Understand barriers and facilitators to follow-up care for infants with bronchopulmonary dysplasia (BPD).Qualitative study of parents and clinical stakeholders caring for infants with BPD. The interview guide was developed by a mother of a former 23-week preterm infant, neonatologist, pulmonologist, nurse, and qualitative researcher. Purposive sampling obtained a heterogenous sociodemographic and professional cohort. Subjects discussed their experience with BPD, barriers to care, caregiver quality of life and health education. Interviews were audio-recorded, transcribed and coded. Thematic analysis was used.Eighteen parents and 20 stakeholders completed interviews. Family-level themes included pragmatic barriers like transportation being multi-faceted; and caregiving demands straining mental health. System-level themes included caregiver education needing to balance process needs with future trajectories; and integration of primary care, specialty care, and community supports.Individual and system barriers impact follow-up for infants with BPD. This conceptual framework can be used to measure and improve care. Infants born extremely preterm are at high risk of developing bronchopulmonary dysplasia (BPD).–7 In theMultidisciplinary supports after NICU discharge are intended to improve outcomes for infants; however, specialty care can only improve outcomes if families can access supports. Unfortunately, families of infants with BPD may face significant barriers to care. Prematurity disproportionately impacts families experiencing socioeconomic disadvantage, who in turn experience barriers to accessing the outpatient follow-up care that could improve health outcomes.–24 SocioThe goal of this study was to better understand barriers and facilitators to care among stakeholders and parents of infants of BPD, in order to understand how to improve discharge preparation and follow-up care for infants with BPD.This was a qualitative study using semi-structured interviews of parents and clinical stakeholders caring for infants with BPD, following consolidated criteria for reporting qualitative research. Parents Interviews were conducted individually by a research assistant trained in qualitative interview methods. The interviewer is a doctoral student and mother of a former 23-week preterm infant, working in collaboration with a neonatologist, pediatric pulmonologist, nurse, and qualitative research expert to construct the interview guide. Stakeholders and parents were told about the members of the interview team and the background of the interviewer. Interview guides followed a similar format for parents and stakeholders . For parInterviews were audio-recorded, transcribed verbatim and coded using MAXQDA 2022 qualitative analysis software; field notes were made after each interview. Transcripts were not returned to interviewees for review, but a preliminary summary of findings was made available to interested participants for feedback. Four members of our team, representing both clinical and methodological expertise, read two transcripts and discussed a high-level summary of themes to develop a preliminary codebook. To facilitate team-based coding, our codebook included a code name, a definition, inclusion and exclusion criteria to help distinguish codes from one another, and examples. The final codebook included stakeholder role (including direct and indirect care), pragmatic barriers , resources, education (including content and delivery), system , policy , family capacity , and addressing barriers or gaps in care (including screening and timing of barriers). We used a three-pronged analytic coding strategy which included open, axial, and selective coding., 36 InteA total of 25 parents were approached for participation; 25 agreed to participate, and 18 completed interviews with the remaining 7 not completed due to scheduling difficulty and thematic saturation. A total of 22 stakeholders were approached for participation; 20 completed interviews. Parents represented a range of education, income, race and ethnicity. Stakeholders represented a range of specialty and primary care, social work, care coordination, and community services . Each inInterviews of parents and stakeholders identified four primary themes . Family-Pragmatic barriers to attendance in the NICU and post-discharge appointments were commonly described by both parents and stakeholders . TranspoMost parents felt that the NICU and clinics do well in addressing needs such as transportation. While receiving resources was helpful in reducing barriers, some parents described wanting to be aware of resources sooner. Stakeholders agreed that there was a lack of awareness of available resources, which may be due in part to limitations in systematic screening for social needs. Reasons provided for limited systematic screening included changing needs over time which may not be uncovered during initial screenings, a perceived overwhelming degree of needs, and insufficient supportive resources.Parents commonly expressed challenges balancing the competing life demands of employment and family in addition to the caregiving needs of an infant with a complex health condition . SpecifiStakeholders similarly identified that families were challenged with competing life demands such as balancing work and childcare responsibilities, and the strain placed on individuals and family relationships. Some stakeholders expressed that fear of the healthcare system after their experiences with pregnancy and the NICU can lead to a need to get away from the hospital and potentially avoid subsequent healthcare system exposure, but can also lead to fear of leaving the hospital and hypervigilance about certain symptoms. Clinical stakeholders expressed the importance of family functioning in supporting child health, but most acknowledged that they do not universally ask about these issues due to available time and resources. From a stakeholder perspective, facilitators to improving family function included better resources to support both pragmatic needs and psychosocial support.Parents overall described receiving excellent instruction focused on equipment management and infant care . FacilitStakeholders identified several discrete educational needs. These included process needs such as understanding equipment, handling medication refills, and knowing who to call after discharge; acute care education such as mitigating viral exposures and actions prior to seeking emergency care; and preventive care needs such as the role of specialty follow-up. Specific to infants with BPD who have had ongoing intermittent desaturations in the NICU for weeks to months, a gap was also noted in understanding the importance of appropriate oxygen saturations. Expected trajectory was identified as a gap; examples included expectations for school, exercise limitation, duration of respiratory support, and when childcare outside the home could be safer. Stakeholders emphasized that health literacy and stress were major barriers to educating families around infant diagnosis and care needs.Parents thought that scheduling post-discharge appointments was not a challenge in itself; however, clustering appointments together was difficult given limited appointment availability . ParentsStakeholders also highlighted that specialty provider availability can pose barriers to care. The use of care coordination services was seen as a potential facilitator to help alleviate the challenges of multiple appointments, but limitations included that families may not appreciate that benefit immediately. Another issue that stakeholders highlighted was conflicting recommendations between providers leading to confusion; examples included recommendations on nutrition issues or who to call with acute respiratory symptoms.Some constructs were present across multiple individual and system themes . Social The goal of this study was to identify barriers and facilitators to care among stakeholders and parents of infants of BPD, in order to understand how to improve discharge preparation and follow-up care specific to this condition. Our main findings were: 1) the multi-faceted nature of social needs exacerbates barriers to screening and resource referrals; 2) competing health and caregiving demands strain family functioning and mental health; 3) caregiver education needs to balance tangible process needs and expected trajectories within the context of stress and variable health literacy; 4) care coordination opportunities are both important and constrained by system limitations in pediatric subspecialty care.Given the lengthy NICU stays, and frequent outpatient appointments required of infants with BPD, it is not surprising that pragmatic barriers such as transportation were a major theme impacting access to care. Both parents and clinical stakeholders recognized that supporting needs such as transportation were multi-faceted, and both parents and clinical stakeholders recognized the limitations of community resources in supporting these needs. In response to these barriers and limitations, parents more frequently expressed desires to be provided with earlier, ongoing screening to increase their awareness of resources. Stakeholders were more likely to prefer in-person introductions to establish rapport and understand a family’s needs in more detail; after that introduction, subsequent resource referrals were more likely to occur after a pattern of nonattendance or an explicit request. From a system standpoint, depending on in-person interaction to identify a need for assistance with getting to in-person appointments can delay or prevent understanding of families’ needs and getting them connected to resources. Systematic screening for social determinants of health is increasingly recognized as an important way to improve health outcomes.–43 The aBoth parents and stakeholders recognized the family and mental health strain resulting from competing caregiving demands. While some aspects of social support are not modifiable by a health care team, it was encouraging to observe that parents identified several actionable ways to increase family capacity. Identifying ways to increase educational offerings such that additional caregivers do not need to be trained solely by the parent who was able to be at the bedside could be an important facilitator of post-discharge family capacity, since the differential in caregiver comfort causes frequently reported family strain. Videos or multi-media offerings could assist family caregivers who are not able to be present for all hospital and clinic-based education. Anticipatory support for mental health including the trauma of preterm birth and emotions surrounding a baby who requires significant post-discharge medical supports are important topics to address before and after NICU discharge. Most NICUs have limited social work and psychology resources to assist families, but this limitation is likely even more pronounced in the outpatient setting. Systematic outpatient psychosocial support as part of NICU follow-up is critical especially for fragile infants such as those with BPD, since parents commonly describe that nothing could prepare them for the emotional toll of home caregiving despite their cognitive preparation.While both parents and stakeholders generally identified good education to help teach processes related to their infants’ care needs, they all also agreed on the gap in education on expected needs of a child with BPD over time. Even for infants with multiple outpatient clinical and community support resources, the weeks and months spent in the NICU before going home may be the majority of time available for direct hands-on family caregiver education. This time is spent learning infant care, which can be overwhelming even before adding the complex needs of an infant with BPD. Strategies to enhance anticipatory guidance about life after the NICU might include earlier identification of equipment and medication needs, and more proactive meetings with relevant outpatient specialists to understand early childhood needs. It should be noted that some themes emerged in duality, such that it was difficult to disentangle family functioning from educational themes that pose barriers to meeting the needs of families with a child with BPD. Ongoing psychosocial support and multi-media educational offerings are crucial to working effectively within the context of stress, rotating work schedules, and variable health literacy that limit the ability to process information.Even in the context of perceived high quality specialty care, families and stakeholders noted system limitations to care coordination. Dedicated care coordination teams are helpful facilitators to complex care, but do not always enroll infants with BPD going home from the NICU. NICU-specific transition-home programs have been shown to be effective in reducing health care expenditures and readmissions but have not become widespread across NICUs.–47 Our fStrengths of this study include an interview guide designed to elicit multiple levels of potential barriers to care, parallel interviews between both parents and clinical stakeholders, intentional sampling strategy to recruit a diverse range of participants, and analysis integrating the perspectives of a parent of a preterm infant, nurse, and physician. Our findings provide detail that can be used to understand opportunities for system interventions to improve care for infants with BPD. We acknowledge several limitations. The study was conducted at one health system, although we did explicitly recruit parents of infants cared for at multiple NICUs. Although our qualitative strategy allows for a detailed understanding of perspectives, and we interviewed until reaching thematic saturation, the study cohort may not be representative of the whole population. Although the interviewer self-identified as a parent of a preterm infant and not a direct healthcare provider, there may be some desirability bias affecting parent willingness to acknowledge barriers within the healthcare system. Although the interview guide was constructed by multidisciplinary members of the research team, the interviewer’s life experience as a parent of preterm infant with BPD may have led to researcher bias. Additionally, parents who are unaware of community resources or healthcare system differences may not be able to fully identify potential barriers to obtaining care for their infant. Clinical stakeholders employed by our healthcare system, although anonymous, may also experience desirability bias in discussing potential system limitations to care. They also may differ in their sense of frequency of barriers to care compared to families, as has been demonstrated previously. In this qualitative study of parents and stakeholders, we identified discrete yet inter-related domains of barriers and facilitators to follow-up care for infants with BPD after the NICU. These include pragmatic social barriers, caregiver strain impacting family functioning, family function impacting educational needs, and opportunities and limits to care coordination for pediatric specialty care. Despite different perspectives, families and stakeholders converged on several themes that could improve care for infants with BPD in the transition home from the NICU. This framework can help inform measurement and quality initiatives to improve the process of discharge for infants with BPD.


These findings not only address the central questions of regenerative biology but also have potential implications for regenerative medicine. Whole-body regeneration is a multifaceted process that reinstates a body to its initial three-dimension size and structure after resection injury. It is well-known that signaling waves such as calcium and extracellular signal-related kinase (ERK) signaling waves can efficiently transmit information between tissues or cells. However, the mechanisms responsible for coordinating wound responses over long distances are largely unexplored. A recent study has reported that the propagation of ERK signaling waves  The comprehensive coordination of cellular dynamics at the tissue level that is necessary for appropriate morphogenesis and regeneration, encounters difficulties due to the substantial dimensions of regenerating body parts (Bertero and Murry 2+ waves and transmission of action potentials along neuronal pathways, other signaling waves such as Cdk1, Thrombin, and Notch waves have been shown to have significant impact on a variety of biological processes (Dashkevich et al. In order for spatiotemporal coordination to occur, regenerative signals need to propagate through both space and time. Ways in which signaling molecules can spread through space are well recognized as diffusion and active transport (Deneke and Di Talia Another elegant work presents the critical role of rhythmic travelling EKR waves in regulating the tempo-spatial growth of bone in regenerating zebrafish scales (De Simone et al. When examining the process of regeneration in vertebrates, our attention is typically directed towards a single organ, such as limb, brain and heart, etc. Regeneration of these organs usually takes weeks to months and requires the activation of a number of specific cell pools. And identifying remote responses and mapping communication networks between organs pose significant technical challenges. Planarian flatworms have the ability to regenerate into fully functioning organisms from small pieces of tissues in just a few days. Injury causes extensive alterations in gene expression across the entire organism. The ability to regenerate rapidly together with the rapid response of whole-body tissues at the molecular level makes planarians a valuable model for studying the response of distal tissues to injury and indicates the presence of injury signal that can move at a high speed. The ERK signaling waves are proposed to engage in long-distance communication, but their reported velocity, ranging from 10 to 100 μm/h, is insufficient to account for the initiation of distant wound reactions in planarians (De Simone et al. cebpd-linked enhancer is essential for activating cebpd at a distance and regulating fluid levels following cardiac injury (Sun et al. via ERK waves (De Simone et al. Together, these studies highlight the important phenomenon that local injury initiates and relays a complex signaling network that guides long-distance tissue regeneration, thus elucidating not only the mechanisms of transmission of damage signals over long distances, but also emphasizing the significance of distant tissue feedback to damage signals during regeneration Fig. . Both mT


The growing complexities of clinical medicine and biomedical research have clouded the career path for physician-scientists. In this perspective piece, we address one of the most opaque career stage transitions along the physician-scientist career path, the transition from medical school to research-focused internal medicine residency programs, or physician-scientist training programs (PSTPs). We present the perspectives of medical scientist training program (MSTP) and PSTP directors on critical features of PSTPs that can help trainees proactively align their clinical and scientific training for successful career development. We aim to provide both trainees and MSTP directors with a conceptual framework to better understand and navigate PSTPs. We also offer interview-specific questions to help trainees gather data and make informed decisions in choosing a residency program that best supports their career. Physician-scientists play an irreplaceable role in the biomedical workforce , yet theCareer stage transitions can be stressful and confusing points along a physician-scientist’s career path, both for trainees and their mentors. Yet, focused discussions with established physician-scientists have consistently revealed striking similarities in their career paths across a range of clinical and scientific disciplines. Such conversations have identified gaps in training and mentorship, as well as opportunities to define a more structured and streamlined career path . Here, wWe offer the independent but shared perspectives of medical scientist training program (MSTP) directors and PSTP directors on critical features of PSTPs owing to the current absence of systematically collated data or information about this topic. While we hope that this piece will inspire broader, more formal surveys and studies on this topic, we hope that these perspectives will immediately empower trainees to be more purposeful and proactive in aligning scientific training, clinical training, and career development during residency and fellowship. Rhetorical questions, followed by explanations of their significance and responses, are intended to provide trainees with a conceptual framework for understanding and navigating PSTPs . We thenIsn't "PSTP" just a name used to describe a residency program that follows the American Board of Internal Medicine (ABIM) Research Pathway?ABIM website. Moreover, these requirements provide a regulatory framework around which clinical training programs and trainees can develop cohesive research and career development plans. The ABIM Research Pathway thus facilitates physician-scientist career development but is often insufficient as a stand-alone mechanism for career development. PSTPs are often linked to the ABIM Research Pathway, and many PSTPs offer the ABIM track within their program, but this is not always the case.The ABIM Research Pathway is a clinical credentialing mechanism that enables trainees to consolidate clinical training in internal medicine and  subspecialty fellowship with 36 mo of dedicated research training time (80% protected research effort). This mechanism allows trainees to achieve board eligibility for certification in internal medicine and  a clinical subspecialty while expanding protected research time. Details of this pathway and specific guidance about clinical requirements for even advanced subspecialty training  are available online at the In contrast, PSTPs are postgraduate physician-scientist career development programs that provide structured training and community. Such training includes coaching in career-specific research skills, individualized mentorship, financial support, and, most importantly, a community of physician-scientist peers and mentors to enhance career development. PSTPs can promote diversity, equity, and inclusion in physician-scientist careers, particularly when the community of PSTP trainees and faculty as well as institutional leadership are aligned with this goal. This includes being aware of your peers and the programs available for career development as they can vary among institutions and have an impact on the research faculty available. A list of PSTPs with website links was collated by the APSA and is currently being developed for redeployment as a web resource.It is important to appreciate the distinctions between PSTPs and programs that offer only the ABIM Research Pathway. First, it may help trainees assess how much formal experience programs have with physician-scientist training. Questions about the specific administrative support mechanisms that are (or are not) in place for ensuring regulatory compliance with the ABIM are useful here. Second, and more importantly, it may help distinguish programs best able to develop trainees into independent investigators from those that simply ensure board eligibility. Finally, it may help trainees identify the programs best equipped to meet their specific scientific goals within the framework of a clinical training environment.From an administrative perspective, while the ABIM Research Pathway does not exclude foreign medical graduates, not all PSTPs, or residencies, for that matter, are able to accept foreign medical graduates due to institution-specific visa sponsorship policies. Such policies are of particular relevance to PSTP programs owing to the mixed and extended clinical and research training requirements of the ABIM Research Pathway.Importantly, the ABIM Research Pathway offers a regulatory framework that can be referenced when defining a trainee’s clinical and research activities with clinical training program directors and administrators.Do all PSTPs provide a direct path to clinical fellowship and protected research time?Despite the specific requirements of the ABIM Research Pathway for board eligibility, PSTPs exhibit considerable variation in administrative organization, flexibility, and support. Some PSTPs span departments and disciplines and function on an institutional level, while others are localized within departments or disciplines. Key areas of variation include the following (each point is followed by key questions to consider):Mechanisms and level of fellowship commitments (both within and outside of the same institution). While the ABIM Research Pathway does not require that residency and fellowship training occur at the same institution, many programs offer some form of assurance of a fellowship position in the PGY3 year of their PSTP.How and when do these assurances occur and with what level or form of assurance?Do they extend to advanced subspecialty fellowships such as in cardiology and gastroenterology?What types of administrative and programmatic support are available to facilitate this process?What flexibility is there in choosing or changing subspecialty fellowship preference, both in relation to time and choice of subspecialty and location?Structure and flexibility of clinical and research activities during fellowshipIs there a guarantee of salary support at or above the postgraduate year (PGY) pay scale during the research-intensive phase of fellowship? (See Question #3 for related questions.)What are the clinical responsibilities/expectations during the research phase of fellowship training?Some programs may be structured in a way that research time has interspersed blocks of clinical training. What is the longest continuous block of research time protected from clinical responsibilities  during fellowship? This is a particularly important consideration for those pursuing wet bench work where extended periods of uninterrupted time are often essential.Is there flexibility to frontload or customize the clinical training component?What sort of flexibility is provided for trainees who have family responsibilities arise during this training period? What are the policies on parental/caregiver leave should the need arise?Integration with PSTP during fellowshipWho bears primary responsibility for career development during the fellowship phase of training?Is there continuous oversight from a centralized PSTP, or is there handoff of this responsibility to the fellowship program?Are there regular and structured programming activities and/or mentorship committees explicitly focused on career development?Range of accessible mentors and labsWhat scientific and career mentors are available?Is there a system in place to create structured mentorship dyads and/or mentorship teams, coaches, and sponsors?What resources are available for identifying mentors and determining the postdoctoral training record and funding history of potential mentors? Does the institution provide an avenue for identification of a mentor during the interview process, even before matching?What limitations or restrictions are there on the choice of lab? Are trainees limited to working in the labs of department/division faculty, or are they free to choose from labs across the institution, or even at other institutions?What policies are in place regarding mentors if the relationship doesn’t work?PSTPs also vary in the roster of faculty with track records of training physician-scientists who have successfully transitioned to independent scientific careers. Trainees interested in clinical subspecialty training should become familiar with the track record of the relevant fellowship training program vis a vis physician-scientist trainees, as well as that of the subspecialty Division Chief and/or Fellowship Program Director who are often involved in reviewing applications and/or the interview process.https://reporter.nih.gov), and the Blue Ridge Institute for Medical Research annual report, which depicts institutional and departmental NIH funding levels (https://brimr.org) OR (https://brimr.org/brimr-rankings-of-nih-funding-in-2022/).Perhaps the most important source of variation among PSTP-associated fellowship programs is the cohort of available scientific mentors. Trainees are advised not to select an institution based on a single faculty member whose research aligns with their interests as interests may evolve and faculty may move. However, it is critical to be certain that the institution has and will have appropriate mentorship available during training. Candidates are further advised to learn whether their own research questions and approaches of interest are valued by PSTP-affiliated faculty. Useful resources for current research interests and funding include departmental and laboratory websites, the NIH RePORTER database  milestones among the residency and fellowship program directors and the trainee to ensure adequate preparation for certification in Internal Medicine after the first clinical year of subspecialty fellowship training as well as certification in the subspecialty upon completion of ABIM Research Pathway requirements.A critical element of a PSTP is its ability to guarantee continuous protected research time during the fellowship phase of training. This perspective is often lost in relation to clinical responsibilities. The practical importance of this protected time cannot be overstated. First, and most importantly, this period is the major, if not sole, window of opportunity for trainees to lay the experimental foundation for their future independent scientific careers. Prior research training, whether as an MD-PhD student or research fellow during medical school, is critical for the development of scientific thought processes. Nonetheless, trainees usually pursue research in a different area during the postgraduate phase, from which they transition to their long-term careers. Second, protected research time often comes to a hard stop that usually coincides with completion of the ACGME-accredited duration of clinical fellowship training. This time constraint is rarely a factor for PhD investigators, whose postdoctoral training period is more flexible and often substantially longer than the time afforded by the ABIM Research Pathway. Third, this period of training must usually result in objective demonstrations of productivity (i.e. publications and grant applications/awards) that often require substantial lead time for preparation and/or revision. As a result, the actual time available to achieve these metrics is functionally shorter than the time allotted during training, leading to late-stage attrition of physician-scientists who run out of time to meet these milestones. However, it is relatively common for trainees to negotiate a transition to a non-tenure track faculty position including continued protected research time (see Question #6).Do all PSTPs guarantee salary support for the 3 y of research training required by the ABIM Research Pathway?Despite the administrative requirements of the ABIM, PSTPs vary in their sources and mechanisms of support for research training, which can result in different levels and durations of guaranteed salary support. Below, we provide some questions that will help clarify the specific assurances and expectations at different programs.The first, and perhaps most straightforward question should be, ‘Is my salary guaranteed at the institutional PGY pay scale during the research phase of training?’ This will allow applicants to distinguish programs that answer ‘yes’ from those that provide any other response. More detailed follow-on questions include:What, if any, dedicated financial resources are available to ensure salary support during the research-intensive phase of training, or is salary evaluated on a case-by-case basis?Which fellowships have a T32 and/or other funding sources to support fellows in their research training, and are other resources available to ensure equity on a PGY pay scale ?What, if any, support is there for trainees interested in pursuing an NIH F32 or equivalent award as part of their training in preparation for a K-level, or equivalent, career development award?What limitations or restrictions are associated with any such funding support, including, but not limited to, choice of labs, duration of support, or other administrative or scientific obligations?Equally important questions include the following:after finishing the ABIM Research Pathway portion of training?What support/resources do programs offer for transitioning to faculty or other positions For those requiring additional research training time:What types of non-tenure track positions are available, and what responsibilities are associated with these positions, whether clinical or otherwise?What internal and external funding mechanisms are available, if any, to provide support after completion of training? These might include internal career development awards (CDAs) that provide funding while the junior faculty member is applying for external career development awards such as the NIH K-mechanism CDAs, Veteran’s Administration CDA, or Foundation/Society CDAs.What types of resources/support are available to facilitate transition to bona fide tenure-track faculty positions?Institutional support for trainees in the research years of fellowship and beyond to the point of securing a career development award, such as an NIH K08, K23, or K99 grant, or foundation-based equivalent, is essential. Trainees should thus understand the available mechanisms of support, conditions and/or limitations associated with that support (e.g. choice of lab or mentor), duration of support, and other administrative, clinical, or scientific obligations.https://www.lrp.nih.gov).Trainees should be aware of the opportunity to apply for loan repayment programs designed to pay down debt for trainees pursuing research-based careers. Consistent with the goal of supporting research-based careers, paylines on these mechanisms tend to be high. These mechanisms can further offset financial pressures that might derail one’s career. Examples include the NIH Loan Repayment Program , and career mentorship into their curricula. Some questions to ask in this regard include the following:What resources and/or activities are in place to help identify an appropriate mentor(s) and research project?Are there formal career mentorship committees?What types of resources are available to facilitate work–life balance?Are there resources/mechanisms to assist with spousal employment, child care, or elder care?Having a mentorship committee and/or advisors is important for the career development of physician-scientists, and such committees are required as part of a future career development award. Assembling such a committee early in one’s research training facilitates guidance during the research phase and is a critically important contribution of the PSTP. Mentorship committees need not be static but may change over time. Early in the clinical training, the residency program director and PSTP director may play central roles in this committee, while over time the primary mentors will transition to the fellowship program director and research mentor along with the PSTP director. An external committee member may also help ensure the trainee is publishing and developing research independence in order to advance their career as well as provide critical scientific advice. In addition to mentors, trainees also often benefit from including sponsors and coaches who can help address more specific scientific and career development issues.see below), leadership, responsible conduct of research, and diversity, equity, and inclusion.Well-established programs have close and active relationships with institutional individuals and teams who offer resources, networks/communities, and programs, including those that provide skills in career development  across programs?Are there programs that provide guidance and assistance specifically for assembling CDAs?Does the program have grant banks, grant writing workshops or classes, and/or mock study sections?It is axiomatic to say that grants are the currency of academic career development. Objective measures of grant funding are thus an essential, though admittedly imperfect, metric of PSTP productivity. As some PSTPs are relatively young, metrics of grant productivity may not yet represent the training and potential of recent alumni. However, in the context of the physician-scientist career path, the time-to-first-CDA is an emerging metric of program success. This is an increasingly important issue as trainees often face new and complex work–life balance issues during this period of their lives.What happens after completion of the ABIM Research Pathway component of a PSTP?PSTPs are often viewed by institutions as an internal pipeline for future faculty recruits. However, opportunities available for trainees to transition to faculty positions differ among institutions and may vary depending on whether or not a trainee has secured a CDA or are close to doing so.Trainees who have already secured a CDA at or near the time of formally completing a PSTP are highly competitive (and often actively recruited) for a faculty position on a national level and are poised to begin independent tenure track careers at the Assistant Professor level.Trainees who have not yet secured a CDA or published their primary work typically require additional mentored support and often transition to non-tenure track faculty positions, such as Instructor or equivalent. Because trainees on this pathway have not yet attained the credentials typically indicative of scientific independence, these faculty appointments are often fraught with a diverse range of conditions and expectations that require careful negotiation.Particularly important considerations in this case are the amount of funded, protected research time; expected clinical and administrative responsibilities; and future opportunities for funding and lab space following acquisition of a CDA or equivalent. A particularly important consideration with respect to funded protected research time is the availability of formal post-PSTP ‘bridge’ mechanisms/programs which even when present often vary in both programmatic content and financial support.A closely related issue is the need to avoid inadvertently starting the tenure clock with an Assistant Professor appointment before funding is obtained.What does ‘success’ look like for a graduate from your program?A graduate of a PSTP:Has a deep understanding of the scientific method and is able to apply it in research.Possesses strong analytical skills and can effectively identify the root causes of problems.Has a track record of successful research projects and publications in top-tier academic journals.Is able to collaborate effectively with interdisciplinary teams, including scientists, physicians, and other healthcare professionals.Has excellent communication skills and can effectively communicate complex scientific concepts to both scientific and lay audiences.Is able to secure research funding from a variety of sources, including government agencies and private foundations.Is committed to advancing scientific knowledge and improving patient care through research and innovation, and finally.Is well prepared for a successful career in research and may be employed in academia, industry, or the federal and state governments and a substantial amount of time is devoted to discovery-based activities.We aim to provide prospective applicants with a clearer understanding of the complex environment surrounding PSTPs. For this purpose, we have compiled a concise list of essential questions summarizing the concepts discussed above. These questions will prove valuable for trainees during their residency interviews in a PSTP.Does your program offer a letter-of-intent for specific clinical fellowships and/or an accompanying 3-year assurance of protected research time?What mentors are available, and what has their track record in career development been?Can I work in any lab I choose within the institution?Does your program provide guaranteed salary support on the institutional PGY pay scale throughout the period of protected research time?How is the required 20% clinical time during the research phase of training structured? Do I take call? Could I be conscripted for ‘backup’ clinical coverage?What other resources/support does your program provide for career development?Beyond salary/stipend support, does your program provide research funding during the research training phase?How is your program addressing the challenges and opportunities associated with diversity, equity, and inclusion?What sort of programming/resources are provided at the end of PSTP training for transitioning to faculty (for those staying at your institution)?Tell me about recent outcomes and graduates from your program.


The lymphatic vasculature provides an essential route to drain fluid, macromolecules, and immune cells from the interstitium as lymph, returning it to the bloodstream where the thoracic duct meets the subclavian vein. To ensure functional lymphatic drainage, the lymphatic system contains a complex network of vessels which has differential regulation of unique cell-cell junctions. The lymphatic endothelial cells lining initial lymphatic vessels form permeable “button-like” junctions which allow substances to enter the vessel. Collecting lymphatic vessels form less permeable “zipper-like” junctions which retain lymph within the vessel and prevent leakage. Therefore, sections of the lymphatic bed are differentially permeable, regulated in part by its junctional morphology. In this review, we will discuss our current understanding of regulating lymphatic junctional morphology, highlighting how it relates to lymphatic permeability during development and disease. We will also discuss the effect of alterations in lymphatic permeability on efficient lymphatic flux in health and how it may affect cardiovascular diseases, with a focus on atherosclerosis. The lymphatic vasculature runs in parallel to the blood vasculature with distinct structural and functional roles that differ from blood vessels. The blood vasculature is a bidirectional circulatory system where blood and nutrients are transported both into and away from organs. Conversely, the lymphatic vasculature is a unidirectional circulatory system that drains lymph  away from organ tissue to return it to the blood circulation . AlthougThe lymphatic system begins as blind-ended, finger-like initial lymphatics, which are present in the parenchyma of many organ tissues . Since iCollecting lymphatics are different from the hyper-permeable initial lymphatics. They share similar features to blood vessels, with a thin layer of specialized smooth muscle cells and bi-leaflet valves that together contribute to lymphatic fluid flux . ImportaTherefore, the lymphatic system must initially be permeable enough to receive substances from organ tissues, but later become a barrier to prevent leakage so substances that form lymph are maintained within the vessel . A growiThe differential regulation of lymphatic junctional morphology and how it relates to lymph flux is a core, yet understudied topic in lymphatic research. First, it is important to understand a few key terms in the context of the lymphatic system: permeability and lymph flux. Scallan and Jannaway eloquently described the definition of permeability as a measurement of the rate at which particles, both solute and solvent, can pass through a semi-permeable membrane . From thdb/db) mice which led to increased permeability of collecting lymphatic vessels and dye leakage from the vessel , β-catenin, and p120-catenin) and that of tight junctions  , which w−/− mice had junctions resembling zippers in the initial lymphatics of the diaphragm while also having disrupted junctions resembling buttons in collecting lymphatics of the ear and mesentery, resulting in impaired lymph uptake  and tight junctions (ZO-1) in the dermis, lung, and mesenteric initial lymphatics compared to developing initial lymphatics in control mice which had characteristic zipper formation throughout development  led to increased lymphangiogenesis with zippered initial lymphatic vessels in the pleural side of the diaphragm  which has been shown to negatively regulate Tie2 signaling by promoting its dephosphorylation while also associating with VE-cadherin to promote endothelial junction integrity . CurrentThere is substantial evidence that lymphatic dysfunction often contributes to cardiovascular disease pathogenesis, and enhancing lymphatic functionality may improve some of these diseases . PatientWhen arteries become damaged from the accumulation of oxidized low-density lipoprotein (oxLDL), monocytes are recruited to the subendothelial space where they become macrophages that engulf the oxLDL, contributing to localized vascular inflammation and the formation of foam cells which leads to atherosclerotic plaque formation . This paTo date, no studies have determined the junctional morphology of initial or collecting lymphatic vessels in the adventitia of atherosclerotic aortae, leaving our understanding of this topic under-characterized. Regardless, oxLDL and the formation of reactive oxygen species that ensues in endothelial cells is hypothesized to lead to alterations in lymphatic permeability . AlthougAtherosclerosis development is associated with an increase in adventitial lymphatic vessels, though it is controversial if this lymphangiogenesis is compensatory or disease promoting . SubsequPcsk9−/− mice  also occurs as a result of end-stage atherosclerosis which leads to plaque vulnerability and rupture with subsequent thrombosis and occlusion of a coronary vessel . It is sin vivo, the decreased permeability is possibly from promoting continuous zipper-like morphology of junctions in initial lymphatics which would perpetuate inflammatory edema  how a single molecule Angpt2 can orchestrate both button and zipper formation throughout one continuous lymphatic vessel, 2) the molecular mechanisms determining LEC junctional conversion from buttons to zippers during inflammation, and 3) how junctional morphology and subsequent lymphatic function is altered in other inflammatory diseases such as atherosclerosis. Therapeutic modalities which can regulate lymphangiogenesis and/or lymph flux hold promise as novel therapeutic opportunities to treat cardiovascular diseases. Future research should determine the molecular mechanisms that maintain the differential regulation of lymphatic junctions as it relates to lymph flux in health and disease states.


In the heart, more than 90% of the daily consumed ATP is produced by oxidative phosphorylation at the inner membrane of mitochondria. About 70–80% of this ATP is used to fuel muscle contraction and to regulate the calcium necessary for such cyclic mechanical activity. Therefore, mitochondrial ATP generation must be finely tuned to calcium-dependent contraction in cardiomyocytes, which is sustained by a tightly regulated communication between mitochondria and sarcoplasmic reticulum (SR), in which the ATP generated by mitochondria allows cell relaxation in diastole , whereas calcium released through the ryanodine receptor (RyR) in the SR during systole regulates the rate of mitochondrial ATP generation. One of the earliest phenotypic traits of the aged heart is the energy demand/supply mismatch that underlies its reduced tolerance to exercise and lower adaptability to stress. This energy insufficiency manifests at the level of its most important functional unit, the cardiomyocytes. Although the causes of such energy inefficiency may be several, some studies have documented a defective RyR and VDAC bridging that results in impaired SR-mitochondrial anatomo-functional coupling . This deAging is characterized by a progressive loss of molecular fidelity due to a time-dependent reduction in the efficacy of genetically-encoded cell repairing mechanisms. The paradigm of non-regulated molecular damage is the stochastic chemical attack of dicarbonyl compounds to proteins and other macromolecules. Dicarbonyl compounds are extremely reactive and ubiquitous alpha-oxaldehydes  that are generated as metabolic intermediates of glycolysis, gluconeogenesis and lipid metabolism. They spontaneously and preferentially react with positively charged amino acids within proteins forming heterogeneous and irreversible chemical adducts, collectively named as advanced glycation end-products, that can provoke modifications in the proteins’ tertiary and quaternary structure rendering them dysfunctional . The conThe dicarbonyl stress present in the aged heart has been shown to have deleterious consequences on cardiac mitochondria through different mechanisms. On the one hand, the molecular damage of RyR induced by dicarbonyl species increases spontaneous calcium leak from SR, so that chronic exposure of surrounding mitochondria (mainly interfibrillar mitochondria) to a dysregulated calcium environment favors an excessive mitochondrial calcium uptake and accumulation, a compensatory response that leads to matrix calcium precipitation and damage. This mechanism has been described in human and murine cardiac mitochondria, and contributes to the reduced aerobic capacity of the heart during aging , 5. On tin situ enzyme assay confirmed that dicarbonyl modifications of FoF1-ATP synthase altered the ability of monomers to self-assemble into dimers/oligomers. Ultrastructural images of murine myocardium indicated that defective cardiac FoF1-ATP synthase dimerization/oligomerization is associated with the presence of aberrant cristae in some mitochondria  that are absent in the myocardium of young mice [in vitro evaluation of ATPase activity using denaturalized mitochondria, in which cristae architecture does not have any contribution to energy efficiency, demonstrated that the enzyme activity was preserved in aging. Importantly, both mitochondria from aged mice and from H9c2 cells chronically exposed to dicarbonyl stress were found to have an increased susceptibility to undergo mPTP [By using high throughput mass spectrometry, our group identified five subunits within FoF1-ATP synthase that are targeted by dicarbonyl species in cardiomyocytes from aging mice, including subunits e and g, which are essential for dimerization and cristae folding . Blue-naung mice . As expergo mPTP , an impoIn summary, dicarbonyl stress favored by a deficient glyoxalase-dependent detoxification may represent a fundamental previously underestimated mechanism of mitochondrial damage and energy deficiency in the aged heart . Dicarbo


The results published by Tergolina et al. showed that treatment adherence may be a challenge at these facilities.1As elegantly published by Tergolina et al.,4 Although understandable, this strategy reduced available beds for patients in need of hospitalization due to mental illness.The COVID-19 pandemic added an additional burden to this challenge, overloading healthcare systems and compelling public administrators to redirect resources and staff to the pandemic frontline and convert inpatient psychiatry units located in general hospitals into COVID-19 units.Faced with an overwhelming number of patients with respiratory symptoms, two hospital inpatient psychiatry units in São Paulo were converted into COVID-19 units. To tackle the issue of reduction of psychiatric beds, the Sao Paulo Municipal Health Department took a bold approach and set up a novel temporary hybrid mental health service for these extreme times.This novel hybrid facility was implemented within the existing structure of the Paraisopolis CPSA after a refit had been conducted to enable adequate admission of patients in need of hospitalization, including construction of two separate inpatient units, for patients with and without respiratory symptoms, and sanitary installations, and workforce expansion and implementation of night shifts and a proper legal process for involuntary admission for treatment.Some interesting effects were perceived, such as highly humanized care provided by staff specialized in managing severely ill patients in an outpatient setting and only resorting to hospitalization as a last option, a high sense of importance accorded to patients’ needs and individuality, strong patient-staff bonds that facilitated follow-up treatment in the same unit and the possibility that, during their hospital stay, patients could take part in other activities beyond the inpatient unit under staff supervision, speeding up the rehabilitation process. Additionally, it was also notable that staff were highly committed to the essence of the CPSA, never forgetting that the continuous improvement of mental healthcare in Brazil is a one-way process.Additionally, this temporary unit also provided a great learning opportunity for medical interns and psychiatry residents who were included in its daily routine and reinforced its medical workforce. This novel facility offered a unique learning experience in a multidisciplinary and humanized environment that, it is believed, reduced stigma and benefitted medical training during the pandemic.At first glance, setting up an inpatient unit inside a CPSA established during the Brazilian Psychiatry Reform process may seem strange and could have sparked off a heated debate, but in times when adaptations were needed, new ways of doing things became the standard in everyone’s lives, and it was no different at this facility, where healthcare workers came together to aid patients in need.


Editorial on the Research TopicDigital technology for tobacco control: Novel data collection, study designs, and interventionsTobacco is the leading cause of preventable death and disease and is responsible for nearly one in five deaths in the United States –4. ImporBattalio et al.). Nahum-Shani and colleagues introduce a framework with 5 guiding questions that can be used to select the most appropriate experimental approach . They call for more flexible experimental designs that can efficiently address questions about the integration and adaptation of intervention components at multiple timescales .Several conceptual pieces offer pragmatic guidance for developing digital interventions. Battalio and colleagues review the social determinants of health (SDOH) that may contribute to tobacco-related health inequities. They present a conceptual model to address SDOH with a lens towards developing mHealth tobacco cessation interventions that are optimized to serve populations most in need . Ji and colleagues utilize data from an EMA study of smokers attempting to quit, as well as a simulated data set, to demonstrate how improper accommodation of multilevel intensive longitudinal data structures in multiple imputation may impact study results. They emphasize the importance of properly handling clustered missingness for conclusions drawn from ILD studies that are used to inform the development of tobacco cessation interventions .Despite the tremendous opportunities that mHealth studies offer for understanding dynamic mechanisms of change and informing interventions, they are especially susceptible to missing data due to challenges relating to participant engagement. Two papers discuss these challenges. Sobolev and colleagues leverage data from two EMA studies of smoking cessation to explore the dynamics of engagement with mobile health data collection in real-world settings. They investigate how engagement with data collection (EMA prompts delivered and EMA prompt response) unfolds over time, and based on the results emphasize the importance of integrating multiple indicators to measure engagement . Scherer and colleagues examine the time-varying nature of self-regulation in real-world settings in two high-risk populations . They demonstrate that self-regulation is not static, but rather may vary based on contextual factors , and discuss the implications for interventions targeting momentary self-regulation as a means to reduce health risk behaviors .Several articles examine dynamic factors that influence tobacco cessation success. Coughlin and colleagues review the state of the science of using motivational incentives in smoking cessation interventions. They highlight the benefits of digitally delivered motivational incentives for reducing barriers associated with smoking cessation interventions, such as participant burden, disengagement, and up-front costs. To help mitigate these barriers, they call for the development of digitally delivered motivational incentive interventions that are guided by several principles for constructing JITAIs, which can enhance the feasibility, effectiveness, and scalability of digital motivational incentive interventions for smoking cessation .Finally, Benson and colleagues report on a pilot RCT comparing 3 smoking cessation interventions: a JITAI that tailored treatment in real time, the National Cancer Institute QuitGuide application, and a clinic-based tobacco cessation programing that follow clinical practice guidelines. These interventions target negative affect and urge, factors that influence tobacco cessation in daily life. Based on findings that the within-person association between negative affect and urge was stronger in the post-quit than pre-quit period, and that associations differed by intervention type, the authors discuss the potential importance of personalizing interventions for decoupling momentary associations between negative affect and urge during a quit attempt (Included in this Research Topic are original reports highlighting novel frameworks, study designs, and data collection procedures, as well as intervention and methodological approaches that leverage advances in digital technologies to prevent and treat tobacco use. We believe this Research Topic demonstrates that digital technologies offer a tremendous opportunity to leverage information about an individual's progress in treatment, internal state, and context to recommend whether and how to intervene , which,


The emergence of the COVID-19 pandemic led health care systems and providers worldwide to rapidly adopt telehealth solutions to minimize risk and comply with isolation mandates. This article explores telehealth utilization trends in North Carolina (NC) free and charitable clinics—an ambulatory health care delivery setting where traditional third-party reimbursement policies are not a primary consideration.We surveyed NC free and charitable clinic administrators regarding clinic decisions to adopt an externally sponsored telehealth system, what services are provided by telehealth, clinic implementation processes, which populations used telehealth, how telehealth was incorporated into current clinic workflows, and perceptions of telehealth outcomes.Telehealth was rapidly adopted among free and charitable clinics after the COVID-19 outbreak. Reasons for implementing telehealth included the ability to continue providing services during a public health emergency and to increase access to patients. However, clinics report that telehealth utilization has dropped significantly since the initial pandemic surge. Patient and provider preferences for in-person services are a common reason cited for this drop. Free and charitable clinics report a strong interest in continuing to deliver services through telehealth. The majority reported continuing to offer telehealth services, but primarily as a supplement to in-person visits rather than as a replacement. They perceive that implementing telehealth has increased access to care but are less certain about the impact on cost of care and patient satisfaction. However, clinic administrators believe improvements in interoperability with other data systems, workflows, scheduling, and care delivery approaches are needed to achieve telehealth's fullest utilization.Telehealth can play a significant role in expanding access to services in the free and charitable clinic setting. However, continued refinements in the technology to facilitate integration with other systems and workflow processes are needed to reach its full potential. Critical barriers to telehealth adoption have been shown to include cost, a lack of technical capacity, and uncertain or insufficient reimbursement.4Research has shown that telehealth has the capacity to increase access to physical and mental health services and reduce barriers to care, especially for underserved populations.5–8 However, the continuation of this trend is uncertain as the surge of COVID-19 infections wanes and the public health emergency declaration is lifted.The public health emergency arising from the COVID-19 pandemic in the spring of 2020 produced a unique health care delivery environment. Infectious disease containment concerns coupled with expanded telehealth reimbursement policies prompted a dramatic increase in ambulatory telehealth visits by primary and specialty providers, producing a major shift in the trajectory of telehealth utilization.10Although there is extensive evidence to describe telehealth uptake since COVID-19, little evidence exists on how telehealth has been implemented and integrated into work flows in ambulatory settings serving vulnerable populations, what services are being provided via telehealth and for which patient populations.An American Medical Association survey conducted in 2021 found that a major factor influencing physicians' decisions to continue offering telehealth services in the postpandemic future is uncertain reimbursement policies.The purpose of this study was to explore how telehealth use has changed since the height of the COVID-19 pandemic, what it is used for, and by whom in a unique category of providers: North Carolina (NC) free and charitable clinics.The North Carolina Association of Free and Charitable Clinics (NCAFCC) is a nonprofit organization that supports and provides sustainable funding sources for 70 member clinics and 85 clinic sites across NC.11 In March 2020, NCAFCC offered a comprehensive telehealth platform free of charge to its members.Member clinics are quite varied, differing in the scope of services provided, funding sources, religious affiliation, patient eligibility criteria, whether they accept Medicaid or other payments, and staffing models . The common denominator is that they provide care for the uninsured and underinsured in NC.Since NC free and charitable clinics frequently do not bill for their services and had access to a telehealth technology platform free of charge, they do not face two common barriers for telehealth uptake: lack of resources for technology investment and insufficient or uncertain telehealth reimbursement rates. This study, therefore, provides insight into telehealth utilization patterns for serving uninsured and underinsured populations and the motivation behind those decisions when specific key financial constraints are absent or reduced.12 This study was designed to collect exploratory data on NC free and charitable clinics' experiences and progress along this continuum. Since information on telehealth is widely available, and a single platform was offered to members, eliminating the need for product selection, this study did not focus on the dissemination stage.The Rogers Model of Diffusion outlines five steps integral to fully integrate any new technology into practice: dissemination, adoption, implementation, evaluation, and institutional uptake.Rather, the survey focused on the adoption, implementation, evaluation, and uptake stages by asking questions regarding clinic decisions to adopt the association-sponsored telehealth system or not; what services are provided by telehealth, clinic implementation processes, which populations used telehealth, how telehealth was incorporated into current clinic workflows, and perceptions of the system. The survey was pilot tested by a panel of health care management test readers for usability and face validity before dissemination .Current NCAFCC member clinics were invited to participate in the study. Survey recruitment took place during virtual presentations at monthly regional clinic director meetings in September and October 2022 where the research team introduced the study and invited attendees to participate, offering a $25 gift card to complete the survey. After the meeting, an e-mail describing the study and a link to the online Qualtrics survey were sent to clinic directors. Directors were asked to forward the survey or complete it in collaboration with individuals who may have been more actively involved in the telehealth adoption decision-making and implementation process than the directors themselves.13 crucial to the participant's clinics experience implementing telehealth services. The researchers used the constant comparative method to develop axial codes—categories of themes emerging from the survey comments—and selective codes that identify the linkages among the axial codes to further classify themes.15Descriptive statistics were used to summarize survey response patterns. Open-ended responses were evaluated using thematic analysis and open coding using MaxQDA Analytics Pro 2022. A grounded theory approach was utilized to generate a summary of emerging themes through familiarization with the data, open coding, and identification of significant themesThis study was reviewed and certified exempt by the Appalachian State University Institutional Review Board.16 Some of NCAFCC member clinics only offered dental, prescription medication provision, or referral services; thus, they may have chosen to decline the telehealth system because it was not appropriate for the services they offer. Of the 66 NCAFCC member clinics operating during the first half of 2020, 50 implemented the association-sponsored telehealth platform.Usable survey responses were collected from 32 of the 57 NCAFCC member clinics providing medical and behavioral health services in 2022 (response rate 56%). As given in Of the 32 respondents, 16 reported implementing the NCAFCC system. An additional six reported declining the association-provided system because they either already had a telehealth system in place or chose to implement another platform. Thus, 22 out of 32 (69%) respondent clinics implemented telehealth by mid-2020. An additional four respondents reported implementing another telehealth system after the initial association-sponsored telehealth rollout, but one ceased using telehealth postpandemic. As of the last quarter of 2022, 25 (78%) respondents reported using telehealth services in some form. The clinic characteristic data presented in only reason for implementing telehealth was to be able to continue to offer services during the pandemic, three continued to utilize telehealth beyond the height of the pandemic and reported they were still offering telehealth services in the last quarter of 2022.Objectives cited for adopting telehealth are shown in n = 5), already had telehealth in place or chose another platform (n = 4), too difficult to use (n = 2), incompatibility with electronic health record , lack of interest on part of clinic personnel (n = 1), lack of interest in some patients (n = 2), patient technology limitations (n = 2), and privacy concerns (n = 1).Reasons for not adopting the association-sponsored telehealth platform include providers were not comfortable with the technology  provides a framework for evaluating elements associated with the success, failure, and outcomes achieved by implementing any intervention.Clinics varied with who they chose to lead their telehealth implementation efforts. Efforts were led either by administrative management or personnel (35% for the NCAFCC-sponsored system) or an interdisciplinary team comprising individuals holding different roles across the clinic (35% for the NCAFCC-sponsored system). Almost two-third of the clinics report that someone, either within their organization or easily available outside the organization, has the experience and familiarity with the telehealth system to become an “expert” user that others can rely on when questions or issues arise.Although many clinics reported they needed to purchase additional technology to perform telehealth services such as cameras, headsets, additional computers, and tablets for patient use, most report that they did not need to “customize” the telehealth system and were able to begin using the system “out of the box.” Configuration activities that were reported included modification of templates, adding the ability to create broadcast texts, disabling unnecessary billing features, and incorporation of documentation and subtitles for non-English speakers.User training usually lasted several hours and was conducted in person or through a live webinar with in-house–created content. Forty-five percent of respondents who adopted telehealth rated the system as easy or very easy to learn, whereas only 10% rated it as difficult or somewhat difficult.The primary challenge clinics reported during the initial implementation was integrating telehealth systems with their existing technology. For example, clinics reported challenges linking appointment-scheduling systems with telehealth and incorporating clinical notes into the EHR, requiring duplicative documentation. Clinics report overcoming these difficulties by altering their check-in and scheduling processes or switching telehealth platforms to better integrate them with their EHR system. Overall, 54% of respondents rated their transition to telehealth in their clinic as easy or somewhat easy, whereas 21% rated it as difficult or somewhat difficult.Like the transition to remote work experienced across the economy since 2020, the rise in telehealth has provided greater flexibility in care delivery locations. Seventy-five percent of respondents reported that their providers were conducting telehealth visits, both from the clinic and at home. Twenty-one percent reported that providers were conducting telehealth visits only from the clinic, whereas only one clinic reported that their providers were solely conducting telehealth visits from home.Clinics reported that patient use of telehealth was constrained not only by access to wifi, but also by the availability of devices needed to conduct telehealth visits, such as smartphones, cameras, and computers. Clinics reported that their patients connected to telehealth visits from home, work, “in the parking lot,” “anywhere they can get Wi-Fi,” and from within the clinic itself to connect with offsite providers. If they had technology, patient use of telehealth was also constrained by data plan expenses and limitations. For example, one clinic reported their patients “refused telehealth visits” because clients “with limited resources or minutes would not ‘waste’ 15–30 minutes on a telehealth call.”20 However, the quality of audio-only telehealth and the impact on health equity are still open to debate.21This barrier was not unique to the free and charitable clinics in our study. Studies have suggested that audio-only telephonic telehealth visits instead of the more “higher-tech” audio–video may be a response to overcoming these constraints in uninsured, Medicaid, and other underserved populations.n = 17). In addition, three of these clinics utilized remote patient monitoring, and one used asynchronous communication such as text messaging and e-mail for telehealth delivery. Twenty-two percent (n = 6) are currently offering telehealth using only audio-only calls, and one only uses audio–visual interactive visits.Three-quarters of the clinics in our study reported currently offering telehealth encounters using both audio–visual interactive visits and audio-only calls . None of the respondents indicated that they perceived their patients preferred telehealth; only one reported that their patients refused telehealth, and two indicated that their patients were indifferent between telehealth and in-person visits. Clinics reported that although telehealth may reduce transportation barriers associated with in-person visits, their patient population may experience other barriers to utilizing telehealth.In addition to the clinic perception that patients have a general preference for inpatient encounters, respondents identified access to technology and broadband, expenses incurred by using mobile data plans for telehealth visits, limited digital literacy, interpretation/language difficulties communicating through telehealth, and a general lack of awareness of telehealth availability as barriers to telehealth utilization and uptake by their patients.Ninety percent of respondents reported that they were interested in offering telehealth services in the future, even if they were not currently offering telehealth services. The reasons cited include increasing patient access (92%), reducing unnecessary patient costs (81%), increasing patient satisfaction (54%), virtual care has proven to be clinically and/or operationally effective (50%), and providing more comprehensive care (26%). However, the respondents identified technological and workflow refinements that may facilitate wider adoption and continued use.Refinements to telehealth platforms and workflows suggested to increase usability and facilitate continued use include dedicating distinct appointment slots for telehealth versus in-person visits, addition of more staff to support digital workflows, developing best practices for check-in and check-out procedures, addition of a digital waiting room within the platform, additional telehealth training for all staff, and remodeling of clinic workspace to better support virtual care.The objective of this study was to describe the telehealth adoption and utilization experience of free and charitable clinics, an under-represented sector of the health care system in telehealth utilization research. The clinics in this study were unique in that they received access to a free telehealth platform through the NCAFCC that reduced one of the most critical barriers to telehealth adoption: cost.The findings in this study are consistent with the telehealth adoption and utilization trends observed across the United States in response to the emergence of the COVID-19 pandemic reported in the literature. However, the overall telehealth utilization rates dropped as the initial pandemic crisis eased. Thirteen of the clinics that initially implemented the association-provided “free” telehealth platform reported that they ultimately dropped that system and transitioned to another telehealth platform. This suggests that once in use, clinics saw value in offering services through telehealth, so much so that they were willing to pay for it. Clinics perceived that telehealth increased access to care, but clinic perceptions were mixed about the impact on the cost of care and patient satisfaction.Our finding that respondents expressed an interest in continuing to offer telehealth services in the future, with modifications or under certain conditions, is consistent with the American Medical Association (AMA) survey of physicians practicing in general. Telehealth services are currently predominantly used as a supplement to in-person visits rather than as a replacement. Clinics report that their leadership is supportive of continued telehealth use, but one of the biggest challenges they currently experience is the linkage between the telehealth platform and existing systems, such as appointment scheduling and the EHR.Workflow refinements that clinics believe would facilitate their continued use of telehealth included creating separate scheduling blocks for telehealth and in-person visits (52%), providing telehealth training for all clinic team members (48%), and creating a formal process for telehealth visit check-in/check-out (39%). Technological or resource refinements that would support future telehealth use included telehealth technology that provides a digital waiting room (26%), hiring additional staff to support telehealth workflows (26%), and remodeling office/examination room space to facilitate telehealth visits (22%).This study provides exploratory insights into telehealth adoption and utilization for the uninsured and underinsured populations but has several limitations. Our findings may not be generalizable to telehealth implementation decision making in general, the use of telehealth in free and charitable clinics outside of NC, or clinics that are not members of the NCAFCC since the association provided a free telehealth platform. In addition, the low response rate from smaller, part-time, and rural clinics may cause our findings to under-represent their experiences. Therefore, our results may not be representative of the experience of all NCAFCC member-free and charitable clinics across the state.This study explored the initial telehealth implementation processes during a crisis. Clinics reported that they implemented the telehealth system and transitioned to remote operation over a very short time. Thus, conclusions should not be inferred about implementation processes that might have occurred during “normal times.” This study does not allow us to draw conclusions on how telehealth implementation activities may have been formalized and what additional activities would have occurred had this not been done to rapidly transition operations during a crisis. This should be the focus of future research.22 The exploratory technology adoption and process improvement focus of the survey provide limited information on patient characteristics utilizing telehealth. The lack of data from clinical sources prevents us from drawing in-depth conclusions about specific characteristics of patients using telehealth and the services best suited for telehealth. This should be a focus for future research.The target population for this survey was clinic personnel. Information on patient experiences with telehealth is based on the clinic personnel's perception of patient acceptance of telehealth and the barriers they experience. However, the findings from this study supplement existing literature describing the free and charitable clinic patient perspectives on the use of telehealth to provide a more complete picture.Telehealth plays a significant role in expanding access to services in the free and charitable clinic setting. However, continued refinements in the technology to facilitate integration with other systems and workflow processes are needed to reach its full potential. Although this study illustrated a strong desire on behalf of free and charitable clinics to initiate or continue the use of telehealth services going forward, these organizations, dedicated to serving vulnerable populations, face different barriers to telehealth adoption compared with hospitals and other ambulatory care settings, and represent a new frontier for the expanded use of telehealth services in the future.The recent policy landscape has focused on barriers due to the lack of broadband service availability. We also need to examine the cost of accessing broadband, even when available, which may hinder the use of digital resources by low-income and vulnerable populations. Lastly, future research is needed to understand why patients and providers express a preference for in-person versus virtual visits. Identifying the perceived strengths and limitations of a telehealth visit is the first step toward improving and gaining acceptance. Virtual care delivery is a complete transformation of health care delivery. Best practices for telehealth encounters need to be developed, and both providers and patients need to be trained on how to deliver and receive care in this new model most effectively.We would like to acknowledge the support and cooperation we received from the North Carolina Association of Free and Charitable Clinics. This work could not have been completed without the assistance of Mark Scheerer, Director of Membership Engagement at NCAFCC. His facilitation efforts and insights were instrumental in completing this project and greatly appreciated.J.A.S., A.P., D.N., and A.W. contributed to the design and implementation of the research. J.A.S., A.P., and A.W. contributed to the analysis of the results and to the writing of the article.This study was reviewed and granted exempt from further review status (exempt) by the Appalachian State University Institutional Review Board.


Soil biota consists of an incredible diversity of organisms, including microorganisms, soil animals, and plants that live entirely or partially in or on the soil or pedosphere . DespiteKumar et al. attempted to identify keystone taxa and core microbiota in in the wheat (Triticum aestivum) rhizosphere, as well as their response to soil physicochemical properties, allowing the exploration of approaches for manipulating core microbiota for improved plant growth and yield. This is the first study of its kind in India which includes wheat, one of the world’s big three cereals, along with rice (Oryza sativa) and maize (Zea mays). Their research revealed the existence of bacteria that are beneficial to plants (such as Flavobacterium and Flavisolibacter) in the wheat rhizosphere beneath the Indo-Gangetic plain. Additionally, their findings shed light on how pH and readily available nutrients affect the diversity of bacteria in the wheat rhizosphere.In recent years, there has been an increased research focus on the influence of soil organisms on crop health in order to dissect the relationships between biota diversity and key crop phenotypic traits, such as disease resistance and growth promotion, under a rapidly changing climate . HoweverZhang et al. investigated root morphological and exudation traits of four crops, including bok choy (Brassica chinensis), tomato (Solanum lycopersicum), lettuce (Lactuca sativa), and cowpea (Vigna unguiculate), in response to microbial phosphorus in a pot experiment with various straw and phosphorus additions. They reported that the high abundance of microbes was related to the short roots of the four studied crops. While their study demonstrated that straw addition stimulated the growth of bacteria and fungi to increase microbial phosphorus, root phosphorus-acquisition strategies in response to microbial phosphorus dynamics differed among the four crops evaluated following straw addition. It is important to note that to ensure strong crop growth, high-phosphorus fertilisation may need to be considered in addition to returning straw.It has been demonstrated that soil biota, the primary determinant of resource efficiency in agriculture, can increase agricultural sustainability in various ways, including by increasing crop output and nutrient uptake while reducing nitrogen leaching losses . UnderstZhou et al. investigated how soil organic carbon changes in perennial mugwort and the underlying mechanisms during different cropping years. Their findings indicate that short-term rather than long-term perennial mugwort cropping could benefit soil carbon sequestration and help China achieve its carbon neutrality target. Perennial crops typically have an enormous potential to trap more carbon into agricultural soils and hence ameliorate climate change, and they account for 30% of global croplands with higher biomass than conventional crops.When developing crop management strategies based on improving soil biota-plant interactions, it is critical to consider the farming system and crop association . Zhou etSugimura et al. unveiled novel insights into understanding gene-environment interactions in plant foraging strategies in complex environments by defining the three gene co-expression modules for root development, mycorrhiza formation, and phosphate starvation response. According to their findings, the consistency of the relative expression levels of module member genes across genotype site combinations imply that the genetic modules described by this approach are strongly and robustly regulated across ecosystems and that their regulatory systems are species-specific.Plants are known to have diverse strategies for acquiring mineral nutrients (or foraging), such as mycorrhizae and root system architecture modification . DespiteThe articles included in this Research Topic, individually and collectively, contribute significantly to our knowledge of soil biota and their role in combating climate change and improving agricultural sustainability. There is a need to recognise that the application of modern biotechnology technologies, such as genome editing, can be even more effective when assisted by effective microbes, which is a field ripe for future research .This Research Topic was proposed by AC. Each submission was subject to assessment by the editorial board as well as peer reviewers, and all of the editors collaborated to decide which articles were accepted. AC oversaw this editorial introduction. GG and FD offered thoughts and edits to help shape the published document. All authors contributed to the article and approved the submitted version.


Xenopus laevis, unlike those of mammals, are capable of regeneration and functional reinnervation of central brain targets following injury. Here, we describe a tadpole optic nerve crush (ONC) procedure and assessments of brain reinnervation based on live imaging of RGC-specific transgenes which, when paired with CRISPR/Cas9 injections at the one-cell stage, can be used to assess the function of regeneration-associated genes in vivo in F0 animals. Using this assay, we find that map3k12, also known as dual leucine zipper kinase (Dlk), is necessary for RGC axonal regeneration and acts in a dose-dependent manner. Loss of Dlk does not affect RGC innervation of the brain during development or visually driven behavior but does block both axonal regeneration and functional vision restoration after ONC. Dlk loss does not alter the acute changes in mitochondrial movement that occur within RGC axons hours after ONC but does completely block the phosphorylation and nuclear translocation of the transcription factor Jun within RGCs days after ONC; yet, Jun is dispensable for reinnervation. These results demonstrate that in a species fully capable of regenerating its RGC axons, Dlk is essential for the axonal injury signal to reach the nucleus but may affect regeneration through a different pathway than by which it signals in mammalian RGCs.Retinal ganglion cell (RGC) axons of the African clawed frog,  Xenopus laevis, which enable live imaging of axon regeneration and scalable interrogation of gene function via CRISPR/Cas9. We find that dual leucine zipper kinase (dlk) is essential for RGC axon regrowth and vision restoration. However, the downstream transcription factor Jun seems dispensable for regeneration. Thus, though Dlk seems to assist in conveying an injury signal back to the soma, it may act by different mechanisms in frog RGCs than in mammals.In mammals, damage to retinal ganglion cell (RGC) axons results in neuronal death and irreversible blindness. Most interventions in mice produce only modest regeneration with little vision restoration. Therefore, learning how other vertebrates regenerate their RGC axons is of great interest. We report new assays in one such species, In mammals, the central nervous system (CNS) is incapable of productive axonal regeneration. Injury to axons invariably results in not only the rapid degeneration of the injured axons but also most often subsequent cell death. As the visual system is part of the CNS, optic neuropathies that affect the axons of retinal ganglion cells (RGCs), the sole projecting neurons of the eye, eventually result in partial or complete irreversible vision loss. In acute situations of traumatic brain injury or ischemic optic neuropathies, this vision loss can occur quickly, over days or weeks . In moreXenopus laevis bears significant sequence similarity to that of humans , it X. laevis tadpoles that is suitable to query genes involved in RGC axonal regeneration via CRISPR-based loss-of-function studies. Using these assays, we show that a gene previously known to be important in the response of neurons to injury, dual leucine zipper kinase (dlk), is essential for RGC axonal regrowth and for the restoration of vision after injury. The actions of Dlk are thought to act largely through a MAPK cascade that ultimately phosphorylates the transcription factor Jun, leading to its nuclear translocation and consequent large transcriptional changes. We find that Dlk functions largely cell autonomously within RGCs and that Dlk loss does not impair axon growth by noninjured RGCs, only blocking the regeneration of the damaged RGC axons. We further find that while ONC affects mitochondrial movement along RGC axons soon after axon injury, Dlk loss has no measurable effect on this acute injury response. Finally, Dlk loss eliminates the injury-induced phosphorylation and nuclear translocation of the transcription factor Jun that occurs days later within RGCs and does so in a dose-dependent manner that parallels the dose-dependent effect on regeneration, and yet Jun itself is not required for regeneration. As such, our results suggest that Dlk acts within RGCs across vertebrates in communicating the axon injury signal back to the RGC soma. However, the determination whether the RGCs will regenerate their axons is clearly downstream of Dlk, is surprisingly dose dependent, and does not appear to require Jun-dependent transcriptional changes.Here, we have developed an optic nerve crush (ONC) model in young X. laevis as previously done by us and others , also similar to zebrafish , as thin et al.  found noA more critical question was whether the majority of the tectal innervation observed at 7 days post-ONC came from the axonal regeneration of the RGGs disconnected from the brain by ONC or from the newly born RGCs whose axons were innervating the tectum for the first time. To answer this question, we administered a BrdU pulse alongside either ONC or mock crush to Isl2b:GFP transgenic tadpoles at 8 days postfertilization (dpf), then followed this 6 days later (14 dpf) by insertion of a small Mitotracker-soaked piece of Gelfoam into the injured optic tectum to retrogradely label the RGCs that had successfully innervated the optic tectum. These retinas were analyzed in sections rather than wholemounts as the peripheral-most RGCs are difficult to visualize in wholemounts due to the curling of the flatmounted retinas , also known as dual leucine zipper kinase or dlk. Dlk was chosen because it functions in a mitogen-activated protein kinase pathway upstream of Jun N-terminal kinases, cell-injury signals . An advantage of such an approach is that it can also reveal dosage effects. We bred two founders which carried no WT alleles and a high frequency of frameshift alleles and obtained animals which genotyping revealed were an allelic series: carrying either only frameshift mutations in dlk on both chromosomes, 1 copy (L chromosome) of an in-frame dlk −9 mutation, predicted to delete amino acids 56 to 58 (Dlk Δ56–58), or 2 copies (S and L chromosomes) of this Dlk Δ56–58 allele . The hosts carried a single transgene (Isl2b:GFP) such that their RGC axons expressed only cytoplasmic GFP. We subjected these animals to ONC at 8 dpf and live imaged the crushed optic nerves using a spinning disk confocal microscope with single axon resolution at 1, 3, and 7 days post-ONC. At 1 day post-ONC, GFP fluorescence was largely confined to the nerve region proximal to the injury site, with much weaker GFP fluorescence distal to the injury  populations within the optic nerve, all of which would also be devoid of Dlk in our KO tadpoles, have all been shown in other contexts to be extrinsic regulators of axonal regeneration. Thus, to address whether Dlk acts on RGC axonal regeneration via a cell-intrinsic or a cell-extrinsic mechanism, we transplanted small groups of retinal progenitor cells from the eye anlagen of ury Fig. . Given tinjuries , 36. TheONC Fig. . By 7 daneration , 38, thecontexts , 39, 40.dlk KO embryos with WT embryos expressing the same transgene at Nieuwkoop and Faber (NF) stage 41, the earliest stage at which retinal projections have been documented to innervate the brain in X. laevis  below. Based on what has been observed in other systems, in the frog RGCs, Dlk could be acting locally in axons soon after injury or by leading to a transcriptional response once the axon injury signal reaches the nucleus; both possibilities were addressed next.Since the innervation of the optic tectum 6–7 days post-ONC derives from a mix of axons from the injured RGCs and the recently born CMZ-derived RGCs see Fig. D and E, Caenorhabditis elegans motor neurons and murine spinal cord, Dlk has been proposed to act soon after the injury and locally within the axon itself by helping recruit mitochondria to the injury site . In paret al. . Followiet al. , 34. In  neurons , 40; sim neurons . Addition injury . All thedeletion . Howeverdeletion . Our stuX. laevis to humans, other models that have been more extensively studied in the field of RGC regeneration are closer to humans evolutionarily than are frogs, raising the possibility that the relevant molecular machinery in frogs and humans may be somewhat different. Nonetheless, the fact that multiple species descended from the same vertebrate ancestor retain the ability to regenerate RGC axons suggests that mammals lost this ability over evolutionary time, so determining what is common and not between pro- and nonregenerative RGCs may be a productive path toward making axon regenerative therapies a real possibility.There are some limitations to our study that affect how much the results might be generalizable to adult mammalian RGCs. Our assays utilize a developmental system in which the damaged RGC axons regrow alongside axons from newly born RGCs, themselves largely impervious to Dlk loss. The axons from the noninjured RGCs might provide substrates, cues, or activities conducive to the growth of the regenerating axons; indeed, in our system, there is indirect evidence that they may pioneer the tectal reinnervation. That regeneration of the damaged axons occurs amid other uninjured axons in our system does not necessarily make it irrelevant to humans. In glaucoma, the most prevalent disease of RGCs where regenerative approaches might be implemented, the damaged axons do also largely co-exist with nondamaged axons; although, in glaucoma, these axons are fully differentiated rather than actively growing. Another limitation of the current study is that the tadpoles in which the nerves were crushed have axons that have not yet been myelinated, and myelin-derived proteins are potent inhibitors of regeneration . Both ofjun does not phenocopy the RGC regeneration defect observed after dlk KO, but rather may accelerate the degeneration and regeneration of RGC axons, also merits further attention. It is possible that this is due to the incomplete loss of Jun (as assessed by quantification of frameshift mutations) achieved by our F0 CRISPR injections. However, the highly significant and consistent effect of our partial jun KO on RGC degeneration at 1 day post-ONC suggests that our level of jun KO was sufficient to produce a phenotype and that the effect (or lack thereof) on regeneration that we observed will hold when we analyze F1 animals in the future. In the PNS, Jun is upregulated in axons following injury (jun may not involve the phosphorylation of its n-terminus by JNKs (jun cells other than RGCs, which could be tested in future by the retinal progenitor transplantation method used here for Dlk. Interestingly, our previous finding that a nearly 30-fold increase in Jun mRNA occurs at both 3 and 7 days post-ONC in adult frogs is similar to what occurs in mammalian PNS neurons (X. laevis RGCs. As the genes downstream of Dlk are only partially known at present (Several other points raised by our own data also merit further consideration. The lack of effect of Dlk on mitochondrial movement after ONC stands in contrast to its reported effect in other species. While the mitochondrial effect of Dlk may have simply been missed by our assays, it could also be that in vertebrate RGCs, any effect of Dlk on mitochondria is irrelevant to whether a successful regenerative response is mounted. Perhaps of great interest, the dose dependence of the Dlk regenerative effect in frogs suggests the possibility that regenerative species may have more Dlk activity than species that do not regenerate, and that boosting Dlk activity might be therapeutically useful in mammals, perhaps even in humans. However, it will be critical to determine when and where Dlk action exerts this dose dependence, as MAPK pathways typically exhibit tight spatio-temporal control . Finallyg injury  and is tg injury . However by JNKs  and may, by JNKs , 60; in  neurons . As such present , comprehOverall, our results demonstrate that Dlk is essential for successful RGC axonal regeneration in a species that maintains its CNS regenerative capacity. Our data support the view that it initiates a signaling cascade within the axon that is needed for nuclei to transcriptionally activate the intrinsic pathways required for axonal regeneration. We further believe that our current study reinforces the view that clinically relevant axonal regeneration may depend on a thorough deconstruction of evolutionarily conserved successful RGC axonal regeneration responses.Details on materials and methods are available in pgad109_Supplementary_DataClick here for additional data file.