center and South-West regions. Rubella antibodies (IgG and IgM) were detected using ELISA and rubella IgG avidity testing was done to determine the status of rubella infection. The findings showed that 94.4% of the pregnant women were positive to rubella IgG. This confirms previous exposure to wild type rubella virus , 16 sincFurthermore, as observed in other studies, all the other socio-demographic characteristics were not associated to rubella seroprevalence , 17, 21,This study shows a lack of immunity against rubella among a small proportion of pregnant women in Cameroon as the proportion of susceptible individuals was 5.6%. Despite the high prevalence of rubella IgG in Cameroon, some pregnant women are still at risk of rubella infection during pregnancy which might lead to the birth of infants with CRS. Presently, some young women of child bearing age are still unprotected from rubella which is consistent with some observations of CRS in Cameroon in the past few years . The maiClinical diagnosis of rubella is unreliable , making It is recommended to test pregnant women for IgM only if symptoms are evident, if contact with a known case occurred, or if an outbreak is occurring in the region but no pregnant woman should have rubella diagnosed on the basis of a single positive rubella specific IgM test result. OccasioIn cases where a possible false positive rubella IgM result is suspected, one supplemental assay that can be used to distinguish primary infection from remote infection is the measurement of IgG avidity . We recoThe findings from our study further support the fact that rubella infection represents a public health burden. However, this study was subject to limitations including the small number of IgG negative and IgM positive cases, and no positive result after PCR. Due to limited resources, this cross-sectional survey was done only in two out of ten regions in Cameroon. Despite these limitations, our results highlight the need to investigate rubella during pregnancy, encourage the vaccination of young women of reproductive age presenting with no rubella immunity, and interpret IgM positive results carefully.The seroprevalence of rubella IgM antibodies was 5.0% in the pregnant participants. No participant presented with an acute/recent rubella infection, as confirmed with high avidity. Before taking any decision to interrupt any pregnancy because of a positive rubella IgM result, IgG avidity testing should be done. Our study reveals that susceptible pregnant women without immunity to rubella are present in the population and they are at risk of bearing children with CRS. Hence, rubella screening of women of child bearing age should be encouraged, those who lack immunity should be vaccinated, and rubella-based surveillance should be strengthened to reduce the burden of rubella and CRS in Cameroon.S1 Table(XLSX)Click here for additional data file.


Most lymph node metastasis (LNM) models for early gastric cancer (EGC) include lymphovascular invasion (LVI) as a predictor. However, LVI must be confirmed by postoperative pathology. In this study, we aimed to develop a model for predicting the risk of LNM/LVI in EGC using preoperative factors.n = 1460) were selected as the training set. The risk factors of LNM/LVI were investigated. Data from the International study group on Minimally Invasive surgery for GASTRIc Cancer trial (n = 172) were selected as the validation set.EGC patients who underwent radical gastrectomy at Fujian Medical University Union Hospital and Sun Yat-sen University Cancer Center (P = 0.030). Multivariable logistic regression analysis showed that the four independent risk factors for LNM/LVI were female, tumor larger than 20 mm, submucosal invasion and undifferentiated tumor histological type ; the area under the curve (AUC) was 0.694 . Patients were divided into low-risk, intermediate-risk, high-risk and extremely high-risk groups by recursive partitioning analysis; the incidences of LNM/LVI were 5.4, 12.6, 24.2 and 37.8%, respectively (P <  0.001). The AUC of the validation set was 0.796  and the predictive performance of the LNM/LVI risk in the validation set was consistent with that in the training set.In the training set, the incidence of LNM/LVI was 21.6%. The 5-year cancer-specific survival rates of patients with and without LNM/LVI were 92.4 and 95.0%, respectively, with significant difference (The risk of LNM/LVI in differentiated mucosal EGC is low, which indicated that endoscopic resection is a treatment option. The risk of LNM/LVI in undifferentiated mucosal EGC and submucosa EGC are high and gastrectomy with lymph node dissection is suggested. With the advancement of diagnostic techniques and the popularization of health examinations, the diagnostic rate of early gastric cancer (EGC) worldwide has gradually increased . Lymph nThe clinicopathological data of patients who underwent radical gastrectomy from Fujian Medical University Union Hospital  and Sun Yat-sen University Cancer Center  were retrospectively analyzed. The selection criteria were: (1) the depth of tumor invasion was confined to the mucosa or submucosa; (2) no distant metastasis; and (3) the number of lymph node harvested was > 15. Patients were excluded if they (1) had multiple primary cancers; (2) had received neoadjuvant therapy; or (3) had incomplete clinicopathological information. Finally, the study included 1460 patients. A total of 172 non-Asian subjects in the International study group on Minimally Invasive surgery for GASTRIc Cancer (IMIGASTRIC) trial from January 2000 to December 2014 were selected as the validation set. The median follow-up time in FMUUH was 57 months (5–259 months), the median follow-up time in SYSUCC was 58 months (1–209 months), and the median follow-up time in IMIGASTRIC was 69.5 months (1–176 months). The study was approved by the FMUUH, SYSUCC and St. Mary’s Hospital Institutional Review Board.Variables investigated included age, sex, tumor location, tumor size, depth of invasion, tumor histological types, and LNM/LVI. The best cutoff for tumor size was 20 mm according to the maximum of the Youden index. The depth of invasion was divided into mucosal and submucosal invasion according to the eighth edition of American Joint Committee on Cancer (AJCC) gastric cancer staging system . LesionsThe follow-up policy at our center for the patients after surgery was every 3 to 6 months for the first 2 years consisted of clinic visits, with computed tomography (CT) and labs scans, and every 6 to12 months for following 3 to 5 years, then annually afterwards. Deaths because of cancer were recorded as events, and deaths secondary to other causes were censored.P value < 0.05 was considered statistically significant and all statistical tests were two-sided.Chi-square test or Fisher’s exact test were used for analysis of categorical variables, whereas Mann-Whitney U test or Student’s t test were used for comparisons of continuous variables. The Kaplan-Meier method was used to estimate the cancer-specific survival (CSS). Uni- and multivariable logistic regression analysis were performed to identified the risk factors for LNM/LVI. The receiver operating characteristic (ROC) curves were plotted separately for the training and validation sets and the areas under the curve (AUC) were calculated. According to the results of multivariable analysis, RPA was used to divide the patients into different risk groups. In this study, different groups were obtained according to RPA, and groups with similar incidence of LNM/LVI were reintegrated into one risk group. Finally, four risk groups were obtained, and the incidence of LNM/LVI increased in turn, which were defined as: low risk group, intermediate-risk group, high-risk group and extremely high-risk group. A 1:3 propensity score matching ratio was set to minimize the differences between the training set and validation set due to age, depth of invasion, sex, tumor histological types and tumor size. All statistical analyses were performed using SPSS 22.0  and R 3.4.2 . A A total of 1632 patients with EGC were enrolled in this study, including 1460 cases in the training set and 172 cases in the validation set. The average age of patients in the training set was 57.43 ± 11.5 years, of which 815 (55.8%) were ≤ 60 years and 645 (44.2%) were > 60 years. The training set included 1024 males (70.1%) and 436 females (29.9%); there were 242 (16.6%) patients with tumor located in the upper region, 475 (32.5%) in the middle region, 643 (44.0%) in the lower region and 100 (6.8%) overlapped multiple regions; the average tumor size was 24.7 ± 15.4 mm, of which 850 (58.2%) had tumor size ≤20 mm and 610 (41.8%) had tumor size > 20 mm; there were 641 (43.9%) tumors confined to the mucosa and 819 (56.1%) infiltrating into the submucosa; a total of 502 (34.4%) differentiated tumors and 958 (65.6%) undifferentiated tumors were present; the average number of examined lymph nodes (No. of ELNs) was 28.70 ± 11.5; there were 1189 (81.4%) node-negative (N0) cases and 271 (18.6%) node-positive (N1) cases; most of the patients received D2 lymph node dissection (75.1%); a total of 1145 cases (78.4%) did not have LNM/LVI, and 315 cases (21.6%) presented with LNM/LVI. In the 315 cases with LNM/LVI, LNM−/LVI+ accounted for 44 cases (14.0%), LNM+/LVI- accounted for 226 cases (71.7%), and LNM+/LVI+ accounted for 45 cases (14.3%) ; in patients without LNM, the 5-year CSS rate in the LVI- group was similar to the LVI+ group  . Female, a tumor greater than 2 cm, invasion of the submucosa and an undifferentiated tumor were more likely to present with LNM/LVI. No significant correlation was evident between age or tumor location and LNM/LVI. Multivariable analysis showed that sex , tumor size , depth of invasion  and tumor histological types  were independent predictors for LNM/LVI  low-risk patients , 278 (19%) intermediate-risk patients , 698 48%) high-risk patients  and 262 (18%) extremely high-risk patients . The incidences of LNM/LVI were 5.4, 12.6, 24.2 and 37.8% from low-risk to extremely high risk groups, respectively, with significant difference  . The model’s prediction of the incidence of LNM/LVI in the training set and validation set were not statistically different between the different risk groups  .Our study developed an LNM/LVI predictive model for EGC using four independent variables: sex, tumor size, depth of invasion and tumor histological types. The AUC in the training set and the validation set were 0.694 (95% CI: 0.659–0.730) and 0.796  respectively. The incidences of LNM/LVI for low- to extremely high-risk patients were 5.4, 12.6, 24.2 and 37.8%, respectively . In addition, we compared the differences in the incidence of LNM/LVI between men and women in different age groups. The results showed that the incidence of LNM/LVI was significantly lower in men < 60 years old than in women . While in patients ≥60 years old, the incidence of LNM/LVI in men was comparable to that of women  (Additional file Previous studies on the LNM of EGC mostly report that the tumor size, depth of invasion and tumor histological types have impacts on LNM , 24, 25.Based on LNM/LVI status, we further performed a RPA to reclassify the patients into different risk groups then proposed strategies for lymph node dissection according to the risk group Fig. . RPA is This study had several limitations. First, this was a retrospective study, and bias inevitably existed in the data selection. Second, the tumor size and the depth of invasion in this study were confirmed by postoperative pathology. Although obtaining relatively accurate preoperative data by endoscopy or endoscopic ultrasonography is possible, bias may exist when compared with the postoperative pathological diagnosis. Third, this study lacked subjective diagnostic information, such as the macroscopic types of EGC. Fourth, due to the lack of records of postoperative adjuvant therapy in the SYSUCC and IMIGASTRIC databases, we were unable to provide information about postoperative adjuvant therapy. However, to our knowledge, this study was the first to explore the effect of preoperative factors on potential LNM in patients with EGC using international multicenter data. An effective multivariable prediction model for LNM/LVI was established and validated, and the use of RPA made the model more clinically useful. Based on the findings of this study, we have proposed recommendations for lymph node dissection in EGC for different risk groups, which will be of benefit to surgeons in making better clinical decisions.In this study, by using PRA to divide EGC patients into different risk groups, we have found that the incidence of LNM/LVI in differentiated mucosal EGC is low, which indicated that ER is a treatment option. The incidences of LNM/LVI in undifferentiated mucosal EGC and submucosa EGC are high and gastrectomy with lymph node dissection is suggested.Additional file 1: Figure S1. The 5-year CSS rate of only LNM+ and only LVI+ groups in the training set. a. In the LVI- group, compared the 5-year CSS rate between LNM+ and LNM- group. b. In the LNM- group, compared the 5-year CSS rate between LVI+ and LVI- group.Additional file 2: Table S1. Uni- and multivariable analysis for LNM of EGC patients in the training set. Table S2. Clinicopathological characteristics of EGC patients in the training set and the validation set after 1:3 propensity matching. Table S3. Comparison of the incidences of LNM/LVI between different risk groups in the training set and validation set after a 1:3 matching. Table S4. Comparison of the incidences of LNM/LVI between age groups in male and female.