Background: The Albert J. Solnit Integrated Training Program (AJSP) is a novel educational initiative designed to prepare physician-scientists for independent careers in the investigation and treatment of childhood psychiatric disorders.Methods: We conducted a qualitative study to explore the impact and active components of the AJSP through hour-long individual interviews of its enrollees and graduates. We were specifically interested in identifying individual or programmatic traits for success that could be replicated elsewhere. As components of our theoretical framework, we used sources on Strength, Weakness, Opportunity, and Threat (SWOT) Analysis as applied to healthcare, and on mentorship and career development as pertaining to child and adolescent psychiatry (CAP).Results: Thirty-four individuals matriculated into the AJSP between 2004 and 2020, 33 (97%) of whom participated. Through iterative thematic analysis, we developed a model consisting of quadrants resulting from the intersection of a developmental perspective  and a reflective direction (with outward- or inward-facing vantage points). The model can be of practical utility through putative questions that trainees/program leaders could ask themselves by using the four domains as points of departure: (I) Individual: “Is becoming a clinician-scientist right for me?”/“What traits are we looking for in prospective applicants?”; (II) Program: “Is this the right program for me?”/“What is the right balance between structure and freedom for trainees to thrive in?”; (III) Mentorship: “What is the right number and constellation of mentors for me?”/“How can we optimize our experience and backgrounds toward the benefit of our trainees?”; and (IV) Charting Course: “Who do I want to become?”/“How can we help our charges embrace, find, or reconnect with their true vocation?”Conclusion: Our analytic approach can help identify, refine, and replicate programs that are urgently needed to increase the workforce of clinician-scientists dedicated to improving the well-being and mental health of children and families. The model we describe can be fruitfully applied to the self-reflection by individuals or program leaders. Although based on a single program with very specific goals, the model could also be applied to other training initiatives within psychiatry—and beyond. What you get by achieving your goals is not as important as who you become by achieving your goals.– Henry David Thoreau More physician-scientists are needed to pursue research careers in understanding and addressing the pathogenesis, treatment, and prevention of child and adolescent mental health conditions . The shoInnovative approaches to increase exposure to CAP during medical school have proven effective in raising awareness about the field, including its research opportunities , and in p < 0.05 for all comparisons). From a return-on-investment perspective, the 2.8 million dollars in R25 funding since 2004 has already yielded 4.6 million dollars in new grant funding. Quite aside from hard metrics and fiscal bottom lines, the program has led to the formation of a unique group of clinician-scientists with remarkable scientific creativity, innovation, and commitment.In an earlier study based on data from the program's first 15 cohorts , we docuAs a complement to that report, we report here on a qualitative research study through which we sought to gain a better understanding of the program's unique characteristics—as viewed from the perspective of its most integral stakeholders. We were specifically interested in identifying individual or programmatic traits for success that could be replicated elsewhere. By including currently enrolled trainees and graduates to date, our findings incorporate the views of all but one of the entire 17-year cohort of AJSP participants.The Albert J. Solnit Integrated Training Program (AJSP) was implemented at the Yale Child Study Center in 2004. Named after the Center's third director, the AJSP integrates training in pediatrics, psychiatry, CAP, and research competencies into a 6-year continuous experience. Participants are recruited into the program after graduation from medical school and, upon completion, become board-eligible in both general and CAP. The program's overall structure and specific details are available in prior publications from our group  and on tFunding for the AJSP derives from a range of sources, including traditional graduate medical education training slots through Yale-New Haven Hospital and the Veteran's Administration Hospital, which, combined, provide most of the support for four of the 6 years of training. The remaining 2 years, largely devoted to protected research activities, are funded through a combination of federal and private sources: (1) an R25 grant from NIMH (MH077823), now in its 15th year, designed to target the specific research goals of the AJSP; (2) a T32 training grant from NIMH (MH018268), now in its 36th year, which supports training infrastructure across a range of relevant disciplines; and (3) a significant amount of philanthropic support.n = 34, 2004–2026).Annually, we receive more than 400 applicants for two available training slots. We are committed as a programmatic goal to improve diversity in the CAP physician-scientist workforce. Toward that end, we actively seek applicants from ethnic or racial groups that are underrepresented in the field of medicine, including African American, Hispanic/Latinx, and Native American or Pacific Islander. Interviews are only offered to those graduating students who have displayed during their medical school training a clear interest in both child psychiatry and in research, preferably exemplified through published work. Each year, some 30 applicants are offered in-person interviews, with a formal selection process to finalize a ranked match list. Since the program's inception, we have matched the two available positions each year. To date, we have recruited 17 cohorts .reflexivity . Subjects were encouraged to participate but informed that their participation was not mandatory. They were aware that interviews were conducted as part of a research project and provided recorded verbal consent to participate in the study.Thirty-four individuals matriculated into the AJSP in the 17 years between 2004 and 2020, 33 (97%) of whom agreed to participate in this study and provided consent. Participants comprised 21 graduates and 12 enrolled trainees. Sex distribution was balanced among the 33 subjects, nine of whom (27%) are members of under-represented demographic groups . Two-thirds of participants have an advanced degree separate from their MD . Of those degrees, 17 had been conferred prior to matriculation, and 5 were earned as part of academic work during the course of the AJSP. Half of eligible participants had received financial support in the form of loan relief through the NIH Pediatric Research Loan Repayment Program.Through iterative thematic analysis, we developed the model depicted in The first two domains are organized using a similar “SWOT-B” rubric: (1) Strengths, (2) Weaknesses, (3) Opportunities, (4) Threats, and (5) Balance. This analysis, as applied to individuals, is outlined in Patience | Comfort With Uncertainty | Grit | Tenacity With Long-Term Goals. Participants identified several character traits that had served them well over the course of their training. Patience was paramount, and not only because science and scientific development take a long time, or because time was inherently necessary “to mature and tie things together,” but also because the program they had joined was similarly evolving and resolving its own developmental challenges, particularly during its early years. Progressing in lockstep with their evolving program certainly required comfort with uncertainty, but that trait was necessary well beyond the particularities of any given program: “There are no assurances of success, or of a given experiment even working out. You just buckle up, hold on tight, trust the process, and go go go.” Uncertainty could be not just tolerated but embraced, so long as there was a perspective that “the scientific journey may be more than its destination” and that struggle and failure are inherent to its process:These years have been lovely, and I've found wisdom and I've been on a search, but I've also seen failure and encountered struggle, which I don't see as antithetical to wisdom or to searching. It's obviously part of what makes the search worthwhile, and the wisdom that much more profound.Grit, stick-to-it-ness, and work ethic were deemed essential traits to overcome the vagaries of uncertain outcomes, as was tenacity with long term goals and with the inevitable (and frequent) handling of rejection in its many forms.Self-Directedness | Intellectual Flexibility | Psychological Adaptability. Assertiveness, initiative, self-directedness, “being bold,” and “even having somewhat of a pioneer spirit or entrepreneurial style” were deemed valuable in a setting in which trainees are given considerable range in designing their own program and research goals:Some folks need rulers and margins, they like the color-by-numbers approach. Others love the freedom of the blank page. You have to be a blank-page enthusiast to thrive around here. Or maybe to thrive as a clinician-scientist anywhere.intellectual flexibility was critically useful. As such, it behooves training environments to help trainees enhance such flexibility along the way, specifically around the dual skills of learning to learn and learning with others. The pace at which knowledge advances and the seemingly inexhaustible range of resources at our disposal require a different approach to learning. The information contained in the static books and lectures of old can no longer be today's mainstays. Learning to learn requires dynamic skills that are iteratively refined, lifelong, web-/distal- as well as person-based, asynchronous as well as synchronous, self-initiated, trainee-rather than trainer-centered, and responsive to actual challenges at the individual, community, and policy levels. As specialists dedicated to development and to human interaction, we are in a privileged position to learn not only about others but with others. Indeed, few of us could conceive of practicing alone: our work is multidisciplinary and relationship-based at its core.Having to change research and clinical settings periodically necessarily implied that Psychological adaptability was useful to acclimatize to new environments, to balance the pursuit of one's goals with the pull toward another's, to remain open to unexpected opportunities of the kind “you are never quite ready for, but where a little nudge at the right time can prove critical.” Adaptability was required not only to articulate an early scientific vision but also to change it iteratively over time. Accepting the limitations of our predictive powers required a different kind of humility: “will my endpoint 6 or 10 years from now be in alignment with my goals of today?” As program directors, we were well-positioned to support the psychological adaptation and well-being of our trainees:My own psychotherapy and psychoanalysis, which has now been going on for a long time: that was very unexpected and ended up being a big growth driver for me. I had pigeonholed long-term therapy as something narrower, an indulgence perhaps.Background. We relegate these traits to the end, as they are the less actionable ones by the time of matriculation. It would be disingenuous to deny that some participants had inherent advantages by the time they started the program, whether through prior research or clinical experience, by coming from the same institution, or by having an additional advanced degree (particularly an MD/PhD—“just to give us a ‘fighting chance’ in basic science”). However, we should note that none of these variables, including PhD status, were predictive of higher success rates in the “hard outcomes” examined in our earlier, quantitative study  were much more likely to struggle:The internal hindrances or vulnerabilities that we saw reflected in the interviews can be grouped into three distinct categories. The first may be construed as the reverse of the previous section, as They are clearly bright but when they came in and saw how unsatisfying science can be, how little reward there can be immediately, they just couldn't tolerate it, and abandoned it.Physicians' Pathophysiology. A second category pertained less to the burdens unique to aspiring clinician-scientists, and more broadly to the toll exacted across all medical providers. Participants described a range of difficult feelings, including being overwhelmed, exhausted, unappreciated, or stretched too thin. Others reported fears of failure, confrontation, or conflict; pretending to be fine; feeling wary of a competitive environment; and having experienced (or continuing to experience) imposter syndrome. Even though several participants shared how psychotherapy had been integral to their training experience, few acknowledged personal psychopathology or its impact on their functioning. By contrast, “burnout” was a more readily used term, even as it may have conflated or overshadowed underlying struggles.Disambiguating Ability From Drive. The third category may be more specifically relevant to aspiring clinician-scientists, for whom disappointments, doubts about personal ability, or a fear of letting themselves or others down may have additional downstream consequences. Even as several participants had considered quitting science at some point, few had felt comfortable articulating their doubts outside of the interview setting; it appeared easier to “blame” self-perceived limited abilities than acknowledge that they may no longer have had the drive to pursue science:want to do something? That seems much harder to accept.I am able to do and enjoy doing science, when guided. But do I really, truly want to be a Principal Investigator (PI) and run a lab myself? I've turned down opportunities before, admitting I couldn't do something. But what if I no longer Regardless of their relative strengths and weaknesses, participants shared a common sentiment of gratitude for having the opportunity to grow and develop “in our own way, without having to sacrifice our values.” Having the continuity of 6 years of training in a single program permitted trainees to explore, revisit, and refine in a recursive way “our personal narratives, so that we can work out who it is we are really aiming to become.” “Pluripotentiality” was the term used by an interviewee as a common denominator for the group as a whole, with the program's flexibility for customization “permitting us to develop however it is we want, to choose what kind of psychiatrist we want to become.” Others reflected back on their early and inchoate days, when they had questioned whether they were a good fit and had made the right decision selecting the program,… appreciating it for taking a chance on me, because some folks just jump in and it's really clear what they're going to do from the start. But that was not me: I needed a lot of time, care, and feeding to get there.not to do.” Length of training, opportunity cost (through delayed joining of the workforce by at least 1 year), loan burden, and immigration barriers (with program eligibility restricted to U.S. citizens) were among the potentially impinging externalities that gave pause or, in some cases, led to departure from the trajectory altogether. Additional recurring concerns were the time horizon and uncertainty around scientific independence and a realistic awareness of the challenging funding environment ahead. An additional and discomforting reality was the prospect of having to compete with “pure” scientists who did not have to devote a substantial portion of their effort to clinical training and practice: “I'm up against people who dedicate 100% of their time to the lab. I simply didn't have that.”Pursuit of a clinician-scientist route was described in an interview as “so much easier Poor role models posed a dangerous example that could have a chilling effect. A hierarchical system was described as one that could devolve into “getting so abused in academic medicine and just keep going with it. It's incredible to me. But it is a model that we have seen in medicine over and over again.” Less egregious, but far more common, was the cautionary tale of the research life as “a grind” in whichThey are chronically stressed, always working on a paper, wondering where the next grant is going to come from, feeling like they're one bad grant cycle away from not being able to pay their salary. Maybe I'm just not doing it right myself. But I haven't seen that many people who've pulled it off, to be honest.The quest for an elusive point of equilibrium was at the forefront of the thoughts of most, many of whom had seen cautionary tales of clinician-scientists perceived as “productive yes, but at the price of appearing not so well adjusted.” Among the top priorities to address during training years and beyond: integrating personal and professional goals, nurturing family life, being attentive to significant others or spouses, cultivating outside interests, and, of particular pre-eminence for those with children, being the best parents they could be.A second aspect was at the professional level, aiming to blend the clinician and scientist constituents in proportions that made best sense for each individual. The combination of the two components was a necessity going well beyond the allotment of hours or percent effort; it was about integration into a cohesive personal narrative and trajectory, as exemplified in two complementary reflections:I'm trying to figure out how to make the training valuable in my work, because right now it's not particularly relevant. So far, I haven't yet found a way to directly make that knowledge applicable to my work.not spending with that family or doing the work face-to-face with these kids. That's not a fair way to think about it, because publishing does allow the work to continue through other people who are doing similar things. But I'm just not about that. I have a pressing need to help real people, right now.The tension I feel is that every hour that I spend writing a paper or applying for a grant is an hour that I'm Positive comments of the program fell into four broad categories:Uniqueness of Structure. With no other training program organized in quite the same way, its approach stuck out:I've been able to customize my residency training in a way that is in line with my interests, which I don't think I would have been able to do anywhere else.As with any idiosyncrasy, such singularity was a source of both interest and dissuasion: rather than a program of universal appeal, it became one better suited for those seeking to thrive in an environment with considerable room for customization, one that “provided the raw materials and let you ‘build your own adventure.”’ The program's unheralded amount of autonomy, particularly in its final 2 years, was described as “either thrilling or frightening, depending on your goals, but a definite line in the sand in terms of whether you want to be here.”Integrative Design. Incorporating clinical and research components from the outset, the program was experienced as rigorous, broad in its training experience and settings, and allowing for the simultaneous mastery of core clinical competencies and research immersion and training:The program allowed me to pursue research seriously. It's otherwise too easy as a physician to get swamped with clinical responsibilities and forego research.Developmental Perspective | Early identity formation. There are other programs that seek to integrate clinical and research training, and participants had considered or interviewed at several of them. However, the possibilities narrowed considerably for applicants with a clear commitment to working with children and adolescents. The ability to work with children from the start was a highly valued aspect of the program, including through an internship year in pediatrics rather than medicine and through early exposures to inpatient and consultation-liaison child psychiatry. Incorporating a developmental framework that championed the unique needs of children and their families mirrored the values of an independent department of child psychiatry and resulted in a sense of hopefulness and enthusiasm for “working from the outset with the population and age groups we love, without having to wait.”Continuity Threads. Given that the program spanned at least three distinct departments  and a wide range of research settings, providing continuity in training, education, supervision, and longer-term career planning became paramount for the overall experience to be summative rather than piecemeal. This was approached through longer-term outpatient clinical experiences, program leaders and mentors who were “supportive and informed, but not overbearing or micro managerial,” and by the bonding across classes that resulted from the program's small size. This cross-class peer collaboration proved essential in maintaining institutional memory and in providing for agency in shaping and refining the program:We talked about a challenging rotation and were able, as trainees, to advocate for change. That experience was so affirming, and so different from having a more boilerplate, preordained, this-is-what-you-will-do approach to training.Growing Pains. There was a clear divide in the critiques made by respondents enrolled during the first or second half of the program's existence. Those in the early years, during which components and overall design were still in flux, expressed a deep commitment to the mission of developing not only themselves but also the program with which they were affiliating themselves: “it was about survival back then, not refinement,” “it was free-flowing, work-in-progress, only so much of which is a good thing.” The early years were about working out the kinks, both small and large:It was a small operation back then, but none of the leaders seemed to be talking to each other so much, to the point where they did not coordinate their annual parties one year: symptomatic, but none of it malicious. It was just mind boggling how little coordination there was in those early years.There were mistakes made early on with how funding was structured when we were on grants. Some of those administrative oversights impacted my loan repayment later on. It was solved in the end, but at the time I felt abandoned and let down by the program.Organization. Although such larger, structural problems were resolved in subsequent years, the program continued to feel disjointed to some. Structural, cultural, and organizational differences across component departments could loom large; it could be easy to become disconnected, transient, floating in a no man's land or limbo, “too easy to get lost in the shuffle.” Some described feeling during their training “so special and talked up that it led to sibling rivalry with others” or, alternatively, “so overlooked that we were left off invitations and announcements.” Moreover, the program felt to some too small and insular, challenging trainees' ability to provide meaningful feedback and trusting that it would remain confidential.Moving From Career Prognostication to Timely Diagnosis and Treatment. With an explicit goal to develop clinician-scientists ready for independent careers, the program understandably tries, during recruitment, to prognosticate which candidates will prove a good fit and be likely to succeed. As the training years go on, the outcomes in question become concretized in the form of awards, publications, or grants. Critical as these elements are to the success and longevity of the program, there were a number of comments about overlooking the parallel need to better “diagnose” and “treat” in a timely fashion. From a professional perspective of “career health,” going off track scientifically or contemplating dropping out (from the program or from the pursuit of science) were described as off-limit topics, too embarrassing and shameful to bring up: “but there needs to be a way not only do talk about it, but to have ‘off-ramp’ options available.” Similarly, bringing up personal mental health issues was described as “an additional burden” that could fall on trainees, rather than a routine part of the program's oversight of them.Scholarly Settings and Social Capital. Respondents had made good use of a broad array of clinics, labs, and projects at their disposal. The variety and abundance was particularly relevant to less “traditional” applicants or interests, as in the case of fruitful partnerships with the humanities, or when facilitating a trajectory shift during training. Aside from the broad set of local opportunities, strategic efforts were made over the years to connect trainees with content experts or specific mentors at other institutions. Paradigmatic of this approach were visits organized each year by the program's chief residents to exemplary research settings in the region:I really broadened my outlook, both personally and professionally, during my training years here—partly through all the opportunities that were facilitated in places and with people outside of here.Leveraging Resources. From very early on, trainees were made aware of relevant opportunities for awards or grants. These included internal and external options, as well as private and public, including the federal loan repayment project. Grant-writing skills, opportunities to present in a variety of settings, an ethos that “our teachers and mentors had more confidence in us than we ever did,” and the positive reinforcement of early wins, all translated into a documented high success rate, both during training and after its completion:Getting outside pilot funding for my own ideas during training was so important; securing those early grants helped me build confidence that I could do it and maybe take the next step.There are so few people like us out there, that especially when people decide to stay primarily as researchers, we become like these coveted rare unicorns, it gets crazy. I think that the program really set us up to have this amazing launching pad.Funding. The fiscal worries engendered by a costly program that relies in large measure on the soft monies of renewable federal grants and philanthropy are never entirely subdued. In the early years, those concerns were existential, with no assurance that the program could come into being (“one bad grant decision away from not”); now that the program is instantiated, the apprehension has shifted away from viability toward longevity.The more readily evident sides of the equation involve its clinician and scientist components, or the harmonizing of different sites and institutional structures. But at a broader level, it may be more relevant to consider the optimal setpoint for programmatic flexibility: just how pre-determined and set (“prix fixe”) or customized (“à la carte”) should it be? Erring on the side of the former, the program could turn out to be not meaningfully different from the traditional approach that has led to such limited yields: an internship followed by 2 years of psychiatry, two of child psychiatry, and one of post-fellowship research. Alternatively, erring on the side of too much customization could lead to a disorienting experience, unstandardized training, and an ultimately unsustainable approach in which “anything goes.”Ignition Sequence metaphor: (1) Launch, (2) Orbit, (3) Landing, and (4) Woes, as outlined in The third domain encompasses four themes organized along an The start and the maturing of mentorship relationships was described as a process encompassing four main subthemes:Agency: Relationships Made, Not Found. The trainee had to show initiative and boldness, to be an active agent rather than a passive recipient in the labor-intensive work of mentorship, to have a sense of time urgency by reaching out rather than waiting for things to happen, to “be proactive in that you can't expect your mentors to initiate the contact. During those attempts to connect, you need to have a pitch ready, a selling point: you are ‘selling’ (yourself) as much as you are ‘buying’ (them).” Following through with early openings was as important as showing flexibility and adaptability in shifting gears toward a productive and mutually satisfying working relationship. Pre-assigned pairings rarely proved to be as successful, no matter now well-aligned interests appeared to be. A faculty member's excitement about their work and research proved conducive to many successful relationships, and serendipity (rather than sheer luck) in being at the right place at the right time was never taken for granted by those who benefited from it. Trainees with pre-existing connections and ongoing projects by the time of their arrival to the program had a clear advantage in securing primary mentors, but relationships cemented later on could prove as productive as those set right out of the gate.Specificity: Where the Rubber Meets the Road. Mentorship cannot take place in a vacuum but rather comes alive in the sharing of particular projects. Content areas of mutual interest could be obvious at times but more often took sinuous paths so as to build on, rather than replicate, a mentor's area of expertise. Trainees often felt a sense of pressure to identify a primary mentor, but many were relieved to instead end up with a network of them: “Monogamy is good in marriage, but non-exclusivity may be the better way to go with mentorship.” Indeed, finding mentors across a range of areas proved to be the norm rather than the exception. Some had “in the weeds, hands-on, directive” expertise in particular topics or methods, while others were better at “big picture” development, and yet others became specialists or problem solvers who could be mustered more selectively. Mentors who were able to zoom in and out from big picture to minute details were rare, but trainees had to make such zooming work, which often led to refining their supportive network.Engagement: Meaningful Connection. Interpersonal dynamics, personality styles, and overall goodness-of-fit were essential to effective working relationships. Conducive to that end was supplanting any intimidating sense of hierarchy or distance with one of collegial partnership and being able to see and value each other as “whole persons rather than as research splices.” Demographic congruence across gender, race, or professional affiliation was valuable, when it could be found. And yet, women, underrepresented minorities, and physicians working in PhD-predominant settings clearly had more to overcome:Where are the women physician-scientists who are going to help me figure out how to keep my research program going? There's actually not a ton of them here.Generativity: Setting High, Yet Realistic Expectations—and Shifting to Sponsorship. Effective mentorship was viewed as a two-way street, in which both partners could contribute to each other's growth. Indeed, through the interconnection of like-minded mentees, the process became a multiple-way street, in which the support and guidance of peers led to a virtuous cycle of personal and scientific enrichment:We review each other's grants. We go through difficult cases, we gripe about things. All of us are at a similar stage in our development. I think the peer group sometimes is the best place to go to, just because comradery is so very important.Mentors were in a unique position as social “matchmakers,” making introductions within the home institution and well beyond. Effective mentors were able to enlarge the reach and specificity of the trainee's network. At their best, mentors embodied generosity by becoming not just rainmakers but sponsors. They did so not only by finding opportunities for funding, presenting, writing, or applying for a position, but also by encouraging their charges to take advantage at such developmentally enhancing junctures. Such mentors helped navigate what could otherwise become an overwhelming number of opportunities; they praised and critiqued progress; they guided and pressed gently; but they never pushed to the breaking point:I think the folks who end up sticking it through with research often are those who have had generous mentors.We identified three discrete subthemes related to “attaining orbit,” the ability to gain professional and scientific independence and to move on after postgraduate training:Harnessing Potential: Carving Our Own Paths. A mentor's ability to see the potential of their mentees and help unleash it was described as “game-changing, if not life-changing.” Trainees and graduates uniformly concurred on the critical role the program and its mentorship components had in shaping their professional trajectories, whether as subtle molding or as outright re-routing. They commented on the sheer variety of opportunities available to them, “a diversity of outlooks that so broadened my own.” They appreciated being guided to novel opportunities, as much as being advised which ones to pass over, as “Saying ‘no’ is a hard-learned developmental task.” As they found their way, many commented on their first independent forays or the intoxicating excitement and positive feedback of early successes:I would have never thought that I was ready to write a paper in my first few months of the program. But my mentors thought I was, and they pushed me to do it, for which I am so grateful. I've kept going ever since.Untethering: Role Transitions. As they approached completion of their 6-year program, graduates thought back to their first job talk and their first job. They identified a vacuum regarding how best to think about and approach either of those new and anxiety-laden developmental tasks. Finding no suitable examples relevant to their very unique set of circumstances, they chose to fill the blanks instead: “I prepared a talk on how to get and negotiate a job, and on what a job talk should and shouldn't be. I realized there was no model or manual out there, so I went ahead and created it, and hopefully others can tweak it in the coming years.”Customizing: Against Equifinality. The measurable outcomes of a program designed to produce clinician-scientists are objective: grant funding, scholarly output, scientific independence, academic positions, and national or international recognition. The ability of some participants to “catch fire” during their training or early post-training years was certainly exciting and cause for celebration. However, effective mentorship and a program true to its core values need to remain aligned to the trainee rather than to the trainee's accomplishments: there can be no universal yardsticks for “success,” nor for “independence” (a concept quite distinct from “scientific independence”).Not all successful partnerships end at the grave, last for life, or are necessarily lengthy. A careful landing may be the appropriate endpoint for an effective launch:Transition, Not Termination. When the process runs its course well, as it usually does, mentorship relationships are not eliminated like so much waste, but rather metabolized differently, as befits the nurturance that they provide. The process can then shift to a better developmental fit, perhaps as mutual consultants, advisors, or mere enthusiastic supporters. Formal terminations may be more fitting for psychotherapy than for academic mentorship, although gentle boundary-setting may be appropriate at times:“I really love the work you're doing, but I don't think that I'm able to do this to the level that would satisfy either one of us.” He was fine with that. We still say hi when we see each other, but it's a little awkward, like breakup-awkward.In such a breakup, as in any worthwhile human relationship, internalization is the proof of its success: mentorship often comes to an end, but the meaningful relationship it is based on can long endure. In fact, the best way to close the cycle of mentorship is to pay it forward by transmitting the internalized lessons of the mentor to a new generation of learners.There are many ways in which mentorship experiences can go awry, which we distilled down to two subthemes. Although such instances were less common in our sample than were the successful relationships, they represented an outsized burden that for some led to a premature departure from research altogether. Even those participants who navigated mentorship successfully would have appreciated the opportunity to have candid discussions on “how to make difficult decisions, like leaving a challenging situation, without having to worry about career consequences.”Vulnerability: Neglect, Attrition, Competition. No matter how collegial the relationship, mentorship in an academic setting takes place within a hierarchical setting of career advancement. A mentor has real power over the mentee's progression, no matter how gently such power is wielded. Participants spoke of the position they could find themselves in…when you open yourself up to someone and devote everything to something: that's when you're most vulnerable and you can get hurt the most.neglect  and attrition . Some connections felt too transient to lead to meaningful connection, others left trainees feeling unwelcome, and yet others were hurtful through unsupportive criticism over not having a sufficiently specific project.The range of suboptimal mentorship experiences included examples of Competition took two different forms: in one, there was a sense of working for, rather than working with, a mentor, a situation in which their respective goals could become conflated, usually to the mentee's detriment:My mentor was too busy to spend time mentoring me. It was an approach that came across as a curt “come in and get to work.” Only later, once I was close to the finish line, did he pay close attention.More often, and on several instances, the competition was external, as when different institutions recruited mentors away, leading to destabilization or frank disruption to ongoing projects.Ejection: When All Else Fails. No experiences of outright abuse were reported during our interviews, although they can certainly happen in the mentorship domain. This may be our good fortune or be due to the early recognition of mounting troubles. For example, trainees described acting on their apprehension by ending mentoring relationships gone wrong . Formalizing an end to such challenging relationships proved helpful, and invariably required involvement and support from program leadership:Maybe I could have been more proactive and assertive, or switched sooner out of a bad situation and not spun my wheels, realizing things were not going anywhere. In the end, I am glad to have cut my losses and moved on. I certainly appreciated the support, as the last thing I wanted was any fallout.The last domain encompasses four themes: (1) Focus, (2) Method, (3) Calling, and (4) Creation, as outlined in focus, his what) and on a specific toolkit :Reflecting back on his prodigal career, the late Donald J. Cohen articulated how he had very early on zeroed in on a specific disorder . The content and aim of a career are its what: a commitment to a specific phenomenon .The hallmark of the method question pertains to discrete approaches at the core of someone's expertise . The means to pursue a question are its how, a powerful approach in that it can be applied to multiple goals at once.By contrast, the whats but not any one of them so much as to want to make it their own. The humble tic, by virtue of being small and narrow, had proven irresistible for Cohen, a perfect soil on which he went on to plant and harvest through the methodological hows of biology, genes, imaging, and psychoanalysis. No such luck for many, perhaps most: “if I settle in on this choice, will I close myself off prematurely to other opportunities?” “just how narrow do I have to become in my interests to make my research career happen?” “am I exploring shifting interests or just dabbling aimlessly?”The challenge for many clinician-scientists early in their trajectories is in liking too many The focus and method constructs may be best fitting for those pursuing careers in “uppercase-R Research,” aiming to be principal investigators, leaders of programs that create new knowledge; in brief, all-in scientists or clinician-scientists. Having a well-defined focus-method pairing may in fact be required for success in Research, particularly when assessed through clearly delineated metrics that are either fiscal  or academic .However, trainees need to recognize that finding an optimal focus-method pairing can take time, involve fits and starts, dead ends, cul-de-sacs, and shifting of gears. The process can be as rational and deliberative as it can be sculpted by chance encounters and serendipity. Aspiring clinician-scientists need to be not just patient, but self-compassionate as well with what can be a lengthy process rife with normative, rather than exceptional, disappointments and rejections. Moreover, clinical research in child psychiatry has added complexities to consider, particularly around the “harder” and “softer” sides of its knowledge base:…there's so much diagnostic fuzziness. And then in spite of that, many psychiatric disorders are so highly heritable. that I think it's really exciting, tying something so precise and quantitative to something as fuzzy and ill-defined.In turn, program leaders need to be cognizant that all trainees, no matter how seemingly settled on a given direction, will need support and guidance in order to balance the breadth of their educational requirements with the depth necessary for research. Additionally, a proportion of candidate may not settle ultimately on a clearly defined and explicit research goal; some may be fulfilled with “little-r” research projects . It behooves program leaders to help each of their trainees find a path that is fitting and satisfying, a path that is responsive to their true calling.what and how to pursue, we all too often collude in losing sight of the where and the who reaching out to them. To misquote JFK, they should not ask what they can do for their country, but rather listen to what their country may be asking of them.By virtue of their long training, aspiring clinician-scientists have been socialized to set out goals and pursue them doggedly. They would not be physicians today, let alone pursuing such advanced education, had they not set out to master 5- and 10-year plans and long to-do lists. Given this professional upbringing, it is only natural that they are keen on pursuing targeted goals. Noble and worthwhile as this approach is, we would argue that we have done much less for our trainees when it comes to heeding the calls coming their way. Overtly centered on serve others: to ease their suffering when possible, and to bear witness and accompany them along the way even when not.The term “calling” is usually understood in the sense of altruism, of doing something for its own good rather than for the rewards it may confer. In the case of medicine, for example, calling may be less about wanting to fix (as this would entail that our patients are somehow broken), to cure , or to benefit . Instead, calling should be construed around a wish to where and the with whom to build a residency, a fellowship, or a longer-term settled life. These places and individuals can, and often do, change over time. It is perfectly acceptable, normative in fact, to change “teams” or affiliations. But once settled in a given setting, the key is to listen attentively to what it is that may be missing, to what that location, those colleagues, and that community may be lacking. With the serious workforce shortage in child and adolescent mental health across our country and the world, clinician-scientists can be certain that there will be much that is needed and will be asked of them. It is up to them to listen in, as multiple fronts are sure to be calling on them.There is another way of conceptualizing “calling” —a more literal way, one more akin to listening. Each one of our trainees has to identify where it is that they are geographically, institutionally, and professionally situated at any given time: weighty decisions regarding the As child and adolescent psychiatry graduates, the search for those elusive settings may be actually rather simple, the answers laying hidden in plain sight all along. Their focus is on children, adolescents, their families and the communities in which they live; their method, the vast toolkit of the profession. The two axes of their focus and method can thus effectively ground and place them. As they settle on a given setting, they can set out to find out what in its lineup may be lacking. Each and every setting will need and call upon them; it is up to them to heed the call—and for program leaders to help them heed it. Whether at a clinic, school, hospital, research lab, or any other setting; and at whatever level of training or years after graduation, everyone participating or leading the program had better listen up, for the call is surely out there.The source of the call may have been very personal for some, who became invested through personal or familial psychopathology: “it is more than defensive sublimation: trying to address what ails us or our loved ones is a noble and worthwhile effort.” Others may have gravitated more generally to the suffering of fellow humans:…none of these things, fortunately, were in my family. No one had a hard time like this, so it wasn't personal for anyone close to me. It was really being around the kids in the clinic through my work in medical school and residency that got me interested. This is a disorder that really needs help. Children and their families need help. We need better treatments.The social and racial unrest that became more overt in recent years, and particularly following the 2020 syndemic of COVID-19 and racial inequity, gave a renewed urgency to “community relevance, not just publications when our house is on fire.” The opportunity—indeed, the responsibility—to address communal and societal challenges, “to telescope out from the single child,” “to communicate with the public and share hope,” “to take on the messy realities out there” was invigorating for yet others:I only knew about community-based research because I got a degree in public health, where everybody knows about it as common knowledge. But as a psychiatrist, as a physician, it is not yet part of our standard vocabulary. I want to address that gap.not to remain in a single academic setting for life. They should celebrate this fact. They should embrace vast new opportunities. And they should be instrumental in their creation.Identifying a job and devoting one's life to it is a formerly effective approach to employment that has diminishing relevance in today's world. And what is true for workers of factory plants, rustbelts, or mechanized farms is similarly applicable to clinician-scientists, who are overwhelmingly likely The job that you will have someday does not yet exist. When we first heard these words from well-meaning mentors, we were scared silent. Inventing a future job from scratch appeared too ill-defined, amorphous, and inchoate a proposition for some as comfortable with structure, security, and predictability as we were. However, time proved the prescient wisdom of those words, as we each have seen ourselves and so many of our colleagues reinvent themselves professionally, moving in a way that hardly seemed linear at the time, but that in retrospect appeared so natural—predestined almost.These words can prove frightening to young trainees, just as they once scared us; alternatively, they may come across as too abstract to be of much use. To that end, we have come to suggest a more direct and even prescriptive approach, a thought experiment for trainees to entertain and revisit periodically:can give back. And when they think back to the first three domains they worked so hard to claim as their own, remind them they have valuable and rare skills: they have a focus (children), a method (their child psychiatry toolkit), and a team to call their own . The one thing remaining is to have those hard-earned skills meet with a commitment to service: it is at the intersection of skills and service that they will be able to give back, and in so doing, to live a more fulfilling life, both professionally and personally:Their very own creation, the one tailored to their unique needs and talents, this one-of-a-kind bespoke, may not yet exist. It is up to them to design this beautiful “garment” of theirs. And if they can think of no way of doing so, we invite them to a challenge that helped us as first-time tailors. For starters, think of how to give back. Whether their reach is local or global; whether it centers on patients, parents, or professional colleagues; whether it is through research, volunteer, educational, or any other means, they …the program allowed me to see myself as a leader and also see that maybe the problem of why I hadn't seen myself as a leader or as leading a lab before was because I thought there were probably enough of those people around. The program helped me realize we were the ones we had been waiting for.The findings from this qualitative study of an integrated clinical and research training program, including the four-domain model we developed, can have practical utility for stakeholders involved in the education of clinician-scientists, particularly—though not exclusively—those in the field of child and adolescent mental health. To illustrate the model's practical utility, we provide examples of lessons learned in going through this exercise. Finally, we address the study's limitations and future opportunities.A useful way of approaching the model is through putative questions that relevant stakeholders could ask themselves by using the domains as points of departure:explore my research interest, or am I ready to commit to it?” In turn, program directors looking to identify the most suitable and best-fitting applicants may consider, “What traits are we looking for in our clinician-scientist trainees?”, “What can we learn about them above and beyond traditional metrics?” Questions such as these can be incorporated as a complement to domains of Career Construction Theory (CCT)  , as was ry (CCT) : concernthis the right program for me?” “Does its balance between structured and unstructured components work for me?” “Just what is the right amount of structure and freedom for me to thrive in?” For their part, directors and developers can contemplate, “How can we improve and optimize the program?” In the next section, and based on our own experience, we provide two concrete answers to this question.Once set on a clinician-scientist direction, a candidate can go on to ask: “Is By the time a trainee is settled on a program, en route to it in fact, the questions should swivel to how to maximize the training experience: “Who in the program can help me make the most of my time there?” “What is the right number and constellation of mentors for me?” It could be limiting or even risky to rely on a single mentor, yet an overabundance of mentors could become dilute, confusing, or simply too time-consuming. The sequence and timing of mentor outreach is important, as is bearing in mind that even brief mentorship encounters can be incredibly productive. For their part, mentors and would-be mentors can consider, “How can I be the best mentor for this particular trainee?” or “How can I optimize my experience and background toward the benefit of someone else?”Where your deep gladness meets the world's deep hunger is where you should be: there lies your vocation. The reply we would give our charges works just as well when self-directed: Don't let them worry alone if they can't figure it all out at once; they may get there sequentially, but then again, they may not. Help them anticipate and adapt to change and the certainty of vicissitudes. Support them during the time it will take to find out what gives them real joy, what is the deep gladness looking to break out of them. Help them embrace, find, or reconnect with their true vocation. They will find it at the crossroads of their deep gladness and the deep hunger out there—a hunger so keenly felt by those they are privileged to serve.The fourth domain does not lend itself to as clear a distinction among the perspectives of trainees, mentors, or program directors. And that is because the charting of a career's course should be a lifelong quest for each and every one of us. In answering the key question “Who do I want to become?” words adapted from Frederick Buechner  can provParticipants in the study showed remarkable candor. It was clear that by not holding back in either enthusiasm or critiques, they were providing constructive feedback to a program they care deeply about, whether as trainees or alumni. However, there were two aspects in which they seemed more circumspect, finding it harder to share with quite the same level of comfort or openness: their personal mental health, and doubts about long-term commitment to research. Rather than pressing the issues during the interviews, we have taken them as a call for action.training than to treatment, e.g., “growth-enhancing,” “enriching,” “useful,” “being on the other side.” Moreover, no one overtly acknowledged personal psychopathology, which would represent a major statistical anomaly, considering the high prevalence of psychiatric illnesses in young adulthood. Indeed, physicians have rates of depression even higher than the lay public ; and (2) transferability, or the applicability of findings to other settings and programs .First, we recognize that, as direct stakeholders directly involved in the AJSP, our views may be biased in a way than an outsider's might not be. To that end, we do not consider this study a formal evaluation of the program, for that purpose relying instead on the annual metrics set out by appropriate governing bodies, and on reporting requirements from funding agencies. Moreover, we have an external advisory board, and additionally conducted a consultation with outside experts after the initial decade of the program. We should also note that there was a substantial amount of feedback about programmatic granularities that we left out of this analysis and which may still prove useful in our efforts to improve the overall quality of the program in moving forward. Second, we did not interview stakeholders other than current trainees and graduates from the AJSP; the perspectives of program leaders, mentors, and external advisors are thus lacking. Finally, we recognize the limitations inherent to a single-site study conducted in a developed country and high-resourced setting. However, we consider having done well on the trustworthiness of our report as reflected by two qualitative constructs , 32: (1)In summary, we conducted a qualitative study based on individual interviews of all participants enrolled over the course of the 17-year history of a program designed to develop clinician-scientists dedicated to child and adolescent mental health. We developed, through iterative thematic analysis, a four-domain model resulting from the intersection of a developmental perspective  and a reflective direction (outward- or inward-facing vantage points). The model can be fruitfully applied to individual or programmatic evaluations and can help identify, refine, and replicate programs that are urgently needed to increase the working force of clinician-scientists dedicated to advancing the child and adolescent mental health agenda.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author/s.This study involved human participants and was reviewed and approved by the Yale Human Investigations Committee (Protocol # 2000027895). Written informed consent for participation was not required for this study in accordance with national legislation and institutional requirements.AC and AM designed the study. AC conducted the interviews. AC and OH took the lead in analyzing the transcripts. AM drafted the first version of the manuscript and is responsible for the integrity of the data and the analyses. All authors reviewed and contributed to working drafts and approved the final submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Laryngeal cancer (LaC) remains one of the most common tumors of the respiratory tract with higher incidence in men than in women. The larynx is a small but vital organ on the neck. The dysfunction of the larynx can cause serious health problems such as hoarseness, respiratory distress, and dysphonia. Many lipids  have been recognized as a crucial role in tumorigenesis. However, the lipid biomarkers are lacking and the lipid molecular pathogenesis of LaC is still unclear.via ultra-high performance liquid chromatography (UHPLC) coupled with high resolution mass spectrometry (HRMS). Multivariate and univariate statistics analyses were used to discriminate LaC patients from NC.This study aims to identify new LaC-related lipid biomarkers used for the diagnosis or early diagnosis of LaC and to uncover their molecular characteristics. Thus, we conducted serum and tissue nontargeted lipidomics study from LaC patients (n = 29) and normal controls (NC) (n = 36) As expected, a lipid panel including LPC (16:0) and PE (18:0p_20:4) was defined to distinguish the LaC patients from healthy individuals with very high diagnosis performance (area under the curve (AUC) value = 1.000, sensitivity value = 1.000, and specificity value = 1.000). In addition, the levels of Cer, CerG1, SM, PC, PC-O, PE, PI, PS, and ChE in the LaC group significantly increased as compared with the NC group. However, the levels of LPC, LPC-O, LPE, LPE-p, and DG in the LaC group significantly deceased when the one was compared with the NC group. Among significantly changed lipid species, lysophospholipids containing a palmitoyl chain or an arachidonic acid acyl chain remarkably decreased and phospholipids including a palmitoyl chain or an arachidonic acid acyl chain increased in the LaC patients.Our results not only indicate that lipidomics is powerful tool to explore abnormal lipid metabolism for the laC, but suggest that lysophospholipids and phospholipids may serve as potential biomarkers for diagnosis of LaC. Laryngeal cancer is the most common head and neck cancer, causing heavy health care and economic burdens. Currently, the Global Burden of Disease Cancer Collaboration estimated the prevalence of LaC to be 21.1%, with a male to female ratio of 5:1, and approximately 10% of patients in metastatic or end-stage  and a set of 36 sex-age matched normal controls (NC) were from the Second Hospital of Dalian Medical University  during the period 2018 to 2020. These subjects were in the age range of 53–80 years. Among these LaC serum samples, 15 cases were in the early stage of laryngeal cancer, i.e. T1NOMO stage. The LaC serum samples were collected before surgical resection and then stored at −80°C until lipidomics analysis. Eighteen LaC tissue (LaCT) and 16 adjacent noncancerous tissue (ANT) samples were also provided by the Second Hospital of Dalian Medical University . Among these LaC tissue samples; 11 cases were in T1NOMO stage. This research was approved by the Second Hospital of Dalian Medical University Institutional Ethics Review Board, and all participants provided written informed consent.g) until to form the two-phase system. About 400 µl aliquot of the upper layer were drawn and dried in a vacuum centrifuge and then stored at −80°C prior to LC-MS analysis. Quality control (QC) samples were made by mixing equal aliquots from each serum sample and pretreated using the same procedures as that description of the real samples. The QC sample was inserted into the batch after every six real samples to assess the reproducibility of the preparation and the LC–MS system.Serum samples taken out of the −80° refrigerator were thawed and homogenized by vortex. A total of 300 µl of cold methanol  including seven lipid internal standards , LPC (19:0), Cer (d18:1/17:0), SM (d18:1/12:0), PC (19:0/19:0), PE (17:0/17:0), TG (15:0/15:0/15:0)), purchased from Avanti Polar Lipids , was added into 40 µl of each serum sample, followed by a 30-s vortex. Then, 1 ml of HPLC-grade tert-butyl methyl ether (MTBE) was added and the mixture was homogenized for 10 min. After that, 300 µl of ultrapure water  was added. Next, the mixture was vortexed and centrifuged  until to form the two-phase system. About 200 µl aliquot of the upper layer were drawn and dried in a vacuum centrifuge and then stored at −80 °C before LC–MS profiling. Details on lipid internal standards that were added to samples before lipidome extraction are summarized in Tissue sample were weighed. About 400 µl of cold methanol including seven lipid internal standards was added, followed by the homogenization at 25 Hz for 2 min on a mixer mill MM400 . And then 1 ml of MTBE was added and the mixture was vibrated for 15 min. After that, 300 µl of ultrapure water was added. The mixture was vortexed and centrifuged  and then diluted in the ACN-MeOH-H2O solution (65:30:5 v/v/v). Next, 5 µl of the diluted sample was separated on the C8 ACQUITYTM column , . The column temperature was kept 60°C. The elution rate was set 0.3 ml/min. The mobile phase A was ACN:H2O (6:4 v/v) and the mobile phase B, was IPA: ACN (9:1 v/v), both containing 10 mM ammonium acetate. The initial elution gradient began with 50% B, kept for 1.5 min, followed by a linear increase to 85% B at 9.0 min, then reached at 100% B within 0.1 min, and maintained for 1.9 min. Lastly, it returned to 50% B within 0.1 min and held for 1.9 min to equilibrate column. The scanned m/z range of MS signal was 200–1,250 Dalton in both positive and negative ion modes. The capillary voltages of the positive and negative ion modes were set at 5.5 and −4.5 kV respectively. The interface heater temperature was set at 500 and 550°C for positive and negative ion modes, respectively.The lipidome was analyzed using Waters ACQUITY UPLC  coupled with a Triple TOF 5600 Plus mass spectrometer  system. Before LC–MS analysis, the lyophilized samples were reconstituted in the mixed solution including CHtR. And then, these lipid candidates were further confirmed by comparing the relative tR between the known lipids and the candidate peaks within a given lipid class.The structural compositions (e.g. PC18:0_20:4) of lipids were identified when characteristic ions and fatty acyl fragments appeared in the MS/MS spectrum. For those without fatty acyl fragments but with only characteristic ionic information, they would be annotated with total no. of carbon atoms and double bonds of acyl chains, e.g., PC36:0. Furthermore, for lipids that could not produce MS/MS fragments, extraction ion chromatogram (EIC) was performed based on an in-house lipid database for these lipids with a mass tolerance of 10 ppm to obtain the observed m/z and via MultiQuant™ 2.1  software with a mass error of ±0.05 Da and tR shift of ±0.25 min. Lipidomics data were normalized by the corresponding internal standards.The lipids were identified according to previous published paper . The detvia dividing each variable by the square root of the standard deviation. Nonparametric test in Wilcoxon, Mann–Whitney test mode, was implemented to identify significantly altered lipids (p <0.01 & FDR <0.05) by the comparisons between the LaC and NC groups and heatmap was produced by the open-source software MultiExperiment Viewer . Receiver operating characteristic (ROC) curves of a binary logistic regression using SPSS software version 19  were performed. The bar graph of the significantly differential lipid (sub)classes was drawn on the GraphPad Prism software (6.0 version).The supervised partial least-squares discriminant analysis (PLS-DA) was performed on SIMCA-P software , in Pareto scaling mode, which suppresses noise interference The detailed clinical information of the LaC and NC groups are provided in tR), and/or characteristic fragments. And the list of exact m/z values and retention times and characteristic fragments of all the lipid species identified was provided in Lipidomics profiling was performed for comparative analyses of the serum samples collected from the LaC patients (n = 29) and the NC subjects (n = 36). The total ion current chromatograms of serum were shown in tR, and/or2 =  and Q2 =  shown that this model is stable. These results implied that substantial lipidome alternations occurred underlying the onset and development of LaC. Sixty-two lipids with variable importance for the projection (VIP) >1.0 were recognized as key variables that contribute to the classifications.A supervised PLS-DA model was made based on those identified lipids from serum samples to explore whether abnormalities in lipid metabolism occurred during the development of laryngeal cancer. In At present, the identification of novel serum markers for diagnosing LaC remains a vital task, especially for the early detection of LaC . In the p value <0.01 and false discovery rate (FDR) value <0.05). The information of the differential lipids are provided in p <0.01, FDR <0.05 and VIP >1.0 in the two comparisons  was performed based on the lipidomics data from the LaC and NC groups. The levels of 204 lipids were noted significant changes between the LaC patients and the NCs . The results shown that the relative contents of Cer, CerG1, SM, PC, PC-O, PE, PI, PS, and ChE in the LaC group significantly accumulated relative to the NC group. The levels of LPC, LPC-O, LPE, LPE-p, and DG in the LaC group significantly deceased when the one was compared with the NC group class. For this purpose, the total content of all lipid species within a given (sub)class was compared between the LaC and NC groups according to Student T- test  with an arachidonic acid acyl chain and/or a palmitoyl chain significantly increased in LaC vs NC, and the levels of LPCs with an arachidonic acid acyl chain and/or a palmitoyl chain significantly decreased in LaC vs NC Figure 5In this study, there were no significant differences in most clinical characteristics Table 1 In vivo, Cer can be also generated by the hydrolysis of SM through the actions of sphingomyelinases. Modulation of endogenous Cer levels is considered as a new therapeutic target for anti-cancer intervention strategies , shows preferential use of AA as its substrate and plays a role in the remodeling of AA-containing glycerolphospholipids by binding free AA. In consideration of significant increase of AA-residue-enriched PLs , PE(16:0_20:4), PE(16:0p_20:4), PE(18:0p_20:4), PI(16:0_20:4), etc.), and the level of AA, so-called FA (20:4) significantly decreased in LaC serum, we speculated that ACSL4 may be activated and thereby prompt PLs accumulation, which associated with a greater degree of carcinogenesis in LaC tumor cells characterized by very abundant mitochondria. Of course, further investigation should be performed to explore our findings.In summary, using nontargeted lipidomics method based on UHPLC-HRMS, we successfully identified a lipid panel [including LPC(16:0) and PE(18:0p_20:4)] that can effectively diagnose LaC from their cohort of healthy controls. Similar, this lipid panel shows ultrahigh performance in detection of the early-stage LaC from the healthy volunteers. To our best knowledge, this study provides the first evidence of a systematic alteration in lipid composition between LaC and NC groups. Cer, SM, and AA-enriched PLs showing close association with LaC, may be potential biomarkers and become potential targets for LaC. Out of consideration for the given small sample size, and to ensure the plausibility of our study results, further studies based on large-scale clinical samples and on the expression of related lipid enzymes will be required.https://www.ebi.ac.uk/metabolights/MTBLS2683.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The studies involving human participants were reviewed and approved by the Second Hospital of Dalian Medical University. The patients/participants provided their written informed consent to participate in this study.JW and BY conceived and designed the project. BY collected the clinical samples, performed the experiments, and analyzed the data. BY and JW wrote and improved the manuscript. JW and BY are responsible for the integrity and accuracy of the data in the research. All authors contributed to the article and approved the submitted version.This study was supported by the National Natural Science Foundation of China Grants (No. 11772087), and the Joint Fund Project of Collaborative Innovation Center for Individualized Diagnosis and Treatment (dy2yhws201805).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Aim: The aim of this study was to investigate the utility of serological tests for the diagnosis of COVID-19 during the first week of symptom onset in patients confirmed with the real-time RT-PCR. Materials & methods: A systematic review and meta-analysis of 58 publications were performed using data obtained from Academic Search Ultimate, Africa-wide, Scopus, Web of Science and MEDLINE. Results: We found that the highest pooled sensitivities were obtained with ELISA IgM-IgG and chemiluminescence immunoassay IgM tests. Conclusion: Serological tests have low sensitivity within the first week of symptom onset and cannot replace nucleic acid amplification tests. However, serological assays can be used to support nucleic acid amplification tests. COVID-19 is a pandemic caused by SARS-CoV-2. The virus first emerged in Wuhan, China in December 2019 ..19–76]. The global distribution of identified articles include China (n = 14), the USA (n = 10), France (n = 8), Italy (n = 3), Singapore (n = 3), Germany (n = 3), India (n = 3), Taiwan (n = 2), Belgium (n = 2), while Switzerland, Austria, Bahrain, Brazil, Iran, Italy, Japan, Sweden, Thailand, Qatar and the United Kingdom each contributed one article. Two of the selected studies were conducted in more than one country ,64.A range of serological assays were evaluated in the identified articles and these include CLIA (n = 64), ELISA (n = 49), LFIA (n = 31), luciferase immunoprecipitation system (n = 3), Immunoblot and flow cytometry-based assays were each reported in single studies. One study used synthetic peptides derived from the open reading frame 1a/b, S and N proteins to develop a chemiluminescent assay to detect IgM and IgG against SARS-CoV-2 . The antForty-four papers reported diagnostic data on commercial serological kits while 18 studies reported data obtained using in-house developed kits . In fiveSupplementary Table 6). Specificity data based on days after onset of symptoms was not reported in the identified articles. In three articles [We identified 22 articles that reported the sensitivity data from onset of symptoms up to 7 days post symptom onset and extracted data on sensitivity, the antigens targeted, and the antibodies detected . Eight antigen formats were described in the assays and the most frequently evaluated immunoglobulin classes included IgG (n = 36) and IgM (n = 16). Three studies evaluated IgA and reported sensitivities of 37.5 [A total of 60 serology methods were extracted including CLIA (n = 26), LFIA (n = 17), ELISA (n = 16) and flow cytometry (n = 1). A total of 61 results were extracted and analyzed since some of the methods gave more than one result for immunoglobulin type detection . Significant heterogeneity was observed for all tests except the CLIA IgM-IgG, ELISA IgG, ELISA IgM-IgG and LFIA IgM-IgG tests.We next evaluated heterogeneity for the LFIA, CLIA and ELISA based methods (Supplementary Table 7). A total of 73 serology methods were extracted consisting of CLIA (n = 33), ELISA (n = 27), LFIA (n = 10) and one each for flow cytometry, microarray and immunoblot based assays. Sensitivities reported with the luciferase immunoprecipitation assay [We identified 33 articles that reported the overall sensitivity and specificity  ranged from 0.37 (95% CI: 0.27–0.48)  to 0.96 The overall performance of serological tests compared with the rRT-PCR was evaluated and the results are shown in Supplementary Table 2). Significant heterogeneity was observed only with the CLIA IgG, ELISA IgG, ELISA IgM-IgG tests.We also evaluated heterogeneity for the LFIA, CLIA and ELISA based methods  to 99% (95% CI: 96.09–99.71) compared with the rRT-PCR. Similar studies have reported pooled specificities spanning from 95% (95% CI: 91–98) to 99.9% 97.78–100) ,15,77,78–100 ,15,Supplementary Table 4). Unlike previous studies that have reported lower sensitivities with the LFIA test method compared with the CLIA and ELISA based assays within each antibody class [Overall, CLIA IgM-IgG demonstrated superior diagnostic accuracy with sensitivity and specificity of 88.1% (95% CI: 84.26–91.01) and 98.6% (95% CI: 96.34–99.38) respectively. Since the 95% CIs were overlapping, we performed statistical analysis of the pooled mean sensitivities to determine whether they were significantly different across the different sets of tests used. The pooled mean sensitivity obtained with CLIA IgM-IgG was significantly higher than LFIA IgM and CLIA IgG only  and ELISA IgM-IgG, 44.3% (95% CI: 25.72–63.5) compared with rRT-PCR. Previous meta-analysis reported pooled sensitivities ranging from 0 to 53.2% (95% CI: 28.7–67.6) ,77,78. OSupplementary Table 5).We evaluated the immunoglobulin class and antigens that can be targeted to maximize the performance of serological tests. Overall, CLIA based assays measuring the total antibody against the RBD had the best diagnostic accuracy with sensitivity and specificity of 93.3% (95% CI: 88.54–96.03) and 98.8% (95% CI: 96.54–99.59), respectively . A previSupplementary Table 3). There was no enhanced benefit of assaying both IgM and IgG with the CLIA based assays during the first week of symptom onset. Overall, detecting both IgM and IgG was superior to detecting IgG or IgM with the CLIA and LFIA tests (Supplementary Table 4). However, larger studies would be required to verify these results.We assessed whether serological tests detecting both IgM and IgG have higher diagnostic sensitivity compared with tests measuring either IgM or IgG. Such knowledge would assist in prioritizing the procurement of serological diagnostic kits. Our study shows that combining IgG and IgM yields higher sensitivity compared with measuring IgM alone with ELISA tests and IgG in LFIA tests within 7 days of symptom onset (et al. and Vengesai et al. reported higher pooled sensitivities with the CLIA IgG and LFIA IgG based serological assays compared with the respective IgM test methods albeit with overlapping 95% CIs, while with the ELISA methods higher positivity was obtained by detecting the IgM [The performance of IgM-based assays was evaluated against the IgG based serological tests in our study. Regarding overall estimates of diagnostic accuracy, CLIA IgM and ELISA IgM serological methods had higher pooled sensitivity estimates compared with the CLIA IgG and ELISA IgG test methods. In LFIA tests, detecting the IgG seemed to be a better choice than assaying the IgM. The meta-analysis by Bastos  the IgM ,15. Rega the IgM ,81,82. T the IgM . IgA has the IgM ,85 thus  the IgM , 33.3 [2 the IgM  and 23%  the IgM  within tThis study has some limitations. The magnitude of immune response is influenced by several factors such as age, disease severity and the presence of immunodeficiency disorders which were not considered among the study participants from which blood samples were collected. Studies stratifying the study population according to age, disease severity and immune health are therefore necessary. Studies included in the analysis stratified patients according to the date of symptom onset, relying on participants recalling from memory thus potentially introducing recall bias. In addition, there was insufficient data in the studies to evaluate the cross-reactivity of the serological assays.Choice of antigen did not appear to influence the outcome of sensitivity although there were differences in sensitivity for different types of assays performed. Our results show that serological tests based on CLIA IgM and ELISA IgM-IgG were the most sensitive during the first week post symptoms onset. As mentioned previously, the role of antibody detection has limitations in acute diagnosis because of the time taken for the development of an endogenous demonstrable antibody response. However, in resource-challenged settings, serology could play a role taking into consideration the limitations of sensitivity when interpreting the results.The present systematic review presents a synthesis of the sensitivity of antibody tests commonly used to diagnose COVID-19. It also assesses which antibody tests could be used to support RT-PCR for the diagnostic of COVID-19.Research articles describing or comparing antibody tests for the diagnostic of COVID-19, were extracted from various databases. Those including at least 300 samples tested were included in this study. The sensitivity data were extracted at different time points post positive RT-PCR diagnostic, and a meta-analysis was performed.The data showed that measuring IgG and IgM yields higher sensitivity compared with measuring IgM alone with ELISA and IgG in lateral flow immunochromatographic assay tests within 7 days of symptom onset and the highest pooled sensitivities were obtained with IgM-IgG and chemiluminescence immunoassay IgM tests within the first 7 days.Serological tests have low sensitivity within the first week of symptom onset and cannot replace nucleic acid amplification tests. However, serological assays can be used to support nucleic acid amplification tests and have application in surveillance. Serological tests based on chemiluminescence immunoassay IgM and ELISA IgM-IgG were the most sensitive during the first week post symptom onset.Click here for additional data file.


OBJECTIVES/GOALS: The goal of this project was to a) evaluate the first five years of Miami CTSI’s Pilot Translational and Clinical Studies Program using outcome measures that quantify research productivity augmented by the CTSA Common Metrics; and b) use the results to shape future program management. METHODS/STUDY POPULATION: Pilot Program applicant and awardee demographic data were collected during the first 5-year cycle of the Miami CTSI grant. Projects were categorized into the translation spectrum based on type of research using published guidelines. Research productivity from funded pilot projects were tracked annually using internal institutional grant award databases and external databases such as PubMed and NIH Reporter. CTSA Common Metrics were tracked using the Results Based Accountability framework. Relative Citation Ratio (RCR), NIH percentile and translation impact of pilot project publications were determined using the iCite tool . RESULTS/ANTICIPATED RESULTS: The Miami CTSI’s Pilot Award Program demonstrated notable success in its first five years. Of the twenty-two projects that were funded during that time period, 45% led to follow-on funding for a total of $17.2M—a strong return on investment of 15:1. Further, 77% of awardees had at least one publication. A total of four patents and 43 publications resulted directly from the funded projects. The mean RCR for all publications was 2.7, weighted RCR was 99.87, and nine papers were been cited by clinical documents. Overall, 63% of the projects were classified as T1/T2  and 37% as T3/T4 . DISCUSSION/SIGNIFICANCE OF IMPACT: Miami CTSI’s Pilot Award Program demonstrated success in scholarly output, follow on funding, and scientific impact. These results will serve as benchmarks going forward and will allow the CTSI to leverage program strengths in collaborating with other institutional internal award mechanisms.