With the rapid advancement of artificial intelligence (AI) technologies, AI-powered chatbots, such as Chat Generative Pretrained Transformer (ChatGPT), have emerged as potential tools for various applications, including health care. However, ChatGPT is not specifically designed for health care purposes, and its use for self-diagnosis raises concerns regarding its adoption’s potential risks and benefits. Users are increasingly inclined to use ChatGPT for self-diagnosis, necessitating a deeper understanding of the factors driving this trend.This study aims to investigate the factors influencing users’ perception of decision-making processes and intentions to use ChatGPT for self-diagnosis and to explore the implications of these findings for the safe and effective integration of AI chatbots in health care.A cross-sectional survey design was used, and data were collected from 607 participants. The relationships between performance expectancy, risk-reward appraisal, decision-making, and intention to use ChatGPT for self-diagnosis were analyzed using partial least squares structural equation modeling (PLS-SEM).Most respondents were willing to use ChatGPT for self-diagnosis . The model demonstrated satisfactory explanatory power, accounting for 52.4% of the variance in decision-making and 38.1% in the intent to use ChatGPT for self-diagnosis. The results supported all 3 hypotheses: The higher performance expectancy of ChatGPT  and positive risk-reward appraisals  were positively associated with the improved perception of decision-making outcomes among users, and enhanced perception of decision-making processes involving ChatGPT positively impacted users’ intentions to use the technology for self-diagnosis .Our research investigated factors influencing users’ intentions to use ChatGPT for self-diagnosis and health-related purposes. Even though the technology is not specifically designed for health care, people are inclined to use ChatGPT in health care contexts. Instead of solely focusing on discouraging its use for health care purposes, we advocate for improving the technology and adapting it for suitable health care applications. Our study highlights the importance of collaboration among AI developers, health care providers, and policy makers in ensuring AI chatbots’ safe and responsible use in health care. By understanding users’ expectations and decision-making processes, we can develop AI chatbots, such as ChatGPT, that are tailored to human needs, providing reliable and verified health information sources. This approach not only enhances health care accessibility but also improves health literacy and awareness. As the field of AI chatbots in health care continues to evolve, future research should explore the long-term effects of using AI chatbots for self-diagnosis and investigate their potential integration with other digital health interventions to optimize patient care and outcomes. In doing so, we can ensure that AI chatbots, including ChatGPT, are designed and implemented to safeguard users’ well-being and support positive health outcomes in health care settings. The digital age has witnessed an unprecedented surge in technological innovation, shaping the essence of human-computer interaction. As the world progresses toward a future encompassing artificial intelligence (AI), advanced conversational AI models, such as Chat Generative Pretrained Transformer (ChatGPT), a cutting-edge conversational AI model by OpenAI, have come to the forefront of academic discussion. This paradigm-shifting technology has revolutionized our interactions with machines and introduced profound implications across multiple disciplines. By harnessing the power of machine learning, ChatGPT transcends the limitations of traditional chatbots, yielding increasingly humanlike conversational capabilities. The technology has demonstrated remarkable capabilities, such as understanding context, generating coherent text, and adapting to various natural language processing (NLP) tasks, including but not limited to language translation, answering of questions, and text generation . The sucThe literature has demonstrated the potential of AI-based chatbots, such as ChatGPT, to revolutionize patient care and service delivery -6. NumerHowever, ChatGPT is not specifically trained in medical literature. It is crucial to understand the intended purpose of ChatGPT and acknowledge its negative consequences if used otherwise. The use of ChatGPT in health care has raised concerns about the accuracy and reliability of the information provided, patient privacy and data security, prejudice, responsibility, and the ethical ramifications of using such potent language models. A study also emphasized the importance of using strong cybersecurity measures to protect patient data and privacy when using ChatGPT in health care settings .Although ChatGPT has proven to be a remarkable technological achievement, its application in self-diagnosis poses significant risks that must be noted. We all have used the internet for self-diagnosis. Depending on the user’s health literacy, the source’s validity, and the accuracy of information interpretation, web-based self-diagnosis has resulted in positive and negative consequences. Just like most consumer-facing screen-based technologies, ChatGPT has the potential for misinterpretation and misuse, necessitating a careful approach to implementation. This is important because misuse (using it for tasks it is not designed for) can affect user trust, resulting in the underuse of the technology . The conWe must understand that anyone with a computer and an internet connection can use ChatGPT. Individuals with minimal to no health and technology literacy may not realize the limitations of ChatGPT and its intended use. User character, the intricacy of medical information, and the unique nature of individual patient cases underscore the potential for misinterpretation. Inaccurate or incomplete information provided by ChatGPT may result in misguided self-diagnosis or exacerbation of existing conditions. From a cognitive human factor standpoint, the misalignment between AI-generated information and users’ mental models can lead to erroneous decision-making and unfavorable health outcomes. The possibility of ChatGPT being misused for self-diagnosis is a significant concern. To counteract this, accessing the potential misuse of ChatGPT from a human factor standpoint is essential.Addressing the concerns associated with AI chatbots in health care, this study aims to (1) explore users’ intentions to use ChatGPT for self-diagnosis and (2) gain a deeper understanding of the factors influencing their decision-making processes. By providing novel insights into the implications of AI chatbot adoption in health care settings, we intend to inform the development of guidelines, policies, and interventions that promote the responsible and effective use of AI technologies in health care. The originality of this study stems from its focus on users’ decision-making processes and intentions when using AI chatbots for self-diagnosis, an area of research that remains relatively unexplored in the context of health care applications.As illustrated in By pinpointing the factors contributing to users’ decision-making processes and intentions to use ChatGPT, regulators and health care professionals can develop informed policies and recommendations to ensure AI’s safe and ethical deployment in health care . AdoptinThe conceptual framework see  exploredIn this study, performance expectancy is operationally defined as the extent to which an individual anticipates that using ChatGPT will augment their capacity to accomplish tasks, attain objectives, and alleviate workload proficiently and efficiently. This latent construct encapsulates the user’s perceptions regarding the advantages, effectiveness, and overall satisfaction derived from their interaction with ChatGPT.The construct of decision-making was operationally defined as the extent to which an individual perceives ChatGPT as a valuable tool for assisting them in making informed, timely, and effective choices by providing relevant recommendations and insights. This latent construct encompasses the user’s belief in ChatGPT’s ability to contribute positively to their decision-making process and their willingness to act on the recommendations generated by the technology.Similarly, the risk-reward-appraisal construct can be operationally defined as the extent to which an individual perceives the advantages of using ChatGPT as surpassing any potential adverse consequences or risks associated with its use. This latent construct captures the user’s evaluation of the trade-offs between the positive outcomes derived from ChatGPT and the potential hazards or drawbacks that may arise from its implementation.The following are the hypotheses tested in this study.The higher performance expectancy of ChatGPT is positively associated with improved user decision-making outcomes. Hypothesis 1 (H1) is grounded in established theories, such as the technology acceptance model (TAM) and UTAUT ,16. ThesAlthough this is the first study to explore the impact of the perceived effectiveness of ChatGPT on decision-making, H1 can be justified by drawing on several studies that have explored the relationship between performance expectancy and technology acceptance, usage, or decision-making in other domains. For instance, Al-Emran et al  conducteA positive risk-reward appraisal of ChatGPT is associated with enhanced user decision-making outcomes. Hypothesis 2 (H2) is based on established psychological and decision-making theories, such as prospect theory and protection motivation theory (PMT), as well as the concept of trust in technology ,23,24.Prospect theory posits that individuals evaluate potential gains and losses during decision-making processes and that their choices are influenced by the perceived risks and rewards associated with each alternative . In the In technology adoption, risk perception can significantly affect decision-making. Although there may not be studies directly examining the relationship between risk-reward appraisal and decision-making in the context of ChatGPT, several studies have explored the impact of risk perception and trust in technology on decision-making and technology adoption in other domains. For instance, a study examined the interplay between trust, perceived risk, and TAM in the context of consumer acceptance of electronic commerce (e-commerce) . The finA positive perception of ChatGPT’s role in enhancing decision-making processes is associated with an increased intention among users to use the technology for self-diagnosis. Hypothesis 3 (H3) can be substantiated by drawing upon well-established theories, such as TAM, UTAUT, and research on trust in technology -17. TAM The study, classified as a flex protocol type, received approval from the Institutional Review Board (IRB) of West Virginia University (IRB protocol number 2302725983). Informed consent was obtained from participants. The data gathered through the online survey were securely stored on Centiment’s platform and remained accessible exclusively to the research team.performance expectancy. The construct was established by aggregating questions related to 4 statements:Statement 1: “ChatGPT can help me achieve my goals.” This item gauges the user’s conviction regarding ChatGPT’s capability to facilitate the attainment of their desired objectives within the context of their tasks.Statement 2: “ChatGPT can reduce my workload.” This item appraises the user’s perception of ChatGPT’s potential to mitigate the burden of task completion by streamlining processes and increasing efficiency.Statement 3: “I was successful in achieving what I wanted to accomplish with ChatGPT.” This item measures the user’s perception of the degree to which their interaction with ChatGPT has led to the realization of intended outcomes, reflecting the efficacy of the technology in practical applications.Statement 4: “I am satisfied with ChatGPT.” This item examines the user’s overall contentment with the performance of ChatGPT, capturing their appraisal of its utility and effectiveness in addressing their needs and expectations.decision-making:In addition, 2 statements were developed to form the latent construct Statement 1: “ChatGPT helps me make informed and timely decisions.” This item evaluates the user’s perception of ChatGPT’s capacity to provide pertinent information, insights, and guidance, which in turn facilitates well-informed and timely decision-making processes.Statement 2: “I am willing to make decisions based on the recommendations provided by ChatGPT.” This item measures the user’s trust in the recommendations offered by ChatGPT and their readiness to incorporate those suggestions into their decision-making processes.Furthermore, 1 statement measured the extent to which an individual perceives the advantages of using ChatGPT as surpassing any potential adverse consequences or risks associated with its use: “The benefits of using ChatGPT outweigh any potential risks.”Lastly, users’ willingness to use ChatGPT for self-diagnosis was captured using 1 statement: “I am willing to use ChatGPT for self-diagnosis purposes.”All the items were assessed using a 4-point Likert scale, allowing participants to indicate their level of agreement with each statement, ranging from “strongly disagree” to “strongly agree.”Note that we used a forced Likert scale in this study. By precluding the inclusion of a neutral or midpoint option, a forced Likert scale necessitates respondents to articulate a definitive opinion or predilection, thereby generating data that are more incisive and unequivocal . This apThe data collection for this study took place in February 2023, using an online survey administered through Centiment, a reputable service provider for survey deployment and data gathering . By leveUpon obtaining informed consent from participants, they were directed to the survey, which contained questions designed to measure the constructs under investigation. The survey used forced 4-point Likert scale questions to elicit decisive responses from participants, thus reducing potential biases. Additionally, the survey incorporated a checking question to verify that respondents thoroughly read all questions before providing their answers, further ensuring data quality. Upon completing the data collection process, the team meticulously reviewed and processed the data to ascertain their quality and accuracy before advancing to subsequent data analysis.The data analysis for this study consisted of 2 primary stages: descriptive statistics and partial least squares structural equation modeling (PLS-SEM). Descriptive statistics were calculated for all survey questions to provide an overview of the responses’ central tendency, dispersion, and distribution. These statistics offered initial insights into the participants’ attitudes and perceptions regarding the constructs under investigation.Following the descriptive analysis, the research team used PLS-SEM to examine the relationships between the latent constructs. PLS-SEM is a powerful multivariate analysis technique that allows researchers to estimate complex cause-effect relationships between latent constructs and their indicators . This meR2) for each endogenous latent construct.After confirming the measurement model’s adequacy, we evaluated the structural model to test our hypotheses. This analysis included assessing the path coefficients, significance levels, and determination coefficients  and between risk-reward appraisal and decision-making . Moreover, the analysis identified a noteworthy positive relationship between decision-making and the intent to use . Concerning indirect effects, the findings revealed that performance expectancy significantly influences the intent to use, mediated by decision-making . Likewise, risk-reward appraisal demonstrated a meaningful positive impact on the intent to use via decision-making .PLS-SEM analysis results elucidated the significant associations among the study variables. The direct effects indicated a significant positive association between performance expectancy and decision-making (β=.547, The “total effects of study variables” section of We acknowledge that conversational AI systems, such as ChatGPT, can be crucial in health care by providing numerous possibilities to elevate patient care, optimize medical workflows, and augment the overall health care experience. In this study, we highlighted specific obstacles that must be tackled for secure and efficient implementation of ChatGPT. Although our study is the first to investigate the effects of perceived ChatGPT effectiveness and risk-reward appraisal on decision-making, its validity is supported by numerous studies examining the relationships among performance expectancy, technology acceptance, usage, risk-reward appraisal, and decision-making in other domains.The findings of our study contribute to the growing body of the literature on AI chatbots in health care and their potential applications, particularly in the context of self-diagnosis. In recent years, research has increasingly focused on developing and evaluating AI chatbots for various health care purposes ,36. HoweOur research builds on earlier studies investigating the factors affecting the adoption of AI chatbots in health care -40. AlthBy focusing on ChatGPT, our study contributes to the broader conversation on AI chatbots’ ethical and societal implications in health care. The increasing popularity of AI chatbots, such as ChatGPT, for self-diagnosis raises important questions about the responsibilities of AI developers, health care providers, and policy makers in ensuring such technologies’ safe and responsible use. Our findings highlight the need for a collaborative, interdisciplinary approach to addressing these challenges, involving stakeholders from various sectors, including AI development, health care, policy, and ethics.The implications of our findings from a policy and pragmatic standpoint suggest a need for proactive preparation and policy alteration concerning the use of ChatGPT for self-diagnosis in health care.Human behavior has consistently demonstrated a tendency to repurpose technology for purposes beyond its original design, even when aware of the potential risks or drawbacks. In the context of our study, people are inclined to use ChatGPT, a technology not specifically designed for health care applications, for self-diagnosis, as they perceive it to be useful and easy to use. Similarly, as evidenced by our prior study on internet use and mental health, people often turn to online sources for self-diagnosis and health information, despite the potential negative impact on mental health . The relIn both cases, people’s behavior can be understood by observing the balance between perceived benefits, ease of use, and potential risks. The desire to reduce uncertainty and the convenience of technology may outweigh the awareness of potential drawbacks or misuse. This highlights the need to develop and regulate technologies like ChatGPT and online health information sources to meet health care applications’ unique requirements and ethical considerations, ensuring that they are user-friendly and trustworthy and minimize negative impacts on users’ health and well-being.First, policy makers and health care stakeholders should collaborate to establish guidelines and ethical standards for using ChatGPT in health care settings . These gSecond, by tailoring the chatbot to address medical inquiries and concerns better, users can receive more reliable and valuable information to inform their decision-making processes. In addition, incorporating evidence-based medicine, reliable sources, and expert opinions into the chatbot’s knowledge base can further improve its credibility and usefulness in the health care . To exteThird, educating and informing users about the appropriate use of ChatGPT for self-diagnosis and its limitations are essential. Public health campaigns and educational materials should emphasize the importance of consulting health care professionals for accurate diagnosis and treatment, while highlighting the potential benefits of using chatbots as an adjunct tool for health information and decision-making support. A feedback mechanism could be proposed to ensure shared understanding and improve user awareness. This mechanism would involve users providing feedback on their experience with ChatGPT, including the accuracy and relevance of the information received and any concerns or misconceptions they may have encountered. Health care professionals could also be involved in this process, sharing their perspectives on the chatbot’s performance and suggesting improvements to enhance its reliability and user-friendliness. The feedback collected would then be used to refine ChatGPT’s algorithms, knowledge base, and user interface, ensuring it remains current with the latest medical knowledge and best practices. This iterative process would foster continuous improvement of the chatbot’s performance and promote greater awareness and understanding among users about the appropriate use of ChatGPT and its limitations in the context of self-diagnosis. Additionally, educational resources, such as tutorials and guidelines, could supplement the feedback mechanism to guide users in interacting with ChatGPT effectively and responsibly. By implementing a feedback mechanism and providing educational support, users can better perceive ChatGPT’s capabilities and limitations, ultimately promoting responsible and effective use of AI chatbots in health care settings.Lastly, continuous monitoring and evaluation of ChatGPT’s use in health care should be conducted to assess its impact on health care outcomes and decision-making. This will enable policy makers and health care providers to make informed decisions about the potential benefits, risks, and practical applications of ChatGPT in health care settings.Our study has limitations that warrant consideration. First, we did not control for potential confounding factors, such as age, medical condition, health literacy, previous experience with comparable technologies, or demographic characteristics, which might significantly influence users’ intentions to use ChatGPT for self-diagnosis. The results among younger and healthier populations could differ substantially from those among older populations with existing medical conditions. Younger individuals may be more inclined to use AI chatbots due to their familiarity with technology. In comparison, older individuals or those with medical conditions may seek additional reassurance or support for managing their health concerns.Second, the cross-sectional survey design constrained our capacity to examine the evolving nature of users’ interactions with AI chatbots. Moreover, relying on self-reported measurements may introduce various biases, including social desirability, recall, or imprecise reporting. Self-report measures obtained through surveys inherently capture users’ perceptions rather than objective reality. Although the participants’ subjective experiences can provide valuable insights, there may be discrepancies between these perceptions and the actual situation. Furthermore, the cross-sectional design of the study limited our ability to draw causal inferences over time. Future research could use a triangulation approach to mitigate these limitations, incorporating objective measures and longitudinal data collection to provide a more comprehensive understanding of the phenomenon under investigation. Lastly, focusing on ChatGPT, which is not specifically intended for health care applications, may limit the applicability of the findings to other AI chatbots explicitly designed for health care purposes.To address these limitations, future research should consider using longitudinal data, stratifying the sample by age group and medical condition, and accounting for potential confounding factors, such as participants’ familiarity with AI technology, prior experiences with chatbots, and demographic information. Various methodologies could provide additional insights, including monitoring chatbot usage and conducting qualitative interviews to assess trust and user behavior. Enhancing the data collection frequency and guaranteeing participant anonymity may also help reduce biases. By addressing these constraints, future research can contribute to a more comprehensive understanding of AI chatbot adoption in health care settings and enable more targeted interventions to optimize patient care and outcomes across diverse populations and health statuses.In conclusion, our research investigated the factors influencing users’ intentions to use ChatGPT for self-diagnosis, a purpose for which the technology is not specifically designed. The study aimed to explore the implications of these factors for the safe and effective integration of AI chatbots in health care settings. By examining performance expectancy, risk-reward appraisal, and decision-making processes, our findings contribute to the growing body of the literature on AI chatbots in health care and provide insights into AI chatbot adoption in health care contexts.The clinical message of this study is to emphasize the importance of ongoing collaboration among AI developers, health care providers, and policy makers in ensuring the safe and responsible use of AI chatbots in health care. Addressing users’ expectations, risk-reward appraisal, and decision-making processes can help develop AI chatbots tailored to human needs and preferences, providing consumers with reliable and verified sources for health-related information. This approach can not only enhance health care accessibility but also improve health literacy and awareness among the public.As the field of AI chatbots in health care continues to evolve, future research should further investigate the long-term effects of using AI chatbots for self-diagnosis and explore the potential integration of AI chatbots with other digital health interventions to optimize patient care and outcomes. In doing so, we can better understand the implications of AI chatbot usage in health care settings and ensure that these technologies are designed and implemented to safeguard users’ well-being and support positive health outcomes.


Limited diagnostic capabilities, resources and health worker skills have deterred the advancement of birth defects surveillance systems in most low- and middle-income countries (LMICs). Empowering health workers to identify and diagnose major external birth defects (BDs) is crucial to establishing effective hospital-based BD surveillance. Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration BD Surveillance System consists of three diagnostic levels: (1) surveillance midwives, (2) MU-JHU clinical team, and (3) U.S. Centers for Disease Control and Prevention (CDC) birth defects subject matter experts (SMEs) who provide confirmatory diagnosis. The diagnostic concordance of major external BDs by surveillance midwives or MU-JHU clinical team with CDC birth defects SMEs were estimated.Study staff went through a series of trainings, including birth defects identification and confirmation, before surveillance activities were implemented. To assess the diagnostic concordance, we analyzed surveillance data from 2015 to 2021 for major external BDs: anencephaly, iniencephaly, encephalocele, spina bifida, craniorachischisis, microcephaly, anophthalmia/microphthalmia, anotia/microtia, cleft palate alone, cleft lip alone, cleft lip with cleft palate, imperforate anus, hypospadias, talipes equinovarus, limb reduction, gastroschisis, and omphalocele. Positive predictive value (PPV) as the proportion of BDs diagnosed by surveillance midwives or MU-JHU clinical team that were confirmed by CDC birth defects SMEs was computed. PPVs between 2015 and 2018 and 2019–2021 were compared to assess the accuracy of case diagnosis over time.Of the 204,332 infants examined during 2015–2021, 870 infants had a BD. Among the 1,245 BDs identified, 1,232 (99.0%) were confirmed by CDC birth defects SMEs. For surveillance midwives, PPV for 7 of 17 BDs was > 80%. For the MU-JHU clinical team, PPV for 13 of 17 BDs was > 80%. Among surveillance midwives, PPV improved significantly from 2015 to 2018 to 2019–2021, for microcephaly (+ 50.0%), cleft lip with cleft palate (+ 17.0%), imperforate anus (+ 30.0%), and talipes equinovarus (+ 10.8%). Improvements in PPV were also observed among MU-JHU clinical team; however, none were significant.The diagnostic accuracy of the midwives and clinical team increased, highlighting that BD surveillance, by front-line health care workers (midwives) in LMICs is possible when midwives receive comprehensive training, technical support, funding and continuous professional development.The online version contains supplementary material available at 10.1186/s12909-023-04760-w. A hospital-based birth defects (BD) surveillance system captures birth defects that occur in selected hospitals within a defined geographic area . Most loIntegrating a successful birth defects surveillance system into an existing hospital structure can be a daunting task. Challenges include, integration of surveillance activities in busy delivery units, burden on staff to conduct additional activities, such as; reporting BD data, recording the clinical presentation of any identified birth defect , rigorouThe objectives of this study were to describe the process for strengthening capacity of health workers to diagnose external major birth defects in four large Ugandan hospitals and to examine the concordance of these diagnoses to those of birth defects subject matter experts (SMEs) at the U.S. Centers for Disease Control and Prevention (CDC) to assess the competence of surveillance staff in diagnosing birth defects and whether or not this improved over time. Positive predictive value (PPV) between 2015 and 2018 and 2019–2021 for both surveillance midwives and the Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration clinical team were compared.In 2015, Makerere University–Johns Hopkins University Research Collaboration, in collaboration with CDC, implemented a hospital-based birth defects surveillance system in Kampala, Uganda. This was the first birth defects surveillance system in Uganda. The surveillance system was designed to provide accurate prevalence estimates of 17 major external birth defects  [The initial training for MU-JHU clinical team included an online 7-week pre-course training and a 5-day in-person birth defects surveillance workshop conducted in 2015 by the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) and the U.S. CDC . The worThe trained MU-JHU clinical team and data managers collaborated with CDC to further develop the surveillance protocol, standard operating procedures (SOPs), data collection logistics, and data collection forms. Additional surveillance study staff  were recruited to conduct the initial examination of all newborns and collect data, support quality control/assurance, and conduct bedside confirmation of birth defects at the hospitals.Surveillance study staff were trained by CDC and the MU-JHU clinical team on the study protocol, SOPs, good clinical practice, data collection, as well as the systematic process of examining all informative births for major external birth defects . AdditioDiagnosis and verification of the birth defects are done at several levels to ensure accuracy. First, the surveillance midwives conduct the initial examination of each newborn to identify any external birth defects. Newborns are examined when they are clinically stable and external birth defects are documented in the relevant study logs at the hospitals. Data are collected electronically on android-based tablets using the Open Data Kit (ODK) platform . Next, sIn all hospitals, if the program manager/clinical consultant is not available to perform bedside confirmation or if consent for photographs of the case is not obtained, the surveillance midwife draws an illustration of the defect and writes a brief narrative description of the condition. This visual data along with the surveillance information are then entered into a tablet for further review by another surveillance midwife and then submitted to the MU-JHU central server. Thereafter, the birth defects records are extracted by the data managers and shared with the MU-JHU clinical team for review and classification.This process is followed in all hospitals except at Kawempe National Referral Hospital, a high volume government hospital where up to 70 mothers give births daily and close to 24,000 babies are delivered annually . The surAfter cases are reviewed by the MU-JHU clinical team, the compilation of birth defects pictures/illustrations, descriptions, diagnoses, and coding are sent to CDC birth defects SMEs by data mangers through encrypted files. Feedback from CDC birth defects SMEs along with any corrections to the diagnoses or coding are sent back to the MU-JHU clinical team as well as the surveillance midwives at the hospital level. Birth defects diagnoses are coded using the International Classification of Diseases (ICD) 10 classification system by the Royal College of Paediatrics and Child Health (RCPCH). All care of live newborns with birth defects is provided through routine care by the hospitals, which includes referral to specialists when available .Birth defects surveillance data were used to calculate PPV of birth defects diagnosis at each level of review , using the CDC subject matter experts’ review as the “gold standard.” PPV was calculated to assess how well the surveillance midwives and MU-JHU clinical team diagnosed and classified the identified birth defects compared to the CDC birth defects SME review. The PPVs for surveillance midwives were calculated as the proportion of a given birth defect diagnosed by the surveillance midwives that was confirmed by the CDC birth defects SME review. The PPVs for the MU-JHU clinical team were calculated as the proportion of a given birth defect classified by the MU-JHU clinical team that was confirmed by the CDC birth defects SME review. For both surveillance midwives and MU-JHU clinical team, the PPVs in the earlier periods of the surveillance activities (2015–2018) were compared to PPVs of the later periods (2019–2021) using the two-sided proportion test where the numbers were quite high. Where the occurrences of defects were rare, like craniorachischisis, a Fisher’s exact test was used to determine if classification improved over time, given the ongoing capacity building and additional staff trainings. STATA version 17 software  was used for analysis.≥ 4 years of surveillance experience. Among surveillance midwives, over 90% (184/202) had ≥ 2 years and 62% (125/202) had ≥ 4 years of surveillance experience , omphalocele (90%), spina bifida (89%), anencephaly (87%), imperforate anus (86%), cleft lip with palate (82%) and gastroschisis (81%)  compared to the earlier period of when the surveillance system began 2015–2018) Table . Among s–2018 TabSuccessful birth defects surveillance programs require skilled and competent staff to identify and diagnose birth defects rapidly and accurately. The importance of birth defect capacity building has been reported in other resource limited settings . For birIn Uganda, strengthening and building capacity among different cadres involved with surveillance activities has been done through organized workshops with international birth defects experts, formalized in-house continuous medical trainings and hands on trainings, and self-learning. In addition, continuous quality improvement activities were implemented to address data quality gaps and ensure the accuracy and completeness of every surveillance record. Several quality control measures were implemented including real-time quality control by surveillance midwives before data submissions, review of submitted data for accuracy and completeness by data managers before inclusion in the study database, and supportive supervision by trained senior surveillance study staff and the MU-JHU clinical team. Accuracy of birth defects diagnosis was positively associated with increasing use of readily available birth defect documentation tools, particularly; the ICD-10 form for standardized coding of birth defects, and the quality control verification form for checking completeness of data variables .One limitation faced by this surveillance program was the high turnover (37%) among surveillance midwives, as it is not unusual for midwives to change hospitals in resource-limited settings like Uganda . HoweverOverall, results from this study showed that the MU-JHU clinical team had a higher PPV for more birth defects than the surveillance midwives. This may have been because there was no turnover in the clinical team at MU-JHU and that the team worked collaboratively, to review the information provided on identified birth defects. A second limitation was the low prevalence of certain birth defects in the surveillance system. The lowest PPV for the MU-JHU clinical team was observed for rare birth defects, such as craniorachischisis and microcephaly. Likewise, among surveillance midwives, the lowest PPV was only observed for craniorachischisis, encephalocele, and cleft lip. The low PPV among midwives, could be attributed to low prevalence of craniorachischisis, encephalocele and cleft lip during the surveillance study period. Additional training and skills-building are needed to help clinical and surveillance staff identify and diagnose rare birth defects. Surveillance teams with capacity similar to the MU-JHU clinical team would also benefit from an additional member with training in clinical genetics, especially for the diagnosis of complicated cases and syndromes.This study also found that both the MU-JHU clinical team and the surveillance midwives have continuously increased their knowledge of birth defects diagnoses, which is evidenced by the increase in PPVs for most of the birth defects between the period 2015–2018 and 2019–2021. This may be attributed to the trainings that the MU-JHU clinical team and surveillance study staff were required to undergo before participating in surveillance activities, as well as additional training surveillance midwives underwent to conduct bedside birth defect confirmation in the absence of a clinical consultant. For surveillance midwives, strengthening capacity through confirmation by a second midwife could also have helped surveillance midwives gain confidence, experience and expertise in diagnosing birth defects by learning from their colleagues. However, there were some drops in rare defects like craniorachischisis though not statistically significant, potentially attributable to defects being rare, some defects being part of a syndrome and high surveillance midwives turn-over. Also, there may have been over-reporting of cases by surveillance midwives as they are trained to report any abnormality. Diagnoses of some defects may have been complicated by the rarity of a defect, the presence of multiple birth defects, or even a typical presentations of birth defects which would have made accurate identification more of a challenge for surveillance midwives. For some birth defects such as abdominal wall defects and orofacial clefts, the presence or absence of the defect was correctly noted; however, the type of defect may have required additional input by the clinical team at MU-JHU or by birth defects subject matter experts at CDC.Compared to the period 2015–2018, additional measures were implemented in 2019–2021, to help hospital surveillance staff improve diagnosis and classification of birth defects. For example, during 2019–2021, a greater emphasis was placed on practical sessions and video trainings for anthropometric measurements, which improved skills among hospital surveillance staff for performing physical exams and ruling out abnormal length, weight, and head circumference, especially microcephaly. During this latter period, standard operating protocols were also modified for identification and coding of cases for inclusion in birth defects surveillance. A quality control verification form was put in place, according to identified gaps. Additionally, video conference calls were regularly held between surveillance midwives and MU-JHU clinical team, to provide feedback on incorrectly diagnosed birth defects.One limitation faced by this surveillance program was the high turnover (37%) among surveillance midwives, as it is not unusual for midwives to change hospitals in resource-limited settings like Uganda . HoweverFurther improvements in PPV can be attributed to the feedback on birth defects diagnoses and coding, provided by CDC birth defects SMEs to the MU-JHU clinical team. This feedback was periodically given to surveillance study midwives, during meetings at their respective hospitals. The feedback process, for both the MU-JHU clinic team and the surveillance midwives, helped staff gain experience in diagnosing birth defects.This study highlighted that birth defects surveillance, by front-line health care workers (midwives) in a low-middle income country like Uganda, is possible when midwives are exposed to comprehensive training, technical support and continuous professional development initiatives. Over the six years of the MU-JHU Research Collaboration Birth Defects Surveillance System, the diagnostic accuracy of the MU-JHU clinical team increased for five defects and decreased for nine defects, but none of the changes in PPV were statistically significant. Among the surveillance midwives, however, diagnostic accuracy increased across several birth defects, four of which were statistically significant. Empowering surveillance midwives to identify and confirm external birth defects is a strategy that is feasible, in a resource limited setting, where there is scarcity of consultants/doctors to provide confirmation.Below is the link to the electronic supplementary material.Supplementary Material 1


Donor derived infections (DDIs) in pediatric kidney transplant recipients remain challenging to diagnose and can result in serious morbidity and mortality. This review summarizes the current guidelines and recommendations for prevention, diagnosis, and treatment of unexpected DDIs in pediatric kidney transplant recipients. We provide a contemporary overview of DDI terminology, surveillance, epidemiology, and recommended approaches for assessing these rare events with an emphasis on the pediatric recipient. To address prevention and risk mitigation, important aspects of donor and pediatric candidate evaluations are reviewed, including current Organ Procurement and Transplantation Network (OPTN) and American Society of Transplantation (AST) recommendations. Common unexpected DDI encountered by pediatric transplant teams including multi-drug resistant organisms, tuberculosis, syphilis, West Nile Virus, toxoplasmosis, Chagas disease, strongyloidiasis, candidiasis, histoplasmosis, coccidioidomycosis, and emerging infections such as COVID-19 are discussed in detail. Finally, we consider the general challenges with management of DDIs and share our experience with a novel application of next generation sequencing (NGS) of microbial cell-free DNA that will likely define a future direction in this field. Kidney transplantation remains the treatment of choice for children with advanced or end-stage kidney failure. However, transplantation is not without risk. Balancing immunosuppression with risk of infection remains an ongoing challenge, especially in the context of donor derived infections (DDIs). DDIs can cause serious morbidity and mortality for solid organ transplant (SOT) recipients. These complications can be even more devastating in pediatric SOT recipients and early recognition, timely reporting, close monitoring, and appropriate management are essential to help mitigate these risks.Unexpected donor derived disease (DDD) was recently reported to occur in 0.18% of SOT recipients in a review of patients from 2008 to 2017 , as outlined in policy 15.4 . With revia SOT and it remains essential for clinical transplantation teams to remain vigilant to this risk, react quickly to potential DDI, and start treatment immediately.In contrast, “unexpected” transmission of various types of pathogens from donor to recipient occur when donor infection is previously unknown, undetected, and/or incompletely treated . For theThe Ad Hoc Disease Transmission Advisory Committee (DTAC) reviews any potential donor derived transmission events in a blinded fashion. After committee review, the probability of a transmission event is determined and classified as proven, probable, possible, unlikely, excluded, intervened upon without documented transmission (IWDT), positive assay without apparent disease transmission, or not assessable as defined in The most recent published report from DTAC describes all reports received between 2008 and 2017 in both pediatric and adult SOT donors and recipients. Of the 2,185 reports during that time period, 335 (15%) were considered a proven or probable donor transmission event with an overall rate of unexpected donor derived disease at 0.18% of all transplant recipients .A prior report of DDD limited to pediatric donors and recipients showed overall similar results. Between 2008 and 2013, there were 103 reported potential DDIs reported to involve pediatric donors or recipients. With regard to pediatric recipients, 11 cases were classified as proven or probable events  using United States Centers for Disease Control and Prevention (CDC) recommended HIV laboratory algorithm-Hepatitis B Virus (HBV) surface antigen (HBsAg), hepatitis B core antibody , hepatitis B surface antibody (HBsAb)-Hepatitis C Virus (HCV) antibody (anti-HCV), hepatitis C ribonucleic acid by nucleic acid test (NAT).As of July 1, 2022, the OPTN updated its policy on pre-transplant evaluation for all candidates less than 12 years of age with regard to HIV, HBV, and HCV testing. Pediatric patients less than 12 years old must be tested any time prior to transplant and the testing must be documented, but it does not have to occur at time of hospital admission for transplant. This policy change was made given incidence of these infectious are very low in this age group and there is a large concern for overdrawing blood, especially immediately prior to a solid organ transplant -certified laboratory or equivalent. For a candidate to be eligible for an organ transplant, the following testing is required  by OPTN per policy 15.2, updated in 2020 :-Human ansplant .-Screening for periodontal disease and treatment prior to transplant-Tuberculosis (TB) with purified protein derivative (PPD) or interferon-gamma release assay and chest x-ray-CMV IgG antibody-EBV with EBV viral capsid antigen IgG, IgM and/or EBV nuclear antigen (EBNA) IgG-Herpes simplex virus IgG-Varicella IgG-Mumps IgG, Rubella IgG, Rubeola IgG-Human T-lymphotropic virus 1 & 2 with IgG serology in candidates from endemic areas-Syphilis with any of the following: treponema pallidum particle agglutination, treponema pallidum immunoassay, rapid plasma regain, venereal disease research laboratory-Toxoplasmosis with IgG antibodyIn endemic areas, other testing should be strongly considered such as strongyloides serologies, coccidiodes serologies, histoplasmosis serologies/urine antigen tests, chagas serologies, malaria screening with a malaria blood smear, West Nile Virus serologies or NAT, and/or hepatitis A total antibody, hepatitis A IgM  guidelines from 2019 and KDIGO Clinical Practice Management Guideline on Evaluation and Management of Candidates for Kidney Transplantation 2020, recommend the following candidate infectious disease screening:is A IgM , 12. ThiThe Coronavirus Disease 2019 (COVID-19) pandemic presented new challenges for infectious disease screening and recommendations are evolving. Based on a review from 2021, the current recommendation is to wait at least 4–6 weeks after recovering from COVID-19 prior to transplantation. It is also recommended that patients undergo pulmonary function testing (PFT) and have SARS-CoV-2 IgG and RT-PCR once fully recovered . If a caAll eligible vaccinations should be administered to patients on the waiting list potentially on an accelerated schedule, if necessary. A 4-week delay of transplantation is recommended after any live vaccinations . Many peWhile it is impossible to eliminate the potential for transmission of DDIs, a thoughtful and thorough approach to donor evaluation can mitigate risk. Various screening protocols have been proposed, although the sensitivity and specificity of these approaches are unknown . In geneSpecific details from the donor medical and social history can provide insight into the risk of DDI transmission. In the case of a deceased donor, the cause of death should be a starting point. For example, a donor who dies from trauma is a much lower infectious risk than one who died from complications of intravenous drug use . AlternaDetails in a social history can help provide risk stratification, although the reliability of this information can be variable in between living and deceased donors. In the setting of a deceased donor, the social history may be limited and/or incomplete. Elements of a social history that suggest increased risk of blood borne viral pathogens include high risk sexual contacts ; men who have sex with men; persons who have had sex in exchange for money or drugs; and persons who have had sex with a person who uses injection drugs nor non-medical reasons), birth to a mother infection with HIV, HBV, or HCV (for donors under 2 years old), persons use injection drugs for non-medical reasons, inmates of a correctional facility for more than 3 days in the past 12 months, persons treated for gonorrhea, chlamydia, or genital ulcers, or persons who have been on hemodialysis in the preceding 12 months . Donors While use of organs at increased risk of infection transmission at adult centers has the potential to decrease wait times, use of PHS increased risk organs in pediatric recipients is uncommon . The pedAny available information about the clinical and physical assessment of the donor needs to be assessed. This can be done by review of available records (such as imaging studies) or direct observation of the donor and organ by a procurement team. Physical evidence of infection includes unexplained rash, abscesses, ulcers and lymphadenopathy. Recent injection drug use can be inferred by the presence of track marks or skin-popping ulcerations. Cross-sectional imaging can also reveal evidence of active infection, such as metastatic foci, lymphadenopathy, or granulomatous disease .The review of infectious disease-related laboratory data is of utmost importance. OPTN policy requires that all donors undergo testing of commonly transmissible infectious diseases . In addiIn deceased donors, all microbiological culture data should be reviewed and ideally a minimum of 48 hours of no culture growth should be available prior to the acceptance of an organ. Ideally, any known active bacterial or fungal infection in the donor should be treated and resolved before transplantation  is not routinely done for decreased donors due to the length of time required for traditional screening methods. Use of the purified protein derivative (PPD) test is not practical due to the time needed to assess a response . Even ifAs noted in the candidate evaluation, COVID-19 presents new challenges for infectious disease screening and recommendations are evolving as new variants arise, changes in therapeutic options, and vaccination availability. SARS-CoV-2 NAT positive organs had similar outcomes compared to COVID-19 NAT negative donors on 30-day patient and graft survival . More inAdditional considerations for pre-transplant deceased donor testing includes testing for endemic infections such as strongyloidiasis, coccidioidomycosis, histoplasmosis, chagas disease, malaria, West Nile, and/or hepatitis A , 29.It is important to consider the limitations of infectious disease screening in donors. There are limitations to diagnostic tests and donor history, especially in the time-sensitive setting of a deceased donor offer. There is always risk of undetected infection for transplant candidates and recipients. Understanding some of these limitations can help inform risk and management of DDIs.Currently, either serologic or nucleic acid testing (NAT) can be performed to detect viral infections. Historically, much of this evaluation was done using serologic testing given it is less expensive. However, NAT is now being used more commonly due as the technology is becoming more affordable and available.Serologic testing is limited by poor sensitivity early after initial infection, as seroconversion may not occur during the acute phase of an infection. This “window period” can result in a false-negative result and be a high risk period for donor transmission . NAT mitThe potential for hemodilution in deceased donors is another important limitation of NAT or serologic tests . Many poThere can be a wide spectrum of presentation of unexpected DDIs and clinicians need to have a high index of suspicion. It is possible that DDIs are an under recognized cause of morbidity and mortality . Early rRecognize Potential Infections-Recipients with atypical post-transplant course-Recipient with early post-transplant bacterial or fungal infection-Multiple recipients of organs from the same donor with the same infection-Atypical infection for the early post-transplant periodConsider DDIs in the following settings:Report and Communicate-Team should NOT wait until donor origin is confirmed.-Report should be made NO later than 24 hours after initial concern.-In the USA, reports should be made to UNOS via the Patient Safety Portal and to the patient safety contact for the transplant centers and OPOs. The patient safety contact is listed in DonorNet.-Inform all key members of the team, including but not limited to the transplant team, risk management, and media relations.-Make direct contact with any involved patients to ensure they are asymptomatic and current clinical status must be obtained.-Provide timely updates and information to your patients.As soon as any team member considers a potential DDI, a report should be made to all involved organ procurement organizations (OPOs), transplant centers, and transplant authorities:Collect and Retain Specimens and Data-Contact pathology – retain any fresh residual specimens, biopsies, and/or discarded tissue from the donor and recipient.-Contact microbiology – retain any cultures and/or residual specimens that were sent for testing.-Contact molecular diagnostics lab – retain any sequences and/or specimens sent for PCR or similar testing.-Contact HLA – retain any donor and/or recipient blood, lymph nodes, cells or tissues, particularly pre-transplant specimens.As soon as you are informed of the potential disease transmission event, collect the following key specimens and data:Test and Manage-For most viral pathogens you will need direct testing of the virus with PCR/NAT or antigen testing.-Serologies may be unreliable in post-transplant period, particularly if there was significant blood transfused.-Provide appropriate therapy based on presumed pathogen.Continue routine monitoring for disease transmission.Perform appropriate testing of the recipient for potential DDI:The American Society of Transplantation Infectious Disease Community of Practice has published general guidelines for the approach to donor-derived infection evaluation in 2019. These guidelines outlined in below involve steps for recognizing potential infections, reporting and communicating, how to collect and retain specimens and data, and tests and management .RecogniWhile every effort is made to treat any known positive cultures prior to transplantation, given the urgency of donation at times, cultures can become positive after transplantation. If a documented bacteremia is found, the recipients should also receive a course of antibiotics targeting the pathogenic organism for at least 7–14 days  prophylaxis which could theoretically also prevented transmission. More studies are needed to understand the risk of positive urine cultures for kidney transplant recipients. Regardless, at this time it is still recommended to treat positive urine culture, especially of virulent or more resistant organisms .Special attention must be paid to any multi-drug resistant organism (MDRO) identified in the potential donor as the risk mitigation is extremely difficult and/or unmanageable . MDROs aIn a multicenter, retrospective, cohort study of 658 adult SOT recipients with deceased donors, it was found that MDRO significantly increased early post transplantation infection risk, although did not appear to affect long term graft or recipient survival the 1-year mark . In thisMycobacterium tuberculosis. The risk of DDI with TB varies depending on geographical location. In non-endemic areas, risk factors for donor derived TB include donors who were born outside the US or prolonged residence outside of the US , history of incarceration, homelessness, alcohol and/or substance abuse, healthcare worker, and known history of TB/latent TB infection (LTBI) (Tuberculosis (TB) is caused by the bacterial pathogen, n (LTBI) . Active n (LTBI) .As noted in the donor evaluation portion of this review, it remains challenging to screen for TB given the time limitations of deceased organ donation typically does not allow for PPD placement and there are challenges with interferon gamma release assay. Interferon gamma release assay most often does not result until post-transplantation and had indeterminate results at least 30% of the time .The median time to presentation of donor derived TB in kidney transplant recipients was 2 months post-transplantation and carries a high risk of morbidity and mortality. In a review from 2018 on adult SOT, graft loss was seen in 18.2% of patients, all-cause mortality was 25%, and specifically TB attributable mortality was 44%. The clinical presentation is usually persistent fever and often has an insidious course, which requires a high index of suspicion for diagnosis. Allograft involvement is common in non-lung SOT, presentation commonly included extrapulmonary TB or disseminated TB presentations  is an arborvirus transmitted to humans by way of bites from infected mosquitos, typically of the d States . In heald States . The mosd States . Risk ofd States .α-2b or Ribavirin (WNV incubation is between 3 and 15 days and methods for diagnosis include serology (IgM and IgG), NAT, or viral culture of serum and/or CSF . Infecteibavirin .Donor screening for WNV is not currently required by OPTN policies and practices vary based on center and OPO . CurrentToxoplasma gondii, which is considered a neglected parasitic infection by the CDC . General treatment recommendations include induction with pyrimethamine, sulfadiazine, and leucovorin for a minimum of six weeks followed by lifelong suppression in conjunction with infectious disease consultation .Trypanosoma cruzi. The majority of infections occur in endemic areas of South and Central America. In immunocompetent individuals, most infections are mild with fever or minimal symptoms. Without treatment, the infection is lifelong and can manifest later as severe gastrointestinal and/or cardiac disease in 20%–30% of patients  . IRIS caMoreover, there is often lack of definitive evidence to determine treatment courses, especially on topics such as secondary prophylaxis in the SOT population . The eviWith the advent of new technologies and diagnostic tools, there is the potential for earlier and more accurate diagnoses of infection to guide decisions about accepting an organ, understand potential risks of transplantation, determine need for post-transplant prophylaxis, and to guide management of DDIs. One example of new technology shaping SOT infectious disease care is next generation sequencing (NGS) of microbial cell-free DNA. There is evidence that NGS of (cf)DNA may result in de-escalation of antimicrobial therapy, shorten duration of therapy, and more rapidly identify microbes than conventional culture-based methods. This also would result in improved antimicrobial stewardship in the SOT population. However, there are still unanswered questions about the challenges of interpretation in immunosuppressed individuals and further investigation is needed .Encephalitozoon cuniculi) approximately 12 weeks status post deceased donor kidney transplantation. Our local OPO was alerted that two other patients who had received organs from same donor had posttransplant infections with Encephalitozoon cuniculi. Despite an array of tests to assess for Encephalitozoon cuniculi, our patient was only found to be positive on microbial cell-free DNA testing. Strong communication with our OPO and transplant teams led to the recognition of Encephalitozoon cuniculi in our pediatric patient prior to the development of fulminant disease. To date, our patient has had no evidence of recurrent microspordiosis and microbial cell free DNA has been used to help track the infection and guide management DNA in the case of pediatric kidney transplant recipient with unexpected donor derived microsporidiosis (nagement . This scAs always, it is essential that the transplant community continues to engage in high quality research and innovation to develop new technologies, directed therapies, and a more personalized approach for our SOT who remain at high risk of DDIs.While DDIs overall rare, the consequences can be devastating, especially in the pediatric kidney transplant population. Prevention is key and clinicians must maintain a high index of suspicion for a possible DDIs, especially in any patient who does not follow the expected post-transplant course. As transplant care providers, we must remain vigilant in staying up to date on emerging infections and highly resistant bacteria. Strong communication between OPOs and transplant teams will always be essential to helping recognize, manage, and/or treat DDIs. Furthermore, new innovative ways to rapidly identify potential pathogens prior to transplantation will be essential to help mitigate risk for candidates.


Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine . In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence. Our literature review identified four generalizable barriers that can impact the training outcomes of students from these marginalized and/or underrepresented groups: 1) discrimination and bias, 2) impostor syndrome and stereotype threat, 3) lack of identity-similar mentors, and 4) suboptimal institutional policies and procedures. We propose goal-oriented interventions that may begin to ameliorate the disparities present in MD-PhD program training environments that affect students from marginalized and/or underrepresented groups in academic medicine. Physician scientists are key contributors to the advancement and bridging of medicine and biomedical research. Yet over the last thirty years, the percentage of physician scientists out of the total biomedical workforce has decreased, suggesting that the growth of the physician scientist workforce through a robust training pipeline has been stunted , 2. The In this article, we provide an overview of the existing literature and propose solutions on MD-PhD program disparities affecting underrepresented racial and ethnic minorities , sexual and gender minorities , individuals with disabilities, and individuals of low socioeconomic status (SES) or financially disadvantaged background. Collectively, these individuals will be referred to as Underrepresented and/or Marginalized students in Academic medicine (UrMAs).Our review is divided into three sections. First, we assess the current state of UrMA training in MD-PhD programs. Second, we discuss four major barriers to successful MD-PhD training of UrMAs. For each barrier, we provide a collection of evidence of how the different underrepresented and/or marginalized groups composing the UrMA umbrella term are affected by that barrier. Lastly, we discuss a selection of published solutions and provide recommendations informed by the literature aimed at addressing these disparities. Peer-reviewed publications that specifically address current trends and outcomes of MD-PhD UrMAs are scarce; therefore, as MD-PhD trainees are de facto participants of curriculums prepared by MD-only and PhD-only programs at all points in their training, our review is supplemented with publications on MD-only, PhD-only, and residency programs. The goal of this review is to support future efforts of MD-PhD programs to address disparities affecting UrMAs pursuing a physician scientist career, and to invite readers and relevant institutions to consider how the intersection of different identities contained in the UrMA umbrella term may exacerbate the identified disparities.Dual-degree training via MD-PhD programs has been established since the 1950s. MD-PhD programs are either partially funded by the NIH through T32 awards from the National Institute of General Medical Sciences and known as a Medical Scientist Training Programs  or funded entirely at the individual institutional level through research grants, fellowships, and institutional commitments . There ipre-clinical phase, students partake in the didactic portion of the medical school curriculum. This first phase typically concludes with the first US Medical Licensing Exam (USMLE 1), after which they begin the graduate phase of their training, following selection of their thesis mentor. During this second phase, MD-PhD students are required to meet certain milestones for graduation that can include: the publication of a first-authored, peer-reviewed research article, the successful composition and defense of a graduate thesis and a mock research proposal , and the presentation of original research in an academic setting. After obtaining their doctoral degree, students move on to clerkship rotations as part of the clinical phase of their training. This last phase has students identifying clinical areas of interest to pursue during their residency training, acquiring advanced clinical knowledge and skills required to pass the US Medical Licensing Exam 2 (USMLE 2), and partaking in residency program interviews.Most MD-PhD programs consist of three training phases and have an estimated completion length of 7–9 years , 21. DurThe overall attrition rate is estimated to be 3% for both MD-PhD and MD-only students. This rate remains well below the 31–50% range estimated for PhD programs in engineering, life sciences, social sciences, mathematics, and physical sciences, suggesting that a commitment to clinical training influences trainee attrition . HoweverUnderrepresented racial and ethnic minorities constituted around 11% of all MD-PhD graduates from 2016 to 2020 . These iConstant exposure to an unsafe academic environment, particularly in the form of microaggressions and discrimination, contributes to the poor well-being of underrepresented racial and ethnic minorities and thereby impacts their performance and retention . Survey According to a 2014 survey administered by the AAMC to second-year medical students, many UrMA subgroups  experience either significantly higher levels of stress, fatigue, financial concerns, significantly lower quality of life, social support, or a combination of these when compared to white cis-gender heterosexual individuals . AnotherMentorship of women and of individuals from underrepresented racial and ethnic minority groups by faculty members that they can identify with benefits and facilitates the success of these students in academic medicine and other higher education settings –51. HoweA survey assessing medical student trainee attitudes toward careers in academic medicine found that the Black/African American and Hispanic/Latino survey respondents were significantly more in agreement with the claim that underrepresented racial and ethnic minority groups have a harder time succeeding in academic medicine relative to white males . This atTrainees in academic medicine who aspire to bear and rear children can encounter poor institutional support for this aspiration, and this burden falls disproportionately on women and SGM trainees. For example, survey data indicates that many residency program directors perceive maternity leave to have more of a negative impact on female trainee’s time-to-board certification and fellowship opportunities than paternity leave does on male trainees . Poor suAs discussed, mentorship of dual-degree trainees from underrepresented racial and ethnic groups by faculty members that they identify with can facilitate these students’ success. Yet, these faculty members tend to be saturated by administrative responsibilities meant to promote institutional diversity and inclusion and therefore may be unable to undertake mentorship responsibilities. This phenomenon has been coined the “ambassador role” or “minority tax”, and many faculty members from underrepresented racial and ethnic groups report that this can undermine their own professional goals and responsibilities , 68. DuaAs discussed, the transition between the different phases of dual-degree training (and the academic milestones required for each) come with a set of challenges frequently cited by non-graduating students that may explain some of the attrition and barriers to performance of trainees from underrepresented racial and ethnic groups . While aIndividual Predoctoral Fellowship to Promote Diversity in Health-Related Research, among others. The NIH also offers “Diversity Supplements” for select funding mechanisms, including the R series and P series awards. These supplements represent additional funding opportunities for the training of students the NIH considers underrepresented in the extramural scientific workforce. Communicating these opportunities to the relevant students is necessary but not sufficient; dual-degree programs should also provide formal guidance on how to apply for these grants, including how to properly address the sections pertaining to diversity and inclusion that are required to receive these awards. MD-PhD programs can also leverage the opportunities for UrMA training enhancement offered by local, identity-based, and student-led organizations that belong to either the medical or graduate schools, including, for example, chapters of the Latino Medical Student Association, “Out Lists” meant to make SGM faculty institutionally visible, among others. Program administrators should proactively advertise the existence of these organizations and their professional development events to applicable UrMA students to not only achieve UrMA engagement with these opportunities, but also help them build community throughout their training [To address performance barriers experienced by UrMA dual-degree students, program administrators must leverage existing opportunities to enhance UrMA students’ training and facilitate UrMA engagement with them. For example, myriad institutions and organizations offer grants specifically geared towards subsets of UrMA students, such as the NIH’s Ruth L. Kirschstein National Research Service Award training .Standardized testing and pre-clinical training grades are not predictive of clinical performance, hence why USMLE 1 has moved towards a pass/fail grading system and many academic medicine institutions have followed suit with their own curriculum , 73. ConMany UrMA subgroups believe that the creation of spaces for discussion of UrMA issues would increase their sense of community and support –76. For minoritized, often as an unintended consequence of systems established from historical legacy [The goal of this literature review was to provide a resource for MD-PhD programs on how underrepresented and/or marginalized identity status may impact training outcomes and what evidence-based interventions could aid UrMA students during their training. To this end, we have summarized the barriers affecting training outcomes and quality of life of UrMAs pursuing the physician scientist career track according to data on MD-only, PhD-only, and MD-PhD students Fig. . Becausel legacy . Without


Drug repurposing, also known as repositioning or reprofiling, has emerged as a promising strategy to accelerate drug discovery and development. This approach involves identifying new medical indications for existing approved drugs, harnessing the extensive knowledge of their bioavailability, pharmacokinetics, safety and efficacy. Levosimendan, a calcium sensitizer initially approved for heart failure, has been repurposed for oncology due to its multifaceted pharmacodynamics, including phosphodiesterase 3 inhibition, nitric oxide production and reduction of reactive oxygen species. Studies have demonstrated that levosimendan inhibits cancer cell migration and sensitizes hypoxic cells to radiation. Moreover, it exerts organ-protective effects by activating mitochondrial potassium channels. Combining levosimendan with traditional anticancer agents such as 5-fluorouracil (5-FU) has shown a synergistic effect in bladder cancer cells, highlighting its potential as a novel therapeutic approach. This drug repurposing strategy offers a cost-effective and time-efficient solution for developing new treatments, ultimately contributing to the advancement of cancer therapeutics and improved outcomes for patients. Further investigations and clinical trials are warranted to validate the effectiveness of levosimendan in oncology and explore its potential benefits in a clinical setting. The process of developing new drugs is time-consuming, challenging and expensive. However, an alternative and effective strategy called drug repurposing offers a promising approach by utilizing existing approved drugs for new medical indications . This apDrug repurposing, also known as repositioning, reprofiling or re-tasking, revolves around the concept of discovering novel applications for drugs that have already gained approval . The keyIn the past, drug repurposing often occurred serendipitously, where the unexpected effects of a drug led to further investigations and new applications. For example, zidovudine, which was originally developed for cancer, subsequently earned the distinction of being the first medication approved by the FDA for HIV treatment . MinoxidDoxorubicin belongs to anthracycline antibiotics approved for medical use in the United States in the late 1950s . Thanks Another example of successful drug repurposing is thalidomide for the treatment of multiple myeloma. Thalidomide, initially conceived as a sedative, gained popularity among pregnant women due to its ability to treat nausea in pregnancy. However, its use was later discovered to cause severe congenital malformations, leading to its withdrawal from the market . In 2006Remarkably, phosphodiesterase 5 (PDE5) inhibitors such as sildenafil were initially developed to treat angina, a disorder characterized by reduced blood flow to the heart. Later, this drug was found to have beneficial effects on erectile dysfunction, leading to their wide use in this context. This successful drug repurposing raises the possibility that PDE5 inhibitors could have additional therapeutic applications beyond their original intended use. With this, sildenafil has also emerged as a potential anticancer agent, considering the urgent need for new cancer therapies ,16,17,18Drug repurposing faces challenges related to intellectual property and economic viability because in certain countries, obtaining patents for additional medical uses is impeded by legal obstacles, which undermines the motivation for pursuing drug repurposing efforts. Data access and compound availability, and the reluctance of pharmaceutical companies to share their compound libraries, hampers the possibilities for drug repurposing, and there is the potential saturation of opportunities for a given disease. However, innovative approaches such as exploring new targets, studying drug combinations and leveraging precision/systems medicine can mitigate these challenges and continue expanding the scope of drug repurposing .Moreover, the use of well-established drugs for purposes beyond their original intended use, such as vasodilators, is a new strategy for treating cancer. In a previous study , our groThe repurposing of this drug to treat cancer has never been studied before. Thus, we are the first group to present the potential antitumour mechanisms of this drug.In summary, the strategy of drug repurposing presents a simplified and cost-effective way to uncover new medical applications for drugs that are already in existence. By capitalizing on the knowledge and data already available for approved drugs, researchers can expedite the development of low-cost therapies and facilitate a new target discovery.Levosimendan [the (−) enantiomer of 4-phenylhydrazonopropanedinitrile] is a calcium sensitizer that belongs to a pyridazinone-dinitrile derivative molecule . The yeaLevosimendan exerts its positive inotropic effects through a mechanism called calcium sensitization that binds to cardiac troponin C (cTnC) in a calcium-dependent manner, thus stabilizing the troponin complex. This interaction enhances the sensitivity of cardiac muscle cells to the available calcium ions . By stabOne important benefit of the levosimendan mechanism of action is that it does not raise the total intracellular calcium levels, which can contribute to arrhythmias. By avoiding an excessive increase in intracellular calcium, levosimendan has a reduced potential to cause arrhythmias compared to other positive inotropic agents .Levosimendan exhibits linear pharmacokinetics within the therapeutic dose range (0.05 to 0.2 μg/kg/min) . Within 2+-saturated cTnC within cardiomyocytes, levosimendan elicits a positive inotropic effect in cardiac muscle, as depicted in By interacting with CaATP channels  and improve pulmonary circulation in cases of acute and advanced heart failure . PreclinATP channels . El. El93]. ROS have been extensively studied in the context of cancer and its various characteristics. They play a significant role in several key aspects of cancer development such as stemness and heterogeneity, suggesting that controlling ROS levels could be a promising approach to mitigating cancer progression. The connection between ROS and inflammation is well-established and is a crucial factor in the development of cancer . When caReducing ROS levels in cancer cells as a therapeutic approach might prevent oncogene activation. Kipka et al. suggest that the active metabolites of levosimendan may inhibit inflammatory ROS formation by preventing the activation of MAPK signaling . In accoThe measurement of plasma malondialdehyde (MDA) is a predominant biomarker for assessing oxidative stress levels in the body . OxidatiSeveral studies have reported elevated serum or plasma MDA levels in association with various types of cancers, including breast cancer ,115, oraRecent evidence indicates that levosimendan could reduce MDA levels ,121,122.Previously, we evaluated the combination of levosimendan with 5-fluorouracil (5-FU), an antineoplastic drug, and found that this drug could help increase the cytotoxicity of 5-FU, decreasing the viability of bladder cancer cells .In the study, the authors propose an innovative drug repurposing approach using levosimendan in the UM-UC-5 neoplastic cell line. The primary objective of this combination approach is to capitalize on the safety and established antitumor activity of levosimendan in cancer cells. By pairing this well-established antineoplastic drug (5-FU) with a repurposed drug known for its acceptable toxicological profile, we aim to enhance the efficacy of 5-FU while simultaneously reducing its required therapeutic dosage.This research findings revealed a remarkable synergistic effect when combining levosimendan with 5-FU in treating UM-UC-5 cancer cells. This combination demonstrated a significantly greater reduction in cell viability compared to using the repurposed drug individually. Particularly noteworthy was the combination of 100 μM of levosimendan with the IC50 value of 5-FU (13.41 μM), which resulted in an impressive 59% decrease in cell viability compared to treating with 100 μM of levosimendan alone .These results underscore the potential of this drug combination as a promising therapeutic approach for bladder cancer treatment. The observed synergistic effect indicates that the interaction between levosimendan and 5-FU enhances their anticancer properties, leading to a more potent and effective treatment.The significant reduction in cell viability achieved through this combination suggests that it could offer a more targeted and efficient treatment option for bladder cancer patients. By utilizing lower doses of each drug in combination, we can potentially reduce the risk of adverse side effects while maximizing therapeutic benefits. These findings are encouraging and shed light on the potential of repurposing levosimendan alongside 5-FU as a novel and impactful strategy in bladder cancer therapy. Further investigations and clinical studies are warranted to validate the effectiveness of this drug combination and explore its potential benefits for patients in a clinical setting. Ultimately, our research contributes to advancing the field of cancer therapeutics and offers hope for improved treatment outcomes for individuals with bladder cancer.Furthermore, the practice of repositioning drugs faces significant obstacles. For example, if initial clinical trials do not meet current regulatory standards, additional Phase I trials may be required to collect the necessary data. The most successful cases are often the result of a thorough understanding of the pharmaceutical pharmacology or clinical efficacy, achieved through a retrospective analysis of the original uses of the medicine. These repositioned medicines are usually accompanied by less robust intellectual property guarantees, which in turn decreases the potential return on investment for companies . ConductMost drug repositioning initiatives are based on encouraging clinical or epidemiological results or the identification of efficacy in live systems. Given the rapid advancement of computational methods and the exponential growth of data, the multifaceted benefits of drug repositioning are about to become increasingly evident .In conclusion, this methodology not only addresses challenges but also paves the way for faster therapeutic advances, ultimately benefiting patients and offering solutions to pressing healthcare needs.Drug repurposing, with levosimendan as a prime example, offers a promising and efficient approach to drug development for oncology. By leveraging the existing knowledge about approved drugs, researchers can save valuable time and resources, accelerating the implementation of new treatments and discovery of novel targets. Levosimendan, originally approved for heart failure, has demonstrated diverse pharmacodynamics including phosphodiesterase 3 inhibition, nitric oxide production and reduction of reactive oxygen species, making it an attractive candidate for repurposing in oncology. Its ability to inhibit cancer cell migration, sensitize hypoxic cells to radiation and reduce oxidative stress showcases its multi-faceted anticancer properties. Additionally, levosimendan has been investigated in combination with traditional anticancer agents like 5-fluorouracil, resulting in a synergistic effect that enhances the efficacy of the treatment. The success of repurposing levosimendan demonstrates the vast potential of this strategy in drug discovery. By building on the well-documented safety and efficacy profiles of approved drugs, researchers can develop innovative and cost-effective therapies for various diseases, including cancer. The exploration of levosimendan’s diverse mechanisms of action in oncology opens up new possibilities for targeted and efficient treatments, potentially leading to improved outcomes for cancer patients. While the preclinical evidence is promising, further clinical studies are necessary to validate the effectiveness and safety of levosimendan as an anticancer agent in humans. Continued research and development in drug repurposing hold significant promise in advancing cancer therapeutics and offering new clinical options for patients in need of effective and accessible treatments. Ultimately, the success of drug repurposing, exemplified by levosimendan, highlights the value of leveraging existing knowledge to drive innovation and improve patient care in oncology and beyond.


Conduction restoration in second- and third-degree atrioventricular (AV) block after revascularization in acute coronary syndrome (ACS) setting is well established, however this is not the case in non-ACS setting. We present a case of a patient referred for permanent pacemaker implantation, due to high degree AV block (HAVB), who restored his conduction possibly due to targeted revascularization. Thus, this case sheds insight in the reversibility potential of HAVB after revascularization in non-ACS patients, which although signified in current literature, is still far from being a recommendation, due to lack of robust scientific confirmation. The perfusion of the atrioventricular (AV) conduction system is normally sustained through the AV node artery and the proximal septal perforators. Conduction restoration in high degree AV block (HAVB), which encloses second- and third-degree AV block, after revascularization in acute coronary syndrome (ACS) setting is well established, however this is not the case in non-ACS setting .A 60-year-old male patient was referred for permanent pacemaker implantation, after being diagnosed with third-degree AV block. The patient reported an episode of syncope in supine position, without prodrome and complained of dizziness and easy fatigability ever since. He also acknowledged suffering angina pectoris episodes during physical activity in the last 5 months.He had been diagnosed with arterial hypertension 5 years ago, and his medication comprised Ramipril 10 mg od, Amlodipine 5 mg od. and Hydrochlorothiazide 25 mg od. Drug and tobacco abuse have been refused. Besides his bradycardia the clinical examination showed no further abnormality.The ECG revealed a third-degree AV block with a ventricular escape rhythm . A bed sThe present case sheds insight in the reversibility potential of HAVB after targeted revascularization in non-ACS patients, which although signified in current literature, is still far from being a recommendation, due to lack of robust scientific confirmation.A small number of case-reports already indicate the relationship between revascularization and AV conduction restoration –4. HowevIn our case pacemaker was finally inevitable, however resolution of complete AV block upon targeted revascularization of a lesion interfering with the perfusion of the AV conduction system, in a patient with persistent HAVB for many hours and subsequent lack of measurable right ventricular stimulation ever since, allows the hypothesis of a possible association to the implemented coronary intervention. Ischemia workup however, remains not a routine diagnostic step for patients with isolated HAVB, unless coronary artery disease is highly suspected .Furthermore, this case demonstrates that even if complete recovery and avoidance of a permanent pacemaker implantation does not occur, the reduction of the need for right ventricular stimulation, has further beneficial effects to be considered. Among them, the reduced risk of pacing-induced cardiomyopathy , increasAll the above point the need for better prediction of conduction responsiveness to revascularization. However, there is also a gap in evidence regarding the subsequent management of patients with reversal of HAVB after revascularization. ILR implantation seems a reasonable alternative to elucidate permanency of normal AV conduction, especially when taking into consideration the low negative predictive value of an electrophysiological study .Overall, the present case report adds to prior publications in acknowledging the potential of reversibility of a HAVB after targeted revascularization, addresses the question of durability of HAVB resolution and suggests a possible proceeding in the clinical scenario of an initially complete resolution of HAVB, using an ILR. This proceeding could be considered as a novelty in the comprehensive treatment of such selected patients, as no recommendations exist. Finally, this case demonstrates that even non-persistent resolution of HAVB could enclose beneficial effects. However, it is necessary to emphasize that due to lack of robust scientific evidence, diagnostic investigation of ischemia cannot be, as of today, recommended in the diagnostic workup in patients with HAVB.