Maternal substance use and deaths due to overdoses are increasing nationwide. Evidence suggests that the rate of resumed substance use, and fatal and non-fatal overdose is greatest in the first year after birth, particularly around six months postpartum, compared to other parts of the perinatal period. Doula care has been linked to improvements in perinatal health and outcomes.In response to the opioid epidemic, the Philadelphia Department of Public Health developed and implemented the Doula Support Program (DSP), with a focus on one year of postpartum care for birthing people with a substance use disorder (SUD). In this paper, we describe the program and its formation and report on the early challenges and successes of the program implementation, based on information we received from program founders and managers in a group interview.Early successes of the program include partnering with local community-based programs to recruit and retain doulas, supplementing traditional doula education with perinatal SUD-specific trainings, and maximizing client referrals by collaborating with local organizations and treatment centers that serve birthing people with SUD. Client retention, however, has proven to be challenging, especially during the COVID-19 pandemic.The DSP continues to grow, and lessons learned will facilitate program improvements. The goal of this paper is to outline the development and launch of the DSP and to act as a model for other state and local health departments interested in providing doula care for birthing people with SUD.The online version contains supplementary material available at 10.1007/s10995-023-03803-4. Maternal substance use and fatal overdoses are increasing in Philadelphia, Pennsylvania. In response to this crisis, the Philadelphia Department of Public Health’s Division of Maternal, Child and Family Health developed the Doula Support Program (DSP), offering doula care to pregnant people with a current or past SUD history up to one-year postpartum. To our knowledge, this is the only doula program in Pennsylvania offering one-year postpartum support to birthing people affected by SUD.The online version contains supplementary material available at 10.1007/s10995-023-03803-4. Philadelphia is one of several epicenters of the nation’s opioid epidemic and has one of the highest overdose mortality rates compared to other large cities , which offers support for up to one-year postpartum.A doula is a trained professional who provides nonclinical services, including emotional, physical, and informational support during labor, delivery, and the postpartum period and who also promotes self-advocacy .System-level training .Interpersonal skills .Infant care .Community health experience, familiarity with the city landscape and the local perinatal SUD system, and attendance at a minimum of 10 births are requirements for becoming a DSP doula. Doulas in this program also must have experience with people who have SUD, but not necessarily in a professional capacity. This requirement ensures that doulas have the compassion and understanding required for the role. The DSP program initially relied on the Maternity Care Coalition to develop basic trainings, but began to supplement the training with additional topics as the program grew and doulas identified challenges they encountered in the field:“You have to know the  terms, interventions, the medications, not to offer advice about them, but to really just be literate in the room when things are happening. I knew that there was so much to learn about different hospital policies and there was not a roadmap for that, so that was definitely a big challenge.”Identifying and developing the program’s trainings, most notably the medical literacy and system level trainings, has been described as a particularly challenging, but necessary, aspect of program development. When describing the initial steps involved in setting up the program, one interviewee shared:“It’s often characterized as an individual’s flakiness or, you know, inconsistency. But I know from working with people living on the street and engaging in street economies and [who are] just really, in the depths of addiction, that engagement and services need to be incentivized. [People] need to be offered [something] beyond just ‘we have this service for you,’ because that’s not how the physiology of addiction and dependence on fentanyl works. It doesn’t matter how much somebody wants to participate in something, it’s just not that simple.” Although clients with SUD were more likely to be lost to follow-up, if clients with SUD remained in the program, they had a higher number of visits with their doula compared to clients without SUD. Even clients who resumed substance use, which typically occurred around three months postpartum, continued to engage with doula services. This demonstrates high engagement among clients with SUD.Although the DSP was designed with a focus on pregnant people with a past or current SUD, the program is open to all pregnant people in Philadelphia who desire doula care. Preliminary program data indicate that clients with SUD are more likely to be lost to follow-up than clients without SUD. Individuals with SUD may be lost to follow-up for many reasons, including logistical challenges such as relocation or restricted use of their phone depending on the rules of their housing, if applicable. During the group interview, one interviewee stated that difficulties with follow-up and client retention are often mischaracterized as an individual’s inattention, rather than as a manifestation of SUD:It is also important to acknowledge that the COVID-19 pandemic made client retention challenging.There is evidence to suggest that a doula can support and advocate for pregnant people with SUD and improve maternal health. The Philadelphia Department of Public Health DSP offers an expanded model of doula care for up to one-year postpartum. It is too early to determine the long-term impact of the DSP and its effect on pregnancy-associated deaths due to accidental overdose, sustained recovery from an SUD, and maternal health. However, our initial reflections of this program show it is promising in offering support to pregnant people with SUD. DSP clients who are not lost to follow-up are highly engaged in the program and receive multiple visits within the critical six-month postpartum period. No incidents of accidental overdose have been reported among the client population, and long-term engagement with the program has enabled doulas to support a client’s recovery when incidents of resumed substance use have occurred.Future research directions include analyzing program data to assess whether easing COVID-19 restrictions and resuming in-person visits has resulted in improved client retention. To understand and improve client engagement with the program, the perspectives of the DSP clients will continue to be sought. Future steps to assess the impact of the DSP include continued research on outcomes among clients with SUD and their infants. For example, authors of this paper will compare maternal and infant health outcomes between birthing people with SUD who engage in the DSP to birthing people with SUD who are not enrolled in the DSP.The goal of this paper has been to provide a description of the DSP and its formation, and to discuss early challenges and successes of program implementation. In doing so, we offer a model for other organizations serving pregnant people with SUD, with a particular focus on incorporating doula care.Supplementary file1 (DOCX 16 KB)Below is the link to the electronic supplementary material.


UniSA’s Invictus Pathways Program (IPP) is motivated by the spirit of the Invictus Games to mobilise the benefits of sport to aid physical, psychological, and social wellbeing. Originally developed to assist veterans to train for and participate in the Invictus Games, the program has extended its scope to promote recovery and wellbeing for all veterans through physical activity. This paper describes the expectations and experiences of the IPP from the perspective of program participants.Objective measures of physical and psychological wellbeing were collected by survey, to enable description of the participating veterans’ wellbeing status. Semi-structured interviews were conducted with 15 participants of the IPP who had not participated in an Invictus Games or Warrior Games. Reflexive thematic analysis was used to analyse the interview data. Coding and themes were developed through a mixture of inductive and deductive approaches to analysis. Initial themes related to previous life experience, expectations of participation, and outcomes of participation were preconceived, but the analysis provided scope for an inductive approach to formulate additional themes.Five of the participants had very high K10 scores, and scores above the norm for PCL-C, whilst one would be classified with an alcohol disorder. The qualitative analysis identified five higher order themes: Life experiences prior to participation in the IPP, Making a choice to participate in the IPP, Expectations of participation in the IPP, Impact of participation in the IPP, and Future Plans. There were perceptions that the IPP was beneficial for the participating veterans, irrespective of their physical and psychological health status. Participants described the positive impact of the IPP on their physical fitness, their social engagement, and their sense of belonging within the IPP and the university. Participants perceived the IPP to be an opportunity for them to ‘give back’ by contributing to the education of the students delivering the IPP. Participants reported the intention to continue being physically active. For some, this meant selection in an Invictus Games team, for others, this meant getting involved in community sporting organisations.The Invictus Pathways Program has been shown to have a positive impact on the physical and psychological wellbeing of the veterans who participated in its initial stages. As the program evolves, the longitudinal impact of participation, for veterans and their families, will be assessed. It is estimated that over 581,000 Australians have served or are currently serving in the Australian Defence Force (ADF) . The incWhile many injuries can be successfully treated, some health conditions and injuries are too debilitating for military personnel to continue with their service, and they are forced to leave the service. Approximately 5000 military personnel transition out of the ADF each year with just over one fifth of those being discharged on medical grounds . The traMental health conditions, specifically Post-Traumatic Stress Disorder (PTSD), depressive disorders, and anxiety disorders, as well as alcohol dependence and abuse are the most common health conditions affecting veterans . FindingDeveloped in 2017, through a collaboration between the University of South Australia (UniSA) and The Road Home , UniSA’s Invictus Pathways Program (IPP) is motivated by the spirit of the Invictus Games to mobilise the benefits of physical activity and sport to aid physical, psychological, and social wellbeing. Originally developed to assist veterans to train for and participate in the Invictus Games, the program has extended its scope to promote recovery and wellbeing for all veterans through physical activity. There are two arms to the program, an exercise and performance program and a community adaptive sports program. Fundamental to the IPP is the provision of ongoing interdisciplinary allied health services  to recovering military personnel and veterans. University students completing their placements within these allied health services work collaboratively with participating veterans to improve their wellbeing, providing one-on-one support and individually tailored programs.A detailed explanation of the specific activities included in the individually tailored training is provided in the paper reporting the process evaluation of the IPP . BrieflyA student trainer is assigned to each participant and works with that participant for the duration of the student’s 12-month placement. Participants are assigned a second student for the duration of their second year in IPP. One-on-one exercise training, using exercise equipment such as hydraulic weight machines, cardio equipment, and free weights, is provided by the student to the participant at UniSA’s exercise physiology clinic and gymnasium facilities, with the regularity of session delivery dependent on the needs of the participant and the student’s availability. Student trainers develop an individualised training program for the participant under the supervision of an AES/AEP member of the IPP staff. Training programs are reviewed every six weeks by the student trainer in collaboration with IPP staff. The student trainer then schedules regular training sessions with the participant, with sessions supervised by IPP staff.Analysis of the IPP will be longitudinal, with the impact of engagement in the program on physical, psychological, social, and emotional factors to be assessed six-monthly across the duration of a participant’s involvement. This paper describes the expectations and experiences of the IPP from the perspective of a sub-set of program participants.This research applied a pragmatist approach, which emphasises communication and shared meaning, leading to the development of practical solutions to problems . PragmatParticipants in this study are a sub-set of participants involved in the IPP. We chose to include only the data of IPP participants who were yet to have participated in competitive activities such as the Invictus Games or Warrior Games. The rationale for this approach was to avoid the potential influence of involvement in these activities on participants’ perceptions of their experiences in the IPP.IPP assessment and survey forms were obtained through data linkage following written informed consent from participants. Information collected from all participants in the IPP at baseline included background detail on the participants  as well as the completion of standard mental health and wellbeing surveys. These included scales used by the Australian Defence Force to assess mental health  ; PosttraThe K-10, a ten-item inventory to assess generalised psychological distress, has good psychometric properties within civilian and military populations with a reported Cronbach alpha of 0.88 . ResponsThe PCL is a standardised psychometric tool used to measure post-traumatic stress symptoms. The PCL consists of 17 questions which are scored from 1 to 5, with scores ranging from 17 to 85. It has excellent test-retest reliability (0.96) and good internal reliability (>0.82) . The PTSThe AUDIT is a screening tool to assess alcohol consumption and risky patterns of drinking . QuestioThe WHOQOL-BREF is a shortened, 26-item version of the original 100 item WHOQOL , which aThe short form-36 is a widely used quality of life measure assessing eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/vitality, and general health perceptions . These eSemi-structured interviews were conducted in person [SF]by a female PhD Candidate experienced in qualitative data collection at [location removed for peer review] and audio recorded. An interview guide was developed see  and piloPrior to each interview, participants were briefed about the aims of the research and provided with the Participant Information and Consent Form (PICF). Written informed consent was obtained. Participants received a copy of the PICF and a copy of the Guidelines for Volunteers to keep. Every effort was made to minimise potential discomfort to the participants. Interviews were conducted next to the university’s health service, so that immediate access to a General Practitioner could be provided in the event that a participant required additional support. Electronic data were stored on a password protected university network drive and accessible only by the researchers.This research was approved by the Department of Defence and Veterans’ Affairs Human Research Ethics Committee  and the University of South Australia’s Human Research Ethics Committee .Reflexivity, the process of examining one’s own role in shaping the study, was employed by all members of the research team as they undertook interview data collection and analysis of the interviews. A conscious effort was made to examine and explicitly acknowledge any aspects of personal background, culture, and experiences which might shape the study and the direction in which it was progressing . FurtherSurvey data were entered into data management files, checked for accuracy and completeness, and are reported as means and standard deviations. Interview data were analysed using thematic analysis . FollowiFifteen participants  consented to the release of their IPP data. The majority (n = 11) were between the ages of 40–49 years , 11 were married or had a de facto partner (1 was never married and 4 were divorced), 13 were medically discharged (2 declined to answer), and 7 were in full-time work with 5 unable to work, and 1 retired. All three services were represented: Airforce (n = 4), Navy (n = 6), Army (n = 4), with one participant not responding to the question. Participants had varied formal education: 1 had a master’s degree, 3 had a post-graduate diploma, 1 had a bachelor degree, 3 had vocational training (outside of their service), 3 graduated Year 12, and 4 left school before completing Year 12.The mean scores and standard deviations for the surveys completed by the participants at baseline are provided in Five of the participants had very high K10 scores (>30), and scores above the norm for PCL-C, whilst one would be classified with an alcohol disorder (scores over 8), with no participants scoring above 20 . Similarly, five had PCS and MCS (composite scores from the VR-36) that were below population norms . HoweverLife experiences prior to participation in the IPP , Making a choice to participate in the IPP , Expectations of participation in the IPP , Impact of participation in the IPP , and Future Plans .Interviews were undertaken with all 15 veterans, between August 2018 and April 2020. None had previously participated in either the Invictus Games or the Warrior Games. Findings from the interviews indicated that few veterans had expectations upon joining the IPP and had mostly positive experiences as a result of participating in the IPP. The key themes identified through analysis included: In order to be able to fully explore veterans’ perceptions of the impact of their participation in the IPP, it is important to firstly understand what their life was like before they joined the program, and how these prior experiences may have influenced their reluctance or enthusiasm to be involved in IPP, their expectations about IPP and its potential impact on their lives. This includes understanding veterans’ prior engagement in sport, their mental and psychological wellbeing, and their experiences prior to joining the IPP.While all participants reported being physically active when they were younger, and some at state and national representative levels, most stated that their physical activity had greatly decreased or had ceased completely due to physical and/or mental health issues, the majority of which were associated with their service. Despite many military service roles being physical in nature, engagement in physical activity as part of their service was not raised by participants, although this specific aspect was not necessarily viewed as important by the researchers with respect to it being a driver of participation in the IPP. Veterans who were engaged in physical activity immediately prior to joining IPP reported going to the gym, swimming, jogging, running half-marathons, and social cycling, with one stating that doing so was ‘more for mental health’ reasons (P3). A few of the participants acknowledged the link between them being physically active and the role this played in their mental wellbeing:I knew that sport made me feel better about myself . . .I just know that the sport and training helps me to focus away from that [distractive thought pattern] and, in a sense, channel my focus . . .towards just, it’s building myself up. (P5)My PTSD goes back to 2005 . . .and so I’m a master avoider of things, and the way that I’ve been able to suppress and avoid it is through my physical activity. By setting goals, pushing myself too hard, which probably contributed to the downfall, but the physical aspect of things is a huge part of keeping me stable. (P15)Participants detailed a range of health issues and negative physical and psychological experiences prior to joining the IPP. All participants lived with physical and/or mental health issues. Participants stated that they were ‘isolated’, ‘just in survival mode, each and every day, trying to push through’ (P2); or felt ‘lethargic’, ‘miserable’ and not motivated to ‘get up and do anything really’ (P7). For others, there were reports of previous suicidal ideation and self-harm:I was extremely suicidal. And that was a horrible place to be in. (P6)I’ve had a relapse of depression, major depression. I’ve had thoughts of killing myself and things like that. I have anxiety. (P8). . .my mental health is a little bit different. I do have a lot of ‘poor me’ days, and I really struggle. (P13)Multiple participants spoke about negative experiences while, or just after, they transitioned out of the Defence Force. Some explained how they felt that their career was ‘cut short’ due to health issues and being medically discharged, with no support offered. For others, their health deteriorated further after discharge:When they offered me a medical discharge, I just took it not knowing what was gonna happen. Back then things were very different. I was walked to the main gate of [location] and I was given a cheque for $2000 and wished good luck. And that was it. There was no rehabilitation. There was no assistance with getting another job or anything like that. It was just out on the street. (P2)[I] . . .discharged in 2007, probably not in a very good mental health state and certainly not in a good physical state either. My physical health deteriorated quite a lot over probably a six or a seven-year period and of course my mental health as well. (P3)Some veterans spoke of their struggle to fit into society post-transition from Defence. For some, this was attributed to the loss of structure that came with the military lifestyle, while for others, there was a sense of being on a ‘different planet’ to the people they were socialising with:. . .it was very difficult getting out of the Defence Force after being in for so long because you become indoctrinated and you know what’s gonna happen, when it’s gonna happen, where it’s gonna happen, where you have to be. Everything is structured. And to go from that through a door that you have no control over anything anymore. You don’t know what’s coming up. (P1)But socially I’d try to fit into groups myself and they were just on, different concerns, on a different planet, so to speak. It’s them that’s on different planet, not me. So they were all more worried about, you know, what they were gonna wear and their hair and all these things and, you know, what they’d look like to other people whereas me, it’s very different. (P6)I find that I have a lot of trouble still in civilian life, talking to people at sporting clubs and that sort of thing, because I’ve got a very different mindset and structure to the way I live life. (P14)The right time to join the IPP? Perceptions about when it was the right time to join the IPP and some of the factors associated with making a choice to participate were varied among the veterans interviewed. Many thought that this type of program was ideal for anyone transitioning out of Defence, particularly those with physical and mental injuries; however, the need to engage people in the program early, for example before they left Defence or before their health deteriorated further, was raised. For others, there was a perception that veterans need to be motivated to get involved:. . .when someone is introduced to the program, it’s because either someone has pushed, directed them in that direction or that pathway, as myself telling another veteran to go and do this because what it’s done for me . . .[or] someone’s gone to [IPP staff member] and saying: “Can you help this person?”. (P4)You’re going to get the person that’s going to walk straight up and say, ’I’d like to do this program.’ And you’re also going to get probably some–what happened to me, like you need someone to just go, ’Look, here. Sign this. Do this.’ And then because I can only talk army, generally once a military person is committed to something they will do it. Once they’re in, they’ll turn up. (P13)Some participants spoke of lacking confidence when it came to joining the IPP, partly attributed to a fear of failure or not meeting people’s expectations of them. For others, hesitation was driven by a resistance to change or uncertainty and unease about what the program was about:… physical fitness and wellness is a long-term objective that has been out of my life for more than 15 years and I’m frightened of failure. (P6)Others spoke about wanting to be involved in something as a driver of their participation or feeling like they had exhausted opportunities to support their wellbeing and that being in the IPP was worth trying:Look, it’s taken me a lot to come out of my shell and I think it depends on how you are mentally focused, if you are or not. So, for me it was like I have to get it; I have to do something; I have to get involved with something. (P10)I was at a point where I thought there was nothing I could do, so I thought what the hell, I’ll give it [IPP] a try. (P7)Most veterans reported being unsure of what to expect or that they did not have any expectations about their involvement in the IPP. In part, this was attributed to a perception of lack of communication about the IPP’s purpose and components. For others, expectations were intentionally kept low in order to avoid disappointment, and for one veteran, the program was simply just something to do:Look, before I joined, I didn’t really have any expectations because I’d been in a place where, you know, I just really wasn’t really feeling much at all. So, when I came to the program I went ‘you know what, I’m gonna go into it with a clear head. If it works, it works. If not, at least I’ve tried something’. (P7)So, I think having no expectations was best way to approach it because… you’re not gonna be disappointed and you’ve got everything to gain (P1).I really came in with zero expectations. It was for me personally, it’s just something to do at the moment. And I know that sounds really horrible, but it’s something to do. (P13)For those who did have expectations, most were related to enhancing their recovery, improving fitness, and losing weight, with others hoping to increase their social engagement or take the opportunity to be part of a team again. Selection for the team to represent Australia at the Invictus Games, as a result of improved fitness, also appeared to be an expectation of participation in the IPP:My expectations were to hopefully improve my physical condition . . .and improve my mental illness as well. So, if I really improved my activity and mobility and my body wouldn’t be as sore and then I’d be a bit happier. (P9)Well, my expectations are that I will increase my level of physical fitness which will take some of the stress off my body and allow me take on more mentally taxing tasks.And as a side-effect of increasing my physical fitness, I hope I will lose a little bit of weight and therefore improve my self-image. (P11). . .I hoped I was actually in a Program where I was doing things physically all the time and actually improving my fitness would give me a better chance of selection [for the Invictus Games].’ (P3)According to all IPP participants who were interviewed, taking part in the program had a positive impact on their wellbeing. Some spoke about the positive outcome in general terms, while others discussed its physical, psychological, and social impact, including how these three aspects interacted. Veterans perceived that taking part in the IPP improved multiple aspects of their lives, and for some, there was an influence on family too:Probably, I would say probably since getting really hooked into the Pathways Program, I think it (life) has probably improved significantly… I’ve got so much out of the program . . .I can’t really begin to say how much I got out of the Program. (P3)I feel stronger and fitter. I feel healthier. Yeah, I feel like I want to help myself. I feel that’s one of the main things. Because it’s making me ‐ it’s encouraging me to help myself . . . I was depressed, frustrated, social anxiety as well. And now I come out and I talk to people and it’s pretty good actually. It’s been so good for me. (P8)I went from being a survivor to starting living again which was really, really good. (P2)We are doing more outside that we wouldn’t have previously, prior to the program. For instance, we quite often go for bike rides out through [place], as a family, so that’s helped us get out and about. That’s something we wouldn’t have done prior to the program. (P12)Taking part in the IPP was reported to have a large impact on veterans’ physical wellbeing. For some veterans, this impact included learning new skills that enabled improvements to their fitness and strength and being able to get more out of their body, although some acknowledged that they were not at the level they had been previously:. . .when I’m doing that sport, I can focus on what I’d been taught . . .it’s amazing when you do something by yourself and you haven’t been taught, and you get it to a certain level and then you, you’re brought up to a new level by instruction, how much more you can get out of it and how much more you can continually surprise yourself just through that whole repetition and building on it… (P5)There’s certainly been an improvement to, you know, a year ago to now on, you know, my ability to be able to do the sports and stuff like that, but like I said, I’m still not quite back to where I was, but, you know, I’m certainly trending towards that direction, I guess. (P3)Further physical impacts of participation noted by veterans included weight loss, increased muscle mass, and in some cases these physical changes were associated with perceptions of a reduction in pain. Most participants commented on becoming fitter, faster, and stronger due to taking part in the IPP. They also appreciated being able to get a personalised and tailored exercise program based on their existing injuries and health conditions:I started the Invictus Pathways Program and started doing the exercises and started doing the riding, I actually gained 4 kilos of muscle mass and lost 4 kilos of body fat. We even, when they measured the fat around your body parts, they measured that I reduced in everything, so that was really quite good. (P2)I still have knee pain, however due to losing weight through this program, the knee pain is not as bad as it used to be . . .And just the knowledge that this was all being written down so that they can tailor a program to my specific needs not to a generic person’s needs. (P7). . .for me personally, it’s had better results in the last 12 months [in IPP] than it has five years of doing rehabilitation through the military . . . I’m healthier. It’s amazing. My injuries haven’t got worse. I don’t think I’ve been to the doctor in the last two years for pain medication whereas I used to be on heavy stuff, like Tramadol, Endo and all those painkillers. (P4)A majority of participants described experiencing improvement in their mental health due to taking part in the IPP, while acknowledging that IPP was not a ‘cure-all’. Veterans highlighted that while they still struggled at times, they either felt more positive overall, or that training in the IPP helped them manage when they were feeling down:. . .yeah, it’s just, it’s helped so much. You know . . .I still have crappy days like everyone does, but it’s definitely, it’s not like a week of feeling down . . .it could be like a couple of hours or a day at most where I might feel like I’m sliding into a hole and then, you know, the next day I’m back at the gym and just releasing all that negativity and, you know, set myself more goals to just keep going. (P7)I think definitely being part of something structured, like the Pathways Program, where I actually look forward to going, not just for the fitness side or my just wellbeing, but for my mental health . . .(P3)I still have nightmares. I drink shit loads of alcohol just to sleep at the night-time. I probably take too many drugs to sleep at the night-time. I find myself waking up lathered in sweat. But having started this Program, it’s allowed me to force myself to come back in to a… I call it the edge of society. (P1)Improvements in veterans’ confidence, their general outlook, mindset, and motivation were also reported, with veterans discussing having goals and something to focus on when they feel like they were struggling:Oh, it’s probably made me a bit more confident again . . .I discharged from [service] . . .I wasn’t in a very positive frame of mind at all. I was probably quite frustrated, disappointed with how I discharged. My career was cut, you know, shorter than what I would have liked . . .so it has given me a chance to rebuild that confidence…(P3)And I loved it from the very first session, you know. I felt a change in me, in my mindset I guess, from the very first time I walked into the gym with my trainer. (P7)Even though now I’m struggling at the moment, I know that in a few months’ time I will be back up in that happy place. Cause if I didn’t have that, I wouldn’t know what I would be doing in three months’ time. So I’ve got goals for a change. I didn’t have those before. (P2)For all veterans who were interviewed, getting involved in the IPP increased their social engagement. Many stated that they had been completely on their own and had avoided any type of socialisation, until they joined the IPP. Being part of the program provided them with “mateship” (P7), and being part of a team again, which they found very beneficial. This extended to being and feeling part of a community again:From being on my own for so long and being in a dark place for a long time, it was nice to step forward and sort of become part of a team, you know. It’s like when you’re in the military, you not only rely on other people to help, but you’re helping other people. So it’s all, it’s a family. It’s a community. It’s the social side of it . . . (P2). . .that actual feeling of community, being part of something again. I think for me that’s been the most positive. I mean obviously, doing the sport and all that sort of stuff is fantastic, but to you know, it wouldn’t be as nice if you come here and no one spoke to you or, you know, you came in and just did your gym work and get out sort of stuff. I mean you don’t feel that way here. (P3). . .I probably didn’t think that, from a relationship or friendship [aspect], the non-physical aspect of the program would be as good as it turned out to be and how much it supported me. (P15)I think the socialisation and integration are the most important bits. Because generally most military people will do the physical stuff . . . you’re creating an environment where there’s a big bunch of people, you’re getting people out. (P13)Beyond the physical, psychological, and social impacts, some veterans reported feeling that they had also learned a lot about exercise, injuries, and the need for recovery as a result of participating in the IPP. Beyond this, one veteran described how they also felt that they learned a lot about themselves:. . .if I walked away from here, I’d feel like I’ve learnt so much. (P4)I think this first part of the journey, I’ve really kind of worked out what, I’ve learned a lot about myself. (P3)The role of IPP staff and students was suggested by veterans to be vital to their success in the program and veterans spoke of a feeling of being respected. Veterans commented on staff and students’ dedication to the program, that they appreciated them attending sporting events for veterans to offer support, even though this is not part of their work and study requirements:. . .we had a whole team of volunteers out there [at event] . . .looking after us and that was just incredible. I mean, the morning after the event, we were all standing around, talking and thanking everybody that was there and a lot of us veterans were, you know, almost in tears because we couldn’t believe the amount of support we were getting from other people. It was really nice. (P2)They [staff and students] showed us the respect we hadn’t been shown by other people. And we work with them. We’re working together with the staff here at UniSA. That was really impressive. Like I said, I was blown away by the way we were looked after and we have, we still continue to be looked after. (P4)And this might sound condescending, but I don’t think the kids–yeah, they are for me–I don’t think they actually quite get it. I think they understand these guys have got mental health stuff and you’re going to learn a bit, but I don’t actually think how much they give to us–I get how they understand what we’ll give to them. With the training and the chats and everything. But I don’t think they understand what they give to us. (P13)Veterans reported that they appreciated the opportunity to give back to the students by supporting their education, through participation in the practical aspects of the IPP and by providing feedback related to the skill development of students. Others offered to champion the IPP or contribute their own experience, skills, and knowledge to the program:And to see some of them coming out of their shells, it’s a win-win situation. So, I’ve gained a lot out of this through seeing them develop… it’s like what you guys give to me, I wanna give back . . .It’s our duty to give back to those who have given to us. (P4)Like I told them, I said it’s a learning thing for both of us . . .I really want them to learn . . .by all means, I’m happy to be their test dummy. It benefits them for their future as well. And that’s sort of why I joined up with the program, is to really help those guys and girls out and get as much out of it. (P10)As one of the main aims of the IPP is rehabilitation and reintegration, including supporting veterans to get involved in sport and join clubs, it is useful to understand veterans’ plans for their immediate future in the IPP, and ultimately, when they transition out of the IPP.Veterans described how they intended to use their time in the program to improve their fitness and to continue with physical activity generally. For those with injuries, their focus was on recovery first and then a return to training in the IPP:And that’s the goal now, just to recover from the injury . . .[the] type of injury that I’ve got now is one that’s very difficult to recover from, so I just gotta get my head around it and slow right down and take one day at a time. (P2)Other veterans spoke about the opportunity to be involved in either the Invictus Games, Masters Games, or the Warrior Games, the need to be adept at multiple sports to increase their chances of selection, and how this influenced their approach to ongoing involvement in the IPP:I’d love to be selected in the team and go overseas and represent; absolutely definitely. (P11)This is it; I kept my eye on Invictus trials. If I’m going to go to Invictus trials and I’m mad keen to get to Invictus trials I have to get back in the pool ‘cause I’m going. (P13)Going to Hague and we’ll have a team of maybe 35, so I’m gonna need to be able to do multiple sports to get selected for that. (P7)For veterans who had already become involved in sports and organisations external to the IPP, there were plans to continue with that engagement. For others, there were longer term plans associated with getting involved in new physical activity opportunities including cycling, wheelchair basketball, wheelchair rugby, athletics, triathlon, and rowing. Some veterans enjoyed competing, while others were more interested in the social aspects of team sports. For some, the potential for long-term impact was also mentioned:. . .so in summer I’m going to make myself known to the [name] Athletics Club and try and become a Master [level of athlete]. See how we go with that. [P13]. . .you know, if I happen to be one of those 60-year-old fit blokes on a bike, then I’m really happy to be that. (P5)For some participants, their involvement in IPP had assisted them in setting goals for their future that extended beyond the program, to include marching in an ANZAC Day parade, and a return to study:My life goals are to be able to march in next year’s ANZAC Day Parade. I wasn’t able to march in this year’s ANZAC Day Parade because I don’t have the stamina to march three kilometres, so I had to sit in a wheelchair while somebody . . .pushed me along. (P11)My goal, actually, the year after, is to study at UniSA in the health sciences area. And that’s purely because of my engagement with UniSA . . .And so just the relationships I’ve built at the uni makes me feel safe about going there, and that’s a huge thing. (P15)The purpose of this study was to examine the perceptions of the veterans who participated in the IPP with respect to the impact of the IPP on their physical and psychological wellbeing. To assist contextualisation of these perceptions, we also sought to understand the life circumstances of veterans prior to commencing with IPP and their expectations of participation in the program.The survey data collected prior to the interviews provided an overview of the population and indicated that the majority of veterans had high levels of psychological distress. This was reflected in the interviews, where veterans described the ongoing impact of their service on their physical and mental health. Some veterans described negative experiences transitioning from the military and into civilian society, with survey data supporting that for some participants, engaging in social relationships and occasions was difficult.The qualitative findings suggest that the impact of the IPP on physical, psychological, and social factors was positive for all interviewed participants, irrespective of whether their survey responses indicated that they had low or very high levels of psychological distress. How this perceived impact translates to objective measures of psychological distress remains to be seen and is the subject of the ongoing evaluation of the IPP for subsequent cohorts of participants.Interdisciplinary programs of this nature, that include allied health services such as physiotherapy, podiatry, occupational therapy, and exercise physiology, and specifically those that are student-led or that involve students in physical training or reablement, do not exist in Australia nor internationally. Two other Australian universities offer a mono-disciplinary (exercise physiology) supported program (based upon IPP) to veterans and student veterans, and information about the impact associated with participation in these programs is yet to be published. Irrespective of this, there is growing evidence for the benefit of exercise for PTSD and other mental health conditions generally in the veteran community. Beyond the potential for positive impact on mental health, involvement in physical activity has been shown to increase social engagement. Additionally, social relationships and particularly the influence of family, have been demonstrated to be key for initiation of engagement in adapted physical activity for people living with disability .For the veterans who participated in the current study, there were perceptions that programs such as the IPP would be ideal for anyone who had been injured during service or was transitioning out of Defence, and further, that this particular program should be introduced prior to veterans leaving the Defence force. The timing of engagement agrees in part with other work that suggests transitioning members should be notified of the availability of a support program during the period between their notification of release from service and their actual release . The samBeyond concepts related to the most appropriate time to join this type of program, some veterans in the current study perceived that veterans need to have a sense of self- motivation to be involved in a program of this nature, irrespective of the point at which they engaged in a program. One veteran mentioned that due to the ‘type’ of people in the military, once they committed to something, they ‘stuck it out’. Research related to predictors of engagement of veterans in ‘bespoke recovery pathways’ found that ‘feelings of failure or inadequacy’, associated with self-perceived competence, was a predictor of engagement, as was perceived social support . FurtherThe positive impact of physical activity for participants and engagement in the social aspects of the program were identified as being beneficial for the veterans’ psychological wellbeing. For some, a sense of ‘belonging’ was articulated as a positive impact of participation in IPP. In some respects, the IPP environment may reflect that of the military environment which can contribute to a sense of familiarity, belonging or being part of ‘something’ again . BelongiBeing able to ‘give back’ to the students and the program, by contributing to the students’ learning, was identified as a driver of participation in IPP by some of the veterans interviewed. The perception of service and continuing to serve to ‘ . . .give back to the community, and to make a difference in the lives of others’  has beenVeterans in this study perceived that they were fitter and stronger and for some, there was an increased sense of knowledge about physical activity and how their own physical composition was impacted by activity. Being physically trained by students, who have more time to spend with the veterans during their time at IPP than what might occur in standard healthcare settings, may lead to the sharing of more health-related information over that time. This in turn may contribute to increased knowledge for the participant. Similar concepts have been identified in peer-led programs involving veterans, whereby engagement in health-related programs that provide time and consider the veteran’s goals and health more holistically may lead to greater engagement of veterans in their own health and care .In the current study, some of the veterans described seeking, or intending to seek, opportunities to engage with sporting organisations outside of the IPP; this is an intended outcome of participation in the IPP. Research examining the involvement of veterans in parasports identified a number of pathways, and phases within these pathways, that facilitated ongoing physical activity for veterans living with a disability . These pOne pathway in the IPP is to support veterans to train for the Invictus Games. While none of the veterans interviewed had competed in the Invictus Games at the time of interview, members of the IPP qualified for the Australian team in 2018 and 2020. Recent research suggests that participation in the Invictus Games supports rehabilitation and physical activity engagement but calls for additional research . The expThere are limitations with this study, some of which relate to program-specific factors. In its initial format, the IPP was not intended to be a holistic approach to wellbeing, instead focusing on physical activity and engagement, and where desired, a pathway for participation in the Invictus Games. Frameworks that incorporated the ongoing collection of data about factors related to mental wellbeing and other behavioural factors were not in place and as a result, we are unable to report objective mental wellbeing outcomes for this population. This does, however, indicate the need for the development and implementation of process, impact, and outcome evaluation frameworks that will support the ongoing activities of IPP.The Invictus Pathways Program has been shown to have a positive impact on the physical and psychological wellbeing of the veterans who participated in its initial stages. Impacts have extended to re-engagement in community adaptive sports, as well as providing veterans with a sense of belonging and the capacity to continue to serve the community through supporting student learning. As the program evolves, the longitudinal impact of participation, for veterans and their families, will be assessed.S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.


Ergosterol is an important sterol commonly found in edible mushrooms, and it has important nutritional value and pharmacological activity. Ergosterol is a provitamin. It has been well established that edible mushrooms are an excellent food source of vitamin D2 because ergosterol is a precursor that is converted to vitamin D2 under ultraviolet radiation. The pharmacological effects of ergosterol, which include antimicrobial, antioxidant, antimicrobial, anticancer, antidiabetic, anti-neurodegenerative, and other activities, have also been reported. This review aims to provide an overview of the available evidence regarding the pharmacological effects of ergosterol and its underlying mechanisms of action. Their potential benefits and applications are also discussed. Natural bioactive compounds are widely used as complementary medicines, including in dietary supplements. Their potential applications have been investigated for several decades. Researchers have identified novel biomolecules with desirable pharmacological properties from natural products, optimized their efficacy and safety using medicinal chemistry and pharmaceutical science, and developed them into pharmaceutical or nutraceutical products for the treatment or prevention of several diseases. Most natural compounds have been isolated from edible sources or used in traditional medicines worldwide for many years; therefore, they are supposed to be relatively safe.Edible mushrooms are rich in proteins, dietary fiber, vitamins, minerals, and many bioactive substances such as polysaccharides, terpenoids, polyphenols, alkaloids, lactones, and sterols ,2. The mThis review is aimed at outlining an overview of the available evidence proving the pharmacological effects of ergosterol and its underlying mechanisms of action. Its potential benefits and therapeutic applications are also discussed. The information inside this review is based on the scientific literature searched and retrieved from the PubMed and Google Scholar databases.Ergosterol, or ergosta-5,7,22-trien-3β-ol, is the most abundant sterol in the cell membrane of fungi, including edible mushrooms. It maintains fungal cell membrane integrity, similar to cholesterol in animal cell membranes . This coErgosterol is found in various sources but is abundant in fungi, particularly mushrooms . Ergostemax) was 2.27 ± 0.19 µg/mL, and the time to Cmax was 8.00 ± 1.18 h. Approximately 62.5% of the administered ergosterol was excreted in feces, whereas 3.2% of the ergosterol was eliminated in urine.The pharmacokinetic characteristics of ergosterol were determined using a rat model . In the max and because of the poor aqueous solubility of ergosterol. However, the bioavailability and effectiveness of ergosterol can be further enhanced using a special drug delivery system. Interestingly, one study demonstrated that the use of nanostructured lipid carriers (NLCs) can improve the solubility and bioavailability of ergosterol. A pharmacodynamic study has also confirmed that the inhibitory effects of ergosterol-loaded NLCs on high-glucose-stimulated mesangial cell proliferation and extracellular matrix (ECM) accumulation were stronger than those of raw ergosterol [The oral bioavailability of ergosterol is not known because the intravenous injection of ergosterol has not been carried out in a pharmacokinetic study for the calculation of bioavailability. However, the oral bioavailability is expected to be low, as reflected from the long amount of time required for achieving Cgosterol . Similargosterol .o/w ≤ 5. Additionally, ergosterol did not cause hepatotoxicity or skin allergy, and its predicted median lethal dose in rats was 2.05 mol/kg [The drug-likeness and toxicity of several bioactive compound from mushrooms, including ergosterol, were previously assessed using an in silico approach by Rangsinth et al. . Accordi5 mol/kg . Moreove•−), hydroxyl (OH•), nitric oxide (NO•), and nitrogen dioxide (NO2•) radicals are byproducts of biological metabolism [The imbalance between the generation and removal of free radicals leads to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which play crucial roles in oxidative stress, and hence, the aging process . ROS andtabolism . Excessitabolism ,43.2O2), thereby inhibiting lipid peroxidation and reducing the intracellular ROS level [Auricularia polytricha mushroom extract showed antioxidant defense against oxidative-stress-induced neurotoxicity by up-regulating mRNA expression of several antioxidant enzymes [The outcome and mechanism of the antioxidant effect of ergosterol are summarized in OS level . ErgosteOS level . Recentl enzymes .Inflammation is a biological reaction that occurs when body parts are exposed to harmful or irritating stimuli. Various cytokines are generated at inflammatory sites as mediators that remove damaged cells, pathogens, or harmful stimuli. Therefore, the initiation of the healing process is important. However, exaggerated and uncontrolled inflammation is a key characteristic and risk factor related to the pathogenesis of many diseases, including atherosclerosis, obesity, metabolic syndrome, diabetes, cancer, and neurodegenerative disorders .Sarcodon aspratus, exerts anti-inflammatory responses in RAW264.7 macrophages by downregulating the expression of low-density lipoprotein receptors and suppressing STAT1-mediated inflammatory responses in HT29 cells [Ergosterol-containing mushrooms suppress the expression of inflammatory mediators through several signaling pathways. One such pathway is the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which is involved in cell division, cell death, tumor formation, immunomodulation, and inflammation. Ergosterol interferes with the expression of JAK3/STAT3 genes in cigarette-smoke-induced chronic obstructive pulmonary disease (COPD) in ICR mice. As a result, ergosterol effectively ameliorates COPD severity by inhibiting the pro-inflammatory cytokines . Similar29 cells . In addi29 cells . Ergoste29 cells . Molecul29 cells .Cordyceps militaris exerts neuroprotective effects by attenuating LPS-activated NO production in BV2 microglial cells [Moreover, ergosterol and its derivatives inhibit 5-lipooxygenase (5-LOX) activity, thereby reducing the inflammatory response ,55. Ergoal cells . Ergosteal cells . Anotheral cells .Penicillium candidum which contained ergosterol and dihydroergosterol exhibited an anti-neuroinflammatory effect on LPS-treated microglial cells, that was induced by reducing the expression of TNF-α and interferon (IFN)-γ, suggesting its potential in delaying the onset of dementia [Ergosterol and its metabolites, ergosterol peroxide and dihydroergosterol, suppress LPS-induced TNF-α release and interleukin (IL)-1α/β expression in RAW 264.7 macrophage cell lines ,50,60. Edementia . Moreovedementia .Ergosterol exerts its anti-neuroinflammatory activity via the TLR4/NF-κB-dependent pathway. Therefore, exploring the potential for developing ergosterol into a novel drug for the treatment of Alzheimer’s disease is viable . It has Hericium erinaceus, a medicinal mushroom which contains ergosterol, can cause a significant decrease in the MDA, NO, MPO, NF-κB, IL-6, and TNF-α levels in trinitrobenzene sulfonic acid-induced colitis in mice [Grifola frondosa and pure ergosterol inhibit histamine release in air pouch-type allergic inflammation and reduce vascular permeability and edema in mice [Grifola frondosa and its ergosterol also prevent pollen-allergy-induced ocular itching in mice by suppressing leukotriene B4 production in mast cells [Ergosterol attenuates the symptoms of dextran sulfate sodium-induced colitis in mice, as indicated by the disease activity index, which is reflected in weight loss, severity of diarrhea, and shortening of the colon . The eff in mice . Additio in mice ,25. More in mice . Similar in mice ,25. The st cells .Although the overall survival rate of cancer patients has increased, cancer remains one of the most common causes of morbidity, mortality, and economic burden. Advanced stage cancer and lethal malignancies may not be completely eradicated by current clinical interventions, such as surgery, radiotherapy, chemotherapy, and targeted therapy. The potent anticancer activities of some natural compounds from terrestrial and marine sources have been identified. Paclitaxel, which is isolated from the Pacific yew, is one of the best examples of a natural compound that has been successfully used in clinical practice . Other eGanoderma lucidum, which are rich in ergosterol derivatives, exhibited cytotoxicity in MDA-MD-231 and HepG2 cell lines but had no effect on normal cells, reflecting the anticancer potential of ergosterol derivatives [Ergosterol has also been reported to exhibit potent anticancer activity . One stuivatives . Consistivatives . Furtherivatives .In vitro studies on LNCap and DU-145 prostate cancer cell lines further confirmed the androgen-receptor-mediated action of ergosterol. In addition, ergosterol showed anti-proliferative activity against MCF7, NCI-H460, and HeLa cells . ErgosteAmauroderma rude, which contain ergosterol as the main bioactive component, suppress tumor growth in Balb/c mice inoculated with B16 melanoma cancer cells. These effects may be mediated through the activation of FOXO-3, which induces the upregulation of various tumor suppressors, including pro-apoptotic genes, such as FasL, Bad, Bim, and Trail [The anticancer effects of ergosterol have also been demonstrated in vivo. Ethanol and chloroform extracts of mushroom nd Trail . The orand Trail . Ergostend Trail . In silind Trail . TherefoIn a pioneering study, oral administration of ergosterol inhibited Matrigel-induced neovascularization in female C57BL/6 mice, suggesting that it may be an antiangiogenic compound . ErgosteDiabetes mellitus is a chronic health condition in which blood glucose levels are persistently elevated due to insufficient secretion of insulin from the pancreas or a decreased tissue response to insulin . NephropPleurotus ostreatus exhibited promising antidiabetic activity [3K/Akt/NF-κB p65 signaling and cytokines  [3K/Akt signaling pathway is controlled by NF-κB and has important functions in metabolic balance [Ergosterol derived from the edible mushroom activity . Ergosteactivity . Ergosted MCP-1) , as welld MCP-1) . PI3K/Ak balance ,92. In a balance . Further balance . Ergoste balance .Auricularia polytricha edible mushroom, could suppress bisphenol-A-induced BV2 microglial cell inflammation by down-regulating the NF-κB signaling and enhancing the antioxidant pathway [Neuronal degeneration is a brain pathology characterized by protein aggregation and decline in the neuronal population, finally leading to neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis . Several pathway . Further pathway . TherefoHelicobacter pylori is inhibited by ergosterol; the minimum inhibitory concentrations are 10–20 μg/mL [Aspergillus flavus, Pencillium digitatum, and Fusarium vericilloides [Trypanosoma cruzi infection is one of the causes of the high incidence of Chagas disease, which is a life-threatening disease. Ergosterol causes rapid plasma membrane and mitochondrial permeabilization owing to alterations in membrane composition, resulting in the disruption and death of trypomastigotes [Auricularia polytricha, a phytochemical investigation revealed the presence of ergosterol, apart from other components such as linoleic acid and two other lipopolysaccharides, as the principal component in the extract [The increased incidence of new microbial infections and the evolution of antibiotic-resistant strains have led scientists to develop new bioactive compounds from natural resources as alternatives for treating infectious diseases . Ergoste20 μg/mL , suggestilloides . Trypanostigotes . Other sstigotes ,103,104. extract . Additio extract . NeverthIn addition to the beneficial effects mentioned above, ergosterol may have therapeutic potential for hepatic steatosis, which is the first step in the development of nonalcoholic fatty liver disease, steatohepatitis, fibrosis, cirrhosis, and hepatic carcinoma. Ergosterol reduces intracellular triglyceride accumulation in HepG2 cells treated with fatty acid. Its mechanism of action involves the direct induction of AMPK and acetyl-CoA carboxylase phosphorylation , which rErgosterol is a versatile compound found in natural sources, especially in edible mushrooms. Continuous pharmacological research on ergosterol may lead to the development of new drugs and nutraceuticals for therapeutic use and promoting health. For example, ergosterol can be formulated as a novel antioxidant or anti-inflammatory agent. It may also be used in combination with other drugs, especially chemotherapeutic agents, to enhance drug efficacy and reduce side effects. Ergosterol-containing nutraceuticals can promote immune function, liver health, and overall well-being. Further studies are required to fully explore its mechanisms of action, and to understand its effects on the human body. In particular, animal studies and clinical trials must be encouraged. Formulation optimization should also be considered in order to increase ergosterol bioavailability.


P < 0.001 for all). Males, smokers and individuals with hypertension and diabetes had lower levels of all four IgM OSE than unaffected individuals . Compared to the lowest quintile, the highest quintiles of IgM MDA-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and MDA mimotope P1 had a lower OR of AMI: OR  of 0.67 (0.58–0.77), 0.64 (0.56–0.73), 0.70 (0.61–0.80) and 0.72 (0.62–0.82) , respectively. Upon the addition of IgM OSE to conventional risk factors, the C-statistic improved by 0.0062 (0.0028–0.0095) and net reclassification by 15.5% (11.4–19.6). These findings demonstrate that IgM OSE provides clinically meaningful information and supports the hypothesis that higher levels of IgM OSE may be protective against AMI.Immunoglobulin M (IgM) autoantibodies to oxidation-specific epitopes (OSEs) can be present at birth and protect against atherosclerosis in experimental models. This study sought to determine whether high titers of IgM titers to OSE (IgM OSE) are associated with a lower risk of acute myocardial infarction (AMI) in humans. IgM to malondialdehyde (MDA)-LDL, phosphocholine-modified BSA, IgM apolipoprotein B100-immune complexes, and a peptide mimotope of MDA were measured within 24 h of first AMI in 4,559 patients and 4,617 age- and sex-matched controls in the Pakistan Risk of Myocardial Infarction Study. Multivariate-adjusted logistic regression was used to estimate odds ratio (OR) and 95% confidence interval for AMI. All four IgM OSEs were lower in AMI versus controls ( Oxidation-specific epitopes (OSE) are generated during lipid peroxidation of unsaturated fatty acids present on lipoproteins, membranes of dying cells, and extracellular vesicles , 2. OSE A consequence of lipid peroxidation is the generation of subtle conformational changes that occur on lipoproteins, cells, and microvesicles, such as the formation of malondialdehyde (MDA) adducts on lysine residues of proteins . PhosphoThe role of IgM OSE levels in patients with acute MI (AMI) is not well defined. We hypothesized that high titers of IgM autoantibodies binding to a variety of OSE would be associated with reduced risk of AMI in the PROMIS study. In addition, we tested the ability of a novel antigen representing an MDA-mimotope as one of the 4 IgM OSE, to reflect a higher risk of cardiovascular events.1) prior history of cardiovascular disease ; 2) a history of a viral or bacterial infection in the previous 2 weeks; 3) documented chronic conditions, such as malignancy, any chronic infection, leprosy, malaria or other bacterial/parasitic infections, chronic inflammatory disorders, hepatitis or renal failure on past medical history; 4) pregnancy; or 5) refusal to give consent. The PROMIS has received approval from the relevant research ethics committee of each of the institutions involved in participant recruitment  and the IgM apolipoprotein B100-immune complexes (IgM apoB-IC) were detected in human plasma with the use of a chemiluminescent ELISA as previously described .In brief, to detect IgM to MDA-LDL, MDA-LDL (5 μg/ml) was coated on microtiter well plates, plasma (1:200 dilution) was added, and IgG or IgG autoantibodies binding to MDA-LDL was detected with alkaline phosphatase–labeled goat anti-human IgG or IgM (Sigma). To detect ApoB-100 ICs, murine monoclonal antibody MB47 recognizing human apoB-100 was plated to bind a saturating amount of human apoB-100. Plasma (1:50 dilution) was added and IgM autoantibodies binding to the captured apoB-100  were detected with alkaline phosphatase labeled goat anti-human IgM. To detect IgM autoantibodies binding to phosphocholine-bovine serum albumin (IgM PC-BSA), phosphocholine-modified bovine serum albumin  (Biosearch Technologies) was plated overnight in 96-well microtiter plates at 4°C. After washing, human plasma samples diluted at 1:200 with 1% BSA/TBS were added. A goat anti-human IgM antibody conjugated with alkaline phosphatase (Sigma-Aldrich) was used to detect IgM bound to the PC-BSA, Lumi-Phos (Lumigen) added, and the plates were read in a chemiluminescent detector.IgM titers against MDA mimotope P1 were measured as previously described . The P1 High and low standards for each variable were used on each plate to detect potential variations among plates, and the results were reported in relative light units (RLUs) in 100 ms. The intra-assay coefficients of variation for all the assays were 6%–12%.To provide evidence that changes in IgM OSE were specific to the risk of MI and do not reflect generalized non-specific increases, total IgM levels were measured as a control variable. EPIC-Norfolk is a prospective nested case–control study among participants of the cohort who did not report a history of heart attack or stroke at the baseline clinic visit. Cases were people who developed CAD during follow-up through 2003 as previously described . Control2-test for categorical variables and Mann Whitney U test was used for continuous variables. Correlations between variables were determined with the Spearman test. Variables with a skewed distribution were log-transformed before being used as continuous variables in analyses. Multivariate-adjusted binary logistic regression models were used to estimate the associations between IgM OSE and risk of AMI as ratios (OR) and corresponding 95% confidence intervals (CI), by quintiles and per standard deviation, with adjustment for sex, age, smoking status, the presence or absence of hypertension and diabetes, LDL-C, HDL-C, and log2 triglycerides.Continuous variables were presented as means ± standard deviations (SD) or medians and interquartile range (IQR) and dichotomous variables as percentages. Differences in baseline attributes between participants were analyzed with ΧThe predictive values of IgM OSE were quantified by: (i) comparing c-statistics of all risk factors in the multivariable analysis, and then adding individual IgM OSE alone and then all together and (ii) calculating the continuous net reclassification improvement (which is suitable for case-control studies because it does not require knowledge about the underlying disease incidence) .P value < 0.05 was considered significant.Formal tests of interaction were used to investigate whether associations of IgM biomarkers with AMI differed according to other participant characteristics. Statistical analyses were performed using IBM SPSS software (version 24). P < 0.001), diabetes , were more likely to smoke , and had higher total cholesterol levels  and LDL-C levels .Demographic variables are shown in P < 0.001], IgM PC-BSA autoantibodies , IgM Apo-B-IC , and IgM MDA Mimotope P1 [3,840  versus 4,362  RLU, P < 0.001  levels of IgM MDA-LDL autoantibodies [14,271  versus 15,541  RLU,  < 0.001 .P < 0.001 for all).A significant and inverse association was present for all 4 oxidative IgM OSE and AMI following multivariable adjustment . Using qTo rule out a potential acute-phase response in IgM OSE levels that may have influenced findings, the distribution of IgM OSE levels was plotted at each hour over 24 h since the onset of chest pain in the cases. The IgM OSE levels were flat over 24 h .The shape of the association of IgM OSE to myocardial infarction was analyzed in more detail by deciles. The data reveals that the odds ratios for myocardial infarction decrease continuously over most deciles, including all deciles in IgM PC-BSA . There dTo rule out a non-specific effect of total IgM titers driving this association, an additional control group was used from the EPIC-Norfolk case–control study. Total IgM titers were measured and OR for CAD determine with the hypothesis that the association would be null. In age, sex-, and smoking-adjusted analyses, there was no significant association of total IgM, IgG, and IgA and the presence of CAD. Details of these analyses are shown in the P interaction >0.05). However, there was evidence of effect modification by diabetes status for all four IgM OSE, with significant interaction tests  per 1 SD for each of four IgM OSE, there were relatively consistent effects across age, sex, hypertension, and smoking status, and by triglyceride <150 versus ≥ 150 mg/dl, HDL-C <45 versus ≥ 45 mg/dl and LDL-C <130 versus ≥ 130 mg/dl thresholds, without evidence of effect modification  and risk classification (15.5% increase in continuous net reclassification index). This study represents the strongest powered study with 4,559 cases of AMI and showed consistent effects in all 4 IgM OSE that were measured. These IgM OSE measured reflect both MDA and OxPL OSE, which are the most well-characterized epidemiologically for association with CVD events , 21, 32,In this study, the association of IgM OSE was consistent among subgroups studied except patients with type 2 diabetes mellitus. Interestingly, there was evidence of effect modification in subjects with diabetes, where the inverse association was strongly maintained among patients without diabetes but not with diabetes. This suggests that any protection provided by IgM OSE is lost in subjects with diabetes, perhaps due to a heightened state of oxidative stress in diabetes  where thSeveral smaller studies measuring levels in AMI or acute coronary syndromes (ACS) have shown similar findings with either AMI , 46, 47 We further demonstrate that the peptide mimotope of MDA, termed the P1 mimotope that has a defined amino acid structure and behaves chemically and immunologically like MDA or the more advanced but related epitope MDA-acetaldehyde (MAA) , provideWe did not measure antiphospholipid antibodies in this study, but it is possible some of these IgM OSE have effects on thrombosis. For example, it has been demonstrated that the risk of recurrent thrombosis was higher in patients with low natural IgM, but not IgG, antibody levels . Further2 = 0.69–0.80)   suggests69–0.80) .A clinical implication of this study is the measurement of IgM OSE may be developed as risk biomarkers independent of traditional risk factors and biomarkers. There are also potential therapeutic implications in that such antibodies modified for human use may offer protection to patients at risk for CVD. For example, infusion of the human oxidation-specific antibody IK17 that blocks the uptake of OxLDL by macrophages, either as a Fab or single chain, significantly reduces the progression of experimental atherosclerosis . SimilarLimitations of this study include the fact that this is a case–control study, and although baseline variables were matched, there may be potential confounding not captured in the database. It is also known that these OSE markers can act as acute phase reactants and rise by 6–24 h following ACS  or percuIn conclusion, higher titers of 4 IgM OSE markers were independently associated with a lower risk of AMI and provided independent risk prediction and risk discrimination in addition to traditional risk factors.Allowable data that support the findings of this study may be made available from the corresponding author upon request.This article contains S. T and J. L. W. are co-inventors and receive royalties from patents owned by University of California San Diego (UCSD) and are co-founders and have an equity interest in Oxitope, Pharmaceuticals and Kleanthi Diagnostics. Although these relationships have been identified for conflict-of-interest management based on the overall scope of the project, the research findings included in this publication may not necessarily relate to the interests of the above companies. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. S. T. has a dual appointment at UCSD and Ionis Pharmaceuticals. J. L. W. is a consultant to Ionis Pharmaceuticals. The other co-authors have nothing to disclose.


Learning by concordance (LbC) is a recent approach that introduces learners to the complexity and uncertainty of clinical practice. Some data on LbC suggest that it stimulates reflection in future clinicians. We developed an online LbC training program on electrocardiogram (ECG) interpretation in general practice at the University of Strasbourg, France, and conducted an exploratory qualitative study to document the impact of this ECG learning-by-concordance training program on reflection in participants.We created 18 clinical vignettes on ECG interpretation based on a review of the literature on frequent and serious cardiovascular diseases that can be identified using an ECG in general practice. The training program was delivered online to postgraduate general practice students in two faculties of medicine. We conducted a qualitative study based on thematic analysis of two focus groups and six individual interviews. Inductive and deductive coding were performed. The five major components of reflection in the Nguyen model were used in the deductive coding: (i) thoughts and actions, (ii) attentive, critical, exploratory, and iterative processes (ACEI), (iii) underlying conceptual frame, (iv) change and (v) self.Two focus groups and six individual interviews were conducted. The qualitative analysis indicated 203 codes in the focus groups and 206 codes in the individual interviews, which were divided into five groups based on the components of reflection in the Nguyen model: (i) the self; (ii) attentive, critical, exploratory, and iterative interactions with (iii) one’s thoughts and actions; and (iv) a view on both the change itself and (v) the underlying conceptual frame. Inductive coding revealed interesting insights into the impact of the identity of the panel members, the absence of a scoring system and the question of uncertainty in ECG reading.This study supports the claim that the use of LbC in the context of ECG interpretation could foster reflection in future general practitioners. We discuss future research avenues on instructional design of LbC and reflection.The online version contains supplementary material available at 10.1186/s12909-023-04799-9. The questions asked are similar to those professionals ask themselves in their practice and participant answers are compared to those of a reference panel. When participants answer the questions, they receive an automated feedback that is two-fold as they see how the panelists respond and justifications each panelist gives for their answer. This provides rich contextual knowledge about the situation, supplemented by a synthesis summarizing crucial points” . Of course, right? Now [during the internship], obviously, you always reassure people, you don’t even realize it, actually” (participant no. 3).“I would put myself in the situation; I’d tell myself, I’m the doctor, this patient is my patient, and yeah, I was truly totally in the case” (attentive interaction – participant no. 8);“Many codes derived from the analysis of the interview transcripts correspond to an attentive, critical, exploratory, and iterative thought process:“As I saw that I was missing something each time, I tried to be more systematic and to read them properly” ,I found it interesting that normal ECGs were included as well, especially to make us think about the limits of normality, which is something we do not see enough of in training courses” (exploratory interaction – participant no. 11).“Well, I adjusted to the answers, anyway – for instance, about reassurance, there was a first case where I hadn’t written it down, and in the answer, he put reassurance, and so in the last case where it was anxiety and all that, I put reassurance” (iterative interaction – participant no. 9).“In fact, it was very long, and at one point I could not manage; I was confusing all the ECGs I saw” (attentive interaction – participant no. 12) - “I believe that the training is planned to last for three hours; I find that three hours, I find that it is tight if we want to pause on the resources to go deeper” (exploratory interaction - participant no. 11).Some aspects could be improved to foster the process of reflection. In particular, the long duration and cognitive overload may have had negative impacts on learning: ““when it is a little too technical [the cardiologist interpretation of the ECG], I can quite easily let it go and say to myself that it is too much for me” .Critical interaction was sometimes limited by the difficulty of understanding the panel answer: for instance, you see [atrial fibrillation] […] I told myself, ‘Okay, we have the right to handle that ourselves’” (participant no. 1).I made sure to do things a little bit more seriously, because, you know, there are actually important things to monitor, so yeah, that and being thorough when I read my ECGs” (participant no. 4) – “Same here, yeah, it’s true that we often tend to just glance at the thing; maybe we don’t necessarily, you know [laughs], do it as well as we did when we were students” (participant no. 7) – “do a better job of reading the ECG” (participant no. 5).“Several utterances made by participants illustrated a desire to change their thought processes: “it is true that for hyperkalemia, it is a typical picture to recognize directly without reasoning too much like that for hyperkalemia; I saw it is typical, and I knew what he had/in that sense it is easier” (participant no. 14). The more typical the clinical picture was, the more oriented the ECG reading was. The participants sought specific abnormalities on the ECG and then ruled out some hypotheses based on their findings. These nonanalytical clinical reasoning strategies were often the source of their errors. Therefore, participants decided to rely more on analytical clinical reasoning strategies: “To interpret […] the first ones I did like that [a global interpretation], in fact, I checked whether there was something obvious afterward as I saw that I was missing something each time. I tried to be more systematic and to read them well” (participant no. 12).Our analysis showed elements in the individual interviews that were related to the underlying conceptual frames of the participants. Participants noted that the program caused them to consider their clinical reasoning processes in light of the clinical cases. They focused on their nonanalytical clinical reasoning strategies: “I remember in the cardio teaching when I was a graduate student, he [the teacher] said that you had to look at all the [ECG leads] because you could be surprised, and it pushed me back to looking properly to be more regular [during the LbC ECG training]” (participant no. 12). In this type of reading, the participants relied on their clinical scripts: “here, there was precordialgia = thoracic pain = PIED pericarditis-infarction-pulmonary embolism-dissection; [there was a] ST segment anomaly, so it can only be infarction or pericarditis” (participant no. 16).Regarding analytical clinical reasoning strategies, some participants used a systematic reading method: “When I saw the answer to each question, I looked again on the internet […] I looked to see whether there were more examples of the same type to have additional images in head” (participant no. 13). Some participants kept these resources to foster a change in their future practice. The main limitation to such change mentioned by participants was the lack of explicitness in the interpretation of the panelists: “I thought it was good to have the opinion of the cardiologist or the general practitioner each time, but I found that it was not always detailed in relation to how we see that it is a Bouveret or a Brugada; I found that it was a little lacking [in details]” (participant no. 13).When participants faced issues related to clinical reasoning, they used resources during the training to develop or create new prototypes and clinical scripts: “In this situation, for example, I would send [hesitates a lot] […] it would have been about the complaint […] I would have sent him to the emergency room, with regard to the ECG; I do not know […] We are still worried” (participant no. 12).Finally, clinical reasoning strategies were also guided by emotional factors and uncertainty: “My way of reasoning is fairly logical compared to the others; I’m a little bit reassured, and I’ve gained a little bit of trust in myself” (participant no. 3). This approach may have encouraged some of them to use the ECG in their future practice: “honestly, I didn’t think I would need to read ECGs afterward [after finishing his or her studies] but in fact there are plenty of GPs who have an ECG, and it’s not bad; it allows a first screening” (participant no. 12).The participants easily connected their thoughts to their ‘selves’ both during and after the training program: “I think it isn’t bad doing it like this because in the end, when I did it, I wasn’t under any pressure, and so you know, you’re not stressed out. When you’re being graded or evaluated, you get stressed out, whereas this is truly just for us” (participant no. 5).The absence of grades and the purely learning-oriented goal of the training program was important with regard to this component: “Inductive coding revealed interesting thoughts that emerged in this LbC format concerning the impact of the identity of the panel members, the absence of a scoring system and the question of uncertainty in ECG reading.they tell us cardiology specialists, but we don’t know who they are at all [in the ECG LbC training program panel]” (participant no. 2) – “The thing is, we know cardiologists, who… you know… [do a bad job] […] so, people we don’t trust completely [the cardiologists panel]”. These parts were also coded as critical thoughts in the ACEI component.Participants were unsure of what value they should attribute to the answers offered. This uncertainty seems to foster a critical distance from the role model that recognized panel members could provide: “I think it isn’t bad [the ECG LbC training program] doing it like this, because in the end, when I did it, I wasn’t under any pressure, and so you know, you’re not stressed out. When you’re being graded or evaluated, you get stressed out, whereas this is truly just for us” (participant no. 5). This part was also coded as an attentive thought associated with the ACEI component.The absence of a scoring system and the assessment of the learning goal of the training program was important to the participants: “they do not all have the same opinion, and that does not mean that if we do not all do the same […] it does not necessarily mean that we’re wrong. I found that these moments when there were different opinions among the cardiologists as well as among the general practitioners were a little less demeaning than the MCQ [multiple choice question] methods, which are it is right or it is wrong and that’s it” (participant no. 11).Uncertainty is often a source of stress in the context of ECG interpretation in real-life situations for participants and a potential obstacle to the use of ECGs in their future practice. The participants highlighted three main elements of this LbC program that facilitated more effective management of this uncertainty. First, the existence of a panel of experts, whose interpretations varied slightly but which led in all cases to an adapted management of the situation: “finally, when I’m least sure of myself is when it is normal/and in that sense, it would be interesting to do more subnormal or physiological ECG” (participant no. 15).Second, situations featuring normal or subnormal ECGs are an important source of uncertainty for the participants, and they felt the need to train on these situations: “it allowed me to better conceptualize the call to the cardiologist, for example, to better understand when we let the patient make an appointment or when I must call. It allowed me to touch upon this notion of temporality, a short term, a long term” (participant no. 11).Finally, participants emphasized the use of transversal skills to manage a patient situation based on the suggestions made by the general practitioners panel: “Based on the model discussed in Nguyen et al. , analysiThese findings are consistent with those of Fernandez et al. from 2016 . In our Learning by concordance could thus either actually increase reflection among learners  or at leTwo methodological choices appear to deserve consideration in cases in which the objective of an LbC program is to boost reflection among learners: the anonymity of panel members and the calculation of a score. While the identity of panel members is usually announced at the beginning of the proceedings –4, not dIn addition, this type of LbC program might increase learners’ tolerance and ability to deal with uncertainty. As acknowledging the feeling of uncertainty helps learners address it, the expression of this feeling by students and panelists should be encouraged during the LbC program . ResearcSuch an LbC program on ECG interpretation may help students develop the ability to self-regulate their learning, which is necessary for their continual professional development . This fiThere are limitations to this study. The principal limitation can be phrased as a question : “how can we prove that an intervention fosters reflection?”. We tried to find components of reflection by reference to qualitative data collected through focus groups and elicitation interviews. However, how can we differentiate between program-related reflection and our data collection-induced reflection? We tried to mitigate potential bias by asking specific questions in our guides that were inspired by previous studies, but part of the reflection we highlighted might ultimately have been the result of our data collection processes . AnotherNevertheless, this study is the first to describe a training program combining the LbC principles of perception and reasoning. It provides arguments that support the use of LbC in the education of health care professionals since uncertainty is a prominent feature of their work and reflection is a desired feature.This study supports the claim that the use of LbC in the context of ECG interpretation programs could foster reflection in future general practitioners. As in Nguyen’s definition, participants engaged in attentive, critical, exploratory, and iterative interactions with their thoughts and actions, as well as their underlying conceptual frameworks, with a view to changing them and a view on the change itself in an LbC training program on ECG interpretation. Health science educators looking to cultivate reflection among their students may consider incorporating LbC into their training programs.Subsequent studies could assess and compare the impact of various instructional designs on the development of reflection with LbC, such as the absence of scoring or the anonymity of members in the reference panel.Below is the link to the electronic supplementary material.Supplementary Material 1: Example of a clinical case of the LbC programSupplementary Material 2: Interviews guides


BCR::ABL1 fusion gene. The derivative chromosome 22 (‘Philadelphia’ or Ph chromosome) usually harbours the fusion gene encoding a constitutively active ABL1 kinase domain.Chronic myeloid leukaemia (CML) is one of the most well characterised human malignancies. Most patients have a cytogenetically visible translocation between chromosomes 9 and 22 which generates the pathognomonic BCR::ABL1 fusion gene can be generated via submicroscopic intrachromosomal insertion of ABL1 sequence into BCR, or, more rarely, of BCR into ABL1. The fusion genes arising from cryptic insertions are not detectable via G-banded chromosome analysis [karyotype] but can nevertheless always be detected using fluorescence in situ hybridisation (FISH) and/or qualitative reverse transcriptase PCR.A small subset of patients have no visible translocation. Historically, these ‘Philadelphia chromosome negative’ patients caused diagnostic confusion between CML and other myeloproliferative neoplasms; it is now well established that the BCR::ABL1 transcripts (e13a2/e14a2), was also negative. Upon review in 2009, the newly recommended reverse transcriptase multiplex PCR  subsequently detected an e19a2 fusion. The patient then responded to tyrosine kinase inhibitor therapy. In contrast, FISH studies of both samples with three commercially available probes remained consistently negative.A 43-year-old female presented with suspected CML in 2007; however, contemporaneous gold standard laboratory investigations, G-banded chromosome analysis and FISH, were both negative. The reverse transcriptase quantitative PCR (RT-qPCR) assay available at the time, which was capable of detecting the common BCR::ABL1 fusion gene arose via a uniquely small insertion of 122 kb ABL1 sequences into BCR.Retrospective whole genome sequencing, undertaken as part of the 100,000 Genomes Project, has now revealed that the patient’s We present a patient with suspected chronic myeloid leukaemia whose genetic investigations were originally negative at the time of diagnosis despite the use of contemporaneous gold standard methods.BCR::ABL1 positive CML which demonstrates that, even after sixty years of research into one of the most well understood human malignancies, whole genome sequencing can yield novel diagnostic findings in CML.This is the first report of a FISH-negative,  BCR and ABL1 in the fusion gene was established in 1984 and 1986, respectively [BCR::ABL1 fusion gene has resulted in CML being the target of many laboratory and clinical firsts, including bone marrow transplantation [CML is one of the most well characterised human malignancies; the toponymous Philadelphia chromosome was discovered in 1960 using some of the earliest genetic techniques . The invectively , 4. Thisantation , internaantation  and one BCR::ABL1 fusion gene can be found in four main variant forms  defined by the breakpoint location within the BCR gene, and thus the size of the resulting fusion protein. Whilst the breakpoints in ABL1 are relatively tightly clustered in a region surrounding exons 1b to 2, breakpoints in BCR can occur within any of several relatively large regions of the gene. Those falling within the major breakpoint cluster region (M-bcr) yield the common 210 kDa fusion protein (P210BCR::ABL1) which is highly specific for chronic myeloid leukaemia [BCR exons 12 to 16 and is approximately 4 Kb. Philadelphia-positive acute lymphoblastic leukaemia (ALL) is also defined by the BCR::ABL1 fusion gene, however, the majority of fusion genes in ALL arise from rearrangements within the minor breakpoint cluster region (m-bcr). This 72 kb m-bcr region between BCR exons 1 and 2 gives rise to the P190BCR::ABL1 protein [BCR introns 18 to 22; these rare transcripts were not identified until more recently [The eukaemia . The M-brecently  and haverecently .BCR::ABL1 fusion gene arises as a consequence of an insertion of ABL1 sequences into BCR, or vice versa [Approximately 1–2% of CML patients have an apparently normal karyotype. In these patients, the ce versa . Such suce versa .recommended multiplex PCR at diagnosis to identify the fusion transcript type, and the 2020 guidelines now state that this is mandatory [Whilst undetectable by karyotype analysis, cryptic insertions can be detected using FISH , reverseandatory . This re9/L and a mild leucocytosis of 23.2 × 109/L, with left shifted myelopoiesis and neutrophils of 16 × 109/L, eosinophils of 1 × 109/L and basophils of 0.4 × 109/L suspicious of CML. However laboratory investigations performed according to the contemporaneous best practice guidelines [BCR::ABL1 was negative  into intron 19 of BCR at chr22:23,312,158  of DNA derived from the patient’s diagnostic peripheral blood sample, and undertaken as part of the 100,000 Genomes Project, has revealed a 121,681 bp insertion of ABL1 sequences into BCR, or vice versa, are not unusual. Approximately 1–2% of CML patients have no apparent Ph chromosome; undertaking FISH in suspected CML referrals with a normal karyotype has thus long been routine. When qualitative reverse transcriptase PCR testing at diagnosis of CML was first recommended by European LeukemiaNet in 2013, this was principally to determine the appropriate transcript for subsequent monitoring in order to avoid falsely assuming a patient had achieved a complete molecular response. This case is unique in that the patient presented with a rare e19a2 fusion and a uniquely small submicroscopic insertion.Cryptic insertions of ABL1 coding region and at least 300 kb of sequence up or downstream  despite all three manufacturers’ probe maps indicating they had full coverage of the entire eam Fig. . Analysieukaemia . UnfortuABL1 exon (the first exon translated in the BCR::ABL1 fusion protein) and 50 kb downstream , all of which are superfluous for the formation of the fusion gene. Hypothetically, an insertion of just 40 kb could contain all the necessary coding sequences for an in-frame BCR::ABL1 fusion; the smallest possible insertion resulting in a functional BCR::ABL1 fusion gene could be considerably smaller than the one reported here. Conversely, a reciprocal insertion of BCR into ABL1 would require a minimal insertion of just BCR exon 1 to form P190BCR::ABL1. BCR-into-ABL1 insertions are documented, however all those reported to date have all been large enough to be detected by FISH [The 122 kb insertion included almost 40 kb intronic sequence upstream of the second  by FISH .BCR::ABL1 positive chronic myeloid leukaemia patient and have been able to fully characterise the fusion. Whole genome sequencing has demonstrated insertion of 122 Kb of coding ABL1 sequence into intron 19 of BCR resulting in a rare in-frame e19a2 fusion transcript, the smallest cryptic insertion reported to date. Despite over 60 years of research into CML and our advanced understanding of its genetics making it the paradigm for the precision medicine era, whole genome sequencing has only now explained a 15-year diagnostic mystery.In summary, we report the first FISH-negative