Gotowa bibliografia na temat „Aligned Discriminative Pose-Free Descriptors”

Photo 190773207 / Transplant Medicine © Victor Moussa | Dreamstime.com ABSTRACT Xenotransplant research offers hope to individuals waiting for vital organ transplants. Nascent first-in-human xenotransplantation research trials present unique ethical challenges which may translate into obligations for researchers and special considerations for institutional review boards (IRBs). Contextual vulnerability is an important consideration in reviewing proposed subject selection methods. Some recipients are uniquely prone to receiving an unfair offer to enroll in an experimental clinical trial when excluded from allograft waitlists due to psychosocial or compliance evaluations. These exclusions represent an allocational injustice. Enrolling research subjects subjectively excluded from allotransplantation into xenotransplant research is not a mechanism of fair access but rather an exploitation of an unjustly option-constrained vulnerable group by the clinical transplant system. Carefully considering contextual vulnerability can help researchers and IRBs clarify eligibility criteria for xenograft clinical trials. A requirement for simultaneous allograft co-listing can safeguard the interests of vulnerable potential subjects. INTRODUCTION In the United States, the supply of allogeneic, or human-derived, organs and tissues from living donors and cadavers available for transplant into critically ill individuals is inadequate.[i] Physicians refer only half of potentially eligible patients for transplant evaluation, and the clinical transplant team ultimately waitlists less than 30 percent.[ii] Waitlists are lengthy for those who make it through the evaluation process, and many individuals die while waiting for a transplant.[iii] In contrast to allogeneic transplants, xenotransplantation, from the prefix, xeno- meaning foreign, is the process of taking live organs or tissues from an animal for surgical placement into a human recipient. Xenografts are typically sourced from porcine animals (domestic pigs) or non-human primates (baboons) and range from simple tissues like corneas to complex vital organs like hearts, lungs, or kidneys. Scientists have explored xenotransplantation methods for decades, but research with vital organ xenotransplants has been in largely haphazard and non-controlled studies, which demonstrated only short-duration survival for recipients.[iv] Recent advances using gene modification and improved immunosuppression in single-patient attempts to transplant porcine organs into brain-dead human recipients have presented more realistic human-environment models; however, these modified xenografts have still functioned only for very short durations.[v] The limited bioethics discourse on xenotransplantation centers primarily on the ethical use of high-order animals and the risks of zoonotic infectious disease spread.[vi] Bioethics pays insufficient attention to the potential for exploitation of vulnerable individuals in need of a transplant amid growing interest in phase I clinical trials in living human subjects. Clinician-investigators in contemporary literature repeatedly recommend that these trials enroll subjects who are medically eligible for, but effectively excluded or outright denied access to, an allograft.[vii] The Food & Drug Administration (FDA) recommends xenotransplants be limited to subjects with serious or life-threatening diseases for whom adequately safe and effective alternative therapies are not available.[viii] The ethically salient difference between the investigator and the regulatory recommendations is why alternatives are not available to potential subjects: because transplant centers have subjectively denied access or because there is a clinical contraindication that proves prohibitively risky. In a notable single-patient emergency use authorization, physician-investigators offered a genetically modified porcine heart to a living male recipient after denying him access to the waitlist for a human-donor heart, citing a history of non-compliance.[ix] This case suggests that a person denied access to a transplant waitlist due to subjective compliance criteria is an appropriate research subject. The physician-investigators failed to acknowledge how offering a xenotransplant to a contextually vulnerable subject is potentially unfair. Contextual vulnerability is a specific feature of a research environment that increases a subject’s risk of harm. Bioethics discourse must address this vulnerability within the transplant research environment. This paper describes the current transplant system’s use of subjective evaluation criteria, particularly psychosocial support and compliance. Subjective evaluation criteria perpetuate discriminatory medical biases rather than advance the transplant system’s goal of additional life-years gained. Researchers designing controlled human subject trials and institutional review boards (IRBs) reviewing and approving proposed protocols must consider how disparate waitlisting practices unjustly preclude some patients from a fair opportunity to access an allograft and impacts their participation in research. It is unethical for physician-investigators to intentionally take advantage of this vulnerability, creating an exploitative and unethical transaction.[x] Protocol inclusion criteria requiring proof of simultaneous allograft listing is a feasible procedural safeguard to protect research subjects’ interests. I. Injustices in Organ Allocation Solid organ allocation systems are varied but aim for equity and efficiency in granting individuals with similar claims a fair opportunity to access the scarce resource. Allocation decisions attempt to maximize the common good of additional life-years gained.[xi] The federal oversight of allograft allocation in the US uses objective clinical metrics like blood type, immune compatibility, body size, and geographic distance to match organs to recipients to increase both graft and patient survival.[xii] Transplant centers additionally use their own evaluations to waitlist patients. Although variation exists between transplant center criteria across more objective measurements, such as lab values and concurrent diseases, significant inconsistencies arise in how they incorporate subjective factors like compliance with medical recommendations, psychosocial support, and intellectual disability into the review process.[xiii] Only 7 percent of renal transplant programs use formal criteria for subjective psychosocial assessments, while no pediatric solid organ transplant programs use formal, explicit, or uniform review to assess developmental delays and psychosocial support.[xiv] Failing to establish uniform definitions and inconsistently applying evaluation criteria in the review of potential transplant candidates introduce bias into listing practices.[xv] The center they present to and the variable evaluative criteria the center uses may discount an individual’s claim to a fair opportunity to access a scarce resource. Labeling a patient non-compliant can preclude both a referral to and placement on a waitlist for potentially suitable recipients. Compliance considerations presuppose that graft longevity will be jeopardized by an individual’s failure to adhere to pre- and post-transplant regimens. It is necessary to distinguish individuals who are intentionally non-adherent to treatment regimens and demonstrate willful disregard for medical recommendations from those who are involuntarily non-adherent due to barriers that limit full participation in care plans. The former would not be offered a spot on the waitlist for an allograft, nor would investigators offer them a spot in a xenotransplantation research study. Significant and repeated refusals to participate in treatment plans would confound the ability of researchers to collect necessary data and perform the safety monitoring required by early-phase clinical trials. Enrolling subjects who are medically eligible for a traditional transplant but denied access requires a population that is suitably compliant to participate in a clinical trial reliably and safely yet judged not worthy of receipt of a standard allograft during the evaluation process. The latter population is most disadvantaged by compliance judgments and unsubstantiated outcome predictions. Multi-center research studies have found that moderate non-adherence to immunosuppression regimens is not directly associated with poor kidney transplant outcomes.[xvi] Nor are intellectual and developmental disabilities, conditions for which transplant centers may categorically refuse evaluation, clear indicators of an individual’s ability to comply with treatment regimens.[xvii] Large cohort studies of both pediatric kidney and liver transplant recipients found no correlation between intellectual disability and graft or patient survival.[xviii] Rather, it is the perpetuation of medical biases and quality-of-life judgments that presumptively label specific populations poor transplant candidates or label their support systems insufficient, notwithstanding data demonstrating their ability to achieve successful transplant outcomes.[xix] Variability in compliance assessments and psychosocial support criteria allows medical biases to persist and disproportionately impedes waitlist access to patients from underserved populations.[xx] Low-income Medicaid patients are 2.6 times more likely to be labelled non-compliant as privately insured patients.[xxi] Additionally, the medical records of Black patients are 2.5 times more likely to contain negative descriptors like non-compliant, non-adherent, aggressive, unpleasant, and hysterical than those of white patients.[xxii] The higher prevalence of stigmatizing, compliance-based language in the medical records of minority, economically disadvantaged, and disabled persons decreases the likelihood that they will be recommended for a transplant, referred for an evaluation, placed on a waiting list, or ultimately receive a transplant.[xxiii] These populations are at heightened risk of being used in ethically inappropriate ways by xenograft research that capitalizes on this precluded access. II. Defining Vulnerability Subjective evaluation criteria in allograft waitlisting disproportionately impact some populations. This precluded access to waitlists increases their vulnerability to experience harm in experimental xenotransplant research. Fair subject selection requires the development of specific and appropriate inclusion and exclusion criteria designed to address and minimize known subject vulnerabilities.[xxiv] This process begins with physician-investigators designing research trials and IRB review of proposed trials in which some or all potential subjects are vulnerable.[xxv] The literature has no consensus on defining vulnerability in the clinical or research setting.[xxvi] Prominent guidelines such as the Common Rule and the Declaration of Helsinki focus on a categorical, consent-based approach to assessing vulnerability. The capacity to provide freely given consent is a necessary prerequisite for ethical human subject research. Still, consent alone is insufficient to establish ethical permissibility or assure that a research transaction is fair.[xxvii] Harm can occur even with informed consent if it results from coercion, undue influence, or exploitation.[xxviii] Subjects have limited ability to avoid exploitation and act as an autonomous moral agents under such circumstances. Categorical assessments label groups whose members share salient features, such as prisoners or children, as vulnerable. This shared characteristic may compromise their capacity for free consent and autonomous ability to protect their interests. Although widely used, broad categorizations create monolithic views of populations but lack clarity as to why a particular feature makes one vulnerable or what a given characteristic decidedly renders one vulnerable to.[xxix] Individuals broadly vulnerable in society, such as the severely economically disadvantaged or incarcerated, are not necessarily vulnerable as research subjects in a given proposed trial.[xxx] Categorical vulnerability is insufficient to recognize that research-related harm is specific to a particular subject potentially participating in a given protocol at a definite time and place. III. Assessing for Contextual Vulnerability Ensuring ethical consent, therefore, requires more than an accounting of capacity, competency, and freedom from coercion. This requires looking beyond voluntariness to ask whether the research offer is fair. Contextual vulnerability recognizes and addresses how some subjects are at a heightened risk of being used in ethically inappropriate ways due to research-specific situations and environments.[xxxi] Contextual vulnerability derives from a specific feature of the research environment that increases a subject’s risk of harm rather than an intrinsic categorical condition of that subject. Accounting for contextual vulnerabilities is necessary because it is ethically unsound for a competent subject to give voluntary consent to an offer that is nonetheless unfair or exploitative.[xxxii] Potential subjects excluded from accessing an allograft are contextually vulnerable in a research environment that may view their diminished range of choice as an opportunity for experimental research enrollment. Proposals to exploit or take advantage of this vulnerability places these individuals at a heightened risk of research-related harm. IV. Exploitative Transactions in Xenotransplant Research In the landmark single-patient case in Maryland, a genetically modified porcine heart was offered to the subject only because he was denied access to the allograft waitlist due to a history of noncompliance with a recommended medical regimen.[xxxiii] Physician-investigators did not define how they evaluated compliance, nor did they elaborate on how this claim demonstrated the subject’s clear and convincing contraindication to receive a conventional cardiac allograft. The subject was presented with a so-called Hobson’s choice, in which there is the illusion of free choice but ultimately there is no real choice as only one outcome, the acceptance of the experimental xenograft, is permitted; access to other choices, such as pursuing standard of care waitlisting, have been removed.[xxxiv] This case set a precedent for researchers and IRBs to view individuals denied access to conventional allografts as an appropriate subject population without acknowledgment of how this transaction is consensually exploitative. Consensual exploitation occurs when researchers intentionally and wrongfully take advantage of a subject’s vulnerability.[xxxv] In the cardiac xenotransplant case, the application of subjective evaluation criteria created a unique contextual vulnerability specific to transplant waitlist practices. Investigators took advantage of the subject’s diminished ability to access the heart transplant waitlist to obtain consent for the xenotransplant procedure. Researchers have no obligation to repair unjust conditions that they bear no responsibility for causing.[xxxvi] The wrongfulness in this case is how subjective compliance-based waitlisting criteria precluded the subject from accessing the heart transplant waitlist and denied him fair consideration in accessing the standard clinical option. Then, the transplantation team exploited this disadvantage they were morally responsible for creating. The subject agreed to the terms for an experimental and high-risk xenograft from a place of vulnerability due to the diminished range of choice specifically constructed by the policy and actions of the transplant center. The options offered by the physician-investigators to the patient were manipulated to promote the research system’s interests through the production of new scientific knowledge, not necessarily the subject’s conception of his own good.[xxxvii] V. Recommendation for Simultaneous Allograft Listing Ethical research design calls for assessments of which vulnerabilities and in which contexts researchers and IRBs ought to offer additional safeguards. Subjects should be clinically suitable to produce robust, reliable, and generalizable scientific knowledge and be presented with a fair research offer. Researchers and IRBs can achieve this through an inclusion criterion requiring that a subject has previously been placed on and maintains a spot on a waitlist for a conventional allograft. Investigators and IRBs must ensure that subjects are selected based on scientific rationale, not because they are easy to recruit due to a compromised or vulnerable position.[xxxviii] Evidence of simultaneous allograft listing would provide verification that a researcher expects a potential subject to survive the burdens of an experimental xenotransplant procedure. Individuals of advanced age or with severe life-limiting comorbidities separate from their end-stage organ failure are less likely to survive after receiving an allograft or a research xenograft. These subjects would not produce valuable data in service to the study’s endpoints or knowledge generalizable to broader patient populations. Requiring evidence of simultaneous allograft listing fulfills the ethical requirement that subjects who withdraw consent are not worse off than if they had not pursued research enrollment.[xxxix] If a subject withdraws consent before receiving a xenograft, their continued place on a waitlist ensures that their fair opportunity claim to an allograft has been maintained. Simultaneous allograft waitlisting excludes contextually vulnerable subjects clinically suitable to receive a graft but denied access to a waitlist. This inclusion criteria provides an additional safeguard against unfairly capitalizing on a subject’s marginalized status. Requiring simultaneous allograft listing will narrow the potential subject population to those clinically suitable and well situated to receive a fair opportunity to enroll in research: individuals listed for an allograft but significantly unlikely to receive or to benefit from that allograft. This potential subject population includes individuals with broadly reactive antibodies who are unlikely to match to a donor organ and individuals with anatomical contraindications who face prohibitive risks with standard allografts or bridging therapies.[xl] This subject population aligns with the FDA recommendation to enroll subjects for whom safe and effective alternatives are not available.[xli] These individuals have not had their claim to a fair opportunity transgressed by a subjective evaluation process, nor has their interest in accessing a scarce resource been unjustly discounted.[xlii] Neither the individual nor the transplant clinicians are responsible for creating a clinical or statistical disadvantage to receiving a standard allograft. An offer of research enrollment extended to this population has not been manipulated to favor one party over the other, but rather appropriately considers the interests of both parties.[xliii] Researchers have an interest in identifying subjects capable of producing scientifically valuable knowledge. Potential subjects have an interest in exploring alternatives to the high morbidity of a traditional allograft. This subject population retains the autonomous choice to pursue a standard-of-care allograft or to enroll in xenograft research. Having few treatment options available does not inexorably undermine the voluntariness of research consent or increase vulnerability.[xliv] The consent transaction is not exploitative or unfair because the transplant system is not responsible for creating this diminished range of choice. Simultaneous allograft listing represents an eligibility criterion that responds to and limits the products of subjective decisions from unjustly impacting trial enrollment. VI. Counterargument: Is Something Better Than Nothing? Some may argue that for medically exigent individuals in need of a transplant, any option to participate in research is better than no option. Autonomy and dignity, however, are not advanced when an inability to access the standard of care compels a subject’s decision to pursue experimental research. An offer of research enrollment that is unfair or exploitative remains unethical regardless of whether the subject stands to benefit. Nor should benefit be expected in early-phase research. The goals of phase I research are primarily to collect short-term safety, toxicity, dosing, and pharmacologic data, not to provide efficacious treatment.[xlv] Expanding access to experimental research trials cannot be conflated with fair access to equitable health care.[xlvi] Broadened access alone does not produce a more ethical research environment. Excluding contextually vulnerable subjects from research should not be the end goal, but rather a necessary interim to call attention to the need to redress biases and existing injustices in transplant access. Research that targets a population’s vulnerability serves to enable the continuation of unjust systems. CONCLUSION In summary, the urgent and significant clinical need for transplantable organs cannot undermine the requirements of ethical research design and conduct. Fair subject selection is a requirement of ethical clinical research.[xlvii] Potential subjects enrolled in upcoming xenograft research must be selected for their ability to answer the scientific objectives of a proposed study and must have the capacity to provide freely given informed consent within a fair research environment. Denying access to allotransplants for subjective psychosocial or compliance-based claims creates contextual vulnerability specific to transplant research that perpetuates the unfairness of the organ allocation system. Ethical research that produces valuable scientific knowledge cannot exploit the rights or interests of subjects in the process. A look beyond categorical vulnerability to contextual vulnerability highlights this currently overlooked area of exploitation. - [i] “Organ Donation Statistics,” Health Resources and Services Administration, accessed April 18, 2022, https://www.organdonor.gov/learn/organ-donation-statistics. [ii] Schold, J.D. et al., “Barriers to Evaluation and Wait Listing for Kidney Transplantation,” Clinical Journal of the American Society of Nephrology 6, no. 7 (2011): 1760-67. [iii] Abouna, G.M. “Ethical Issues in Organ Transplantation,” Medical Principles and Practice 12, no. 1 (2003): 54-69. [iv] Anderson, M. “Xenotransplantation: A Bioethical Evaluation,” Journal of Medical Ethics 32, no. 4 (2006): 205-8. [v] Lambert, J. “What Does the First Successful Test of a Pig-to-Human Kidney Transplant Mean?,” ScienceNews, October 22, 2021, https://www.sciencenews.org/article/xenotransplantation-pig-human-kidney-transplant.; Koplon, S. “Xenotransplantation: What It Is, Why It Matters and Where It Is Going,” UAB News, February 17, 2022, https://www.uabmedicine.org/-/xenotransplantation-what-it-is-why-it-matters-and-where-it-is-going. [vi] Anderson, supra; Daar, A.S. “Ethics of Xenotransplantation: Animal Issues, Consent, and Likely Transformation of Transplant Ethics,” World Journal of Surgery 21, no. 9 (1997): 975-82.; Kim, M.K., et al., “The International Xenotransplantation Association Consensus Statement on Conditions for Undertaking Clinical Trials of Xenocorneal Transplantation,” Xenotransplantation 21, no. 5 (2014): 420-30. [vii] Abouna, supra; Pierson, R.N., et al., “Pig-to-Human Heart Transplantation: Who Goes First?,” American Journal of Transplantation 20, no. 10 (2020): 2669-74. [viii] Food and Drug Administration, Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans (Silver Spring, MD, 2016), 43, https://www.fda.gov/media/102126/download. [ix] Wang, W., et al., “First Pig-to-Human Heart Transplantation,” Innovation (Camb) 3, no. 2 (2022): 100223. [x] Carse, A.L. and Little, M.O. “Exploitation and the Enterprise of Medical Research,” in Exploitation and Developing Countries, ed. J. S. Hawkins and E. J. Emanuel (Princeton, NJ: Princeton University Press, 2008), 206-45. [xi] Halpern, S.D. and Goldberg, D.“Allocating Organs to Cognitively Impaired Patients,” New England Journal of Medicine 376, no. 4 (2017): 299-301. [xii] “How We Match Organs,” United Network for Organ Sharing, accessed April 18, 2022, https://unos.org/transplant/how-we-match-organs/. [xiii] UW Medicine Harborview Medical Center – UW Medical Center University of Washington Physicians, Selection Criteria: Kidney Transplant Recipient (Seattle, WA, 2019), 1-3, https://www.uwmedicine.org/sites/stevie/files/2020-11/UW-Medicine-Kidney-Selection-Criteria-UH2701.pdf; Penn Medicine, Kidney Transplant Selection Criteria (Philadelphia, PA: Hospital of the University of Pennsylvania), 1-2. https://www.pennmedicine.org/media/documents/instructions/transplant/kidney_transplant_selection_criteria.ashx. [xiv] Dudzinski, D.M. “Shifting to Other Justice Issues: Examining Listing Practices,” American Journal of Bioethics 4, no. 4 (2004): 35-37.; Richards, C.T., et al., “Use of Neurodevelopmental Delay in Pediatric Solid Organ Transplant Listing Decisions: Inconsistencies in Standards Across Major Pediatric Transplant Centers,” Pediatric Transplant 13, no. 7 (2009): 843-50. [xv] Dudzinski, supra. [xvi] Israni, A.K., et al., “Electronically Measured Adherence to Immunosuppressive Medications and Kidney Function after Deceased Donor Kidney Transplantation,” Clinical Transplantation 25, no. 2 (2011): 124-31. [xvii] National Council on Disability, Organ Transplant Discrimination against People with Disabilities (Washington, DC, 2019), 25-35, https://ncd.gov/sites/default/files/NCD_Organ_Transplant_508.pdf.; Halpern and Goldberg, supra. [xviii] Wightman, A., et al., “Prevalence and Outcomes of Renal Transplantation in Children with Intellectual Disability,” Pediatric Transplantation 18, no. 7 (2014): 714-19.; Wightman, A., et al., “Prevalence and Outcomes of Liver Transplantation in Children with Intellectual Disability,” Journal of Pediatric Gastroenterology and Nutrition 62, no. 6 (2016): 808-12. [xix] Richards et al., supra; Godown, J., et al., “Heart Transplantation in Children with Down Syndrome,” Journal of the American Heart Association 11, no. 10 (2022): e024883. [xx] Silverman, H. and Odonkor, P.N. “Reevaluating the Ethical Issues in Porcine-to-Human Heart Xenotransplantation,” Hastings Center Report 52, no. 5 (2022): 32-42. [xxi] Sun, M., et al., “Negative Patient Descriptors: Documenting Racial Bias in the Electronic Health Record,” Health Affairs 41, no. 2 (2022): 203-11. [xxii] Ibid. [xxiii] Dudzinski, supra; Garg, P.P., et al., “Reducing Racial Disparities in Transplant Activation: Whom Should We Target?,” American Journal of Kidney Diseases 37, no. 5 (2001): 921-31. [xxiv] Emanuel, E.J., et al., “What Makes Clinical Research Ethical?,” JAMA 283, no. 20 (2000): 2701-11. [xxv] 45 C.F.R. 46.111(b). [xxvi] Hurst, S.A. “Vulnerability in Research and Health Care; Describing the Elephant in the Room?,” Bioethics 22, no. 4 (2008): 191-202. [xxvii] The Nuremberg Code, Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law 2, no. 10: 181-2 (Washington, DC: U.S. Government Printing Office, 1949); Kipnis, K. “Vulnerability in Research Subjects: A Bioethical Taxonomy. Ethical and Policy Issues in Research Involving Human Participants.,” in Ethical and Policy Issues in Research Involving Human Participants, (Bethesda, MD: National Bioethics Advisory Commission, August 2001), G1-G13. [xxviii] Dickert, N. and Grady, C. “Incentives for Research Participants,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 386-96. [xxix] Gordon, B.G. “Vulnerability in Research: Basic Ethical Concepts and General Approach to Review,” Ochsner Journal 20, no. 1 (2020): 34-38. [xxx] Kipnis, supra. [xxxi] Hurst, supra. [xxxii] Lamkin, M. and Elliott, C. “Avoiding Exploitation in Phase I Clinical Trials: More Than (Un)Just Compensation,” Journal of Law, Medicine & Ethics 46, no. 1 (2018): 52-63.; Jansen, L.A. “A Closer Look at the Bad Deal Trial: Beyond Clinical Equipoise,” Hastings Center Report 35, no. 5 (2005): 29-36. [xxxiii] Wang et al., supra; Silverman and Odonkor, supra. [xxxiv] Silverman and Odonkor, supra. [xxxv] Carse and Little, supra. [xxxvi] Wertheimer, A. “Exploitation in Clinical Research,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 201-210. [xxxvii] Brock, D.W. “Philosophical Justifications of Informed Consent in Research,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 606-612. [xxxviii] Council for International Organizations of Medical Sciences, International Ethical Guidelines for Health-Related Research Involving Humans (Geneva: World Health Organization, 2016), https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf. [xxxix] Ibid. [xl] Pierson et al., supra. [xli] Food and Drug Administration, supra. [xlii] Hurst, supra. [xliii] Kipnis, supra. [xliv] Hawkins, J.S. and Emanuel, E.J. “Introduction: Why Exploitation?,” in Exploitation and Developing Countries, ed. J. S. Hawkins and E. J. Emanuel (Princeton, NJ: Princeton Universiy Pres, 2008), 1-20. [xlv] Muglia, J.J. and DiGiovanna, J.J. “Phase 1 Clinical Trials,” Journal of Cutaneous Medicine and Surgery 2, no. 4 (1998): 236-41. [xlvi] Dresser, R. “The Role of Patient Advocates and Public Representatives in Research,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 231-41. [xlvii] MacKay, D. and Saylor, K.W. “Four Faces of Fair Subject Selection,” The American Journal of Bioethics 20, no. 2 (2020): 5-19.

Introduction Toys and games are important elements of child growth and development. When children play, they have fun. They also learn to perform and contest ideas making up their culture. The potential professional affiliations and skills offer an illustration of the roles that children learn about in the early years of their lives. Therefore, toys may serve as a site to research professional aspirations. In light of this, a question emerges: what do toys teach about professions and professionalism? As a feminist communication researcher, I study toys primarily intended for girls – the dolls in the American Girl collection. Even though the doll sets demand an excessively high price, this brand has a cultural significance for the girls and women growing up in the United States because of the historical and contemporary connections found in deeply researched stories and intricately designed accessories (Solly). The American Girl brand started in 1986. Mattel, the American toy conglomerate, has owned the American Girl brand since 1998 and describes the brand as helping "generations of girls find courage, build confidence, and spread kindness" ("American Girl"). The original American Girl dolls represented historical figures: for example, Melody Ellison from the era of the Civil Rights Movement of the 1960s and Kit Kittredge from the time of the Great Depression in 1934. In addition to historical personalities, the American Girl depicts contemporary girls, including the Girl of the Year line introduced annually. These dolls portray modern girls who have special talents or hobbies and who navigate their lives and experience adventures through the prism of their talents. For example, Joss Kendrick’s passion is surfing, Gabriela McBride loves dancing and poetry, and Grace Thomas is interested in baking. As a rule, the talents of the Girls of the Year align with professional work and can inspire future generations to choose specific professions or develop professional qualities. To narrow the subject, this essay examines the professional aspirations presented in the stories and media associated with the American Girl doll, Luciana Vega, released in 2018. Luciana is an aspiring 10-year-old astronaut and scientist who dreams to be the first person to walk on Mars. Luciana is unique because she is the first doll among contemporary characters to exclusively engage in science, technology, engineering, and math, or STEM (Strickland). This doll marks an attempt to address the high barrier for women and underrepresented groups to enter and remain in science, technology, engineering, and math fields. The former NASA chief scientist Ellen Stofan reflects on the importance of Luciana, saying that "a lot of girls are sometimes intimidated by STEM careers" and that characters like Luciana can let "girls of color around the world know they can be astronauts" (Strickland). Therefore, Luciana Vega contributes to the discourse about professions for contemporary girls and women. The focus on professional aspirations represented in toys stems from the research about professionalism, which implies a set of assumptions that are taken for granted yet ambiguous, conflicted – and rarely questioned (Cheney and Ashcraft). The criticism of neoliberalism from the feminist perspective helps examine professionalism critically. Neoliberal feminism celebrates the achievements of individual women in the format of corporate and personal enterprises at the expense of confirming privileges based on race, class, and sexuality (Rottenberg). The essay argues that the lessons about professions and professionalism offered by the American Girl focus on establishing only a symbolic association with professional engagement. The emphasis on personal development through teamwork, leadership, and creativity promotes gendered professional capital that has limited resources to address potential imposter phenomenon and workplace harassment. Dolls and Professional Aspirations Scholars who study toys and playthings associate them with opportunities to display and obtain social rules and cultural values. Gender, race, and class norms are part of cultural production in toys (Foss; Rosner, Playing). As a product of culture, toys and texts associated with them represent professional futures and offer lessons about organisational life, professional identities, and work relations. Kuhn and Wolter report that young people tend to follow gender stereotypes in professional planning even in progressive locations, yet this connection between professional aspirations, career choices, and existing expectations is rather weak, suggesting that parental influence, regional or local specificities, educational programming, and other social factors, such as toys and games, may impact individual choices. The American Girl brand promotes an active lifestyle, teaching children to understand who they are and to bring positive changes to their communities. The company does not explicitly mention preparation for careers and professional education. The company emphasises holistic development for girls, where professionalism and career aspirations may serve as implied targets. Barbour, Rolison, and Jensen argue that “individuals construct professional selves that originate in the early socialisation phases of professional training and are further developed as they are immersed in the rules, language, skills, and work of the profession” (137). As such, playing with dolls and engaging with the issues suggested by the toy brand may have an impact on future generations as they explore potential professions and careers and learn what it means to be a professional. The academic research about the American Girl has not discussed professionalism yet. Scholars focus on exploring historic representations to argue that the company romanticises nostalgia to foster consumerism (Rosner, “The American Girl”) or presents a simplified and whitewashed version of history (Marcus; Valdivia). Marshall argues that the American Girl version of girlhood “reflects a gendered pedagogy of consumption rather than any lessons about empowerment or US history” (95). Scholars nevertheless have already noted the affiliations of the American Girl doll characters with neoliberalism. Neoliberalism refers to an approach to political economy that favours free market, economic growth, and capital accumulation. In feminist research, neoliberalism can be understood as “a sensibility or set of themes that privilege market-friendly notions of individualism, responsibility, and capitalization” (Thornton 273). The American Girl brand strives to empower girls, yet the empowerment offered by the brand is wrapped in a neoliberal frame of thinking, calling for girl power, self-determination, and femininity without changing the system that supports gender and other forms of discrimination and inequality (Rybas and Rybas; Zaslow). The criticism of neoliberal feminism provides a framework to examine professional belonging projected for future iterations of work, professions, and talents. Reading Professions in the American Girl Texts If Luciana Vega’s character offers lessons about professions and professionalism for the fans who play with the doll and engage with her story, it is important to explore these texts. The texts associated with the American Girl brand range from books that have traditionally defined the brand to mobile apps, short videos, feature or animated movies, and social media snippets that have appeared in recent years. The books create narratives about the characters, while multimedia texts offer alternative formats for the narratives as well as promote activities and engagements inspired by the characters. These texts offer rich data to examine the implications of the character for professionalism and being a professional. Further analysis draws from the content created for the 2018 Doll of the Year: the book Luciana by Erin Teagan and videos on the official American Girl YouTube channel and collected into a playlist. Material objects and discursive constructions of practices associated with work produce professional identification and belonging. Being a professional relies on demonstrating special skills and knowledge in work contexts and maintaining professional identities (Caza and Creary; Caza, Vough, and Puranik). As with other professionals, the character experiences contradictions and dilemmas embedded in the tasks (Ahuja). She evokes professional skills and grows her professional potential through the problems and struggles that she deals with. Based on how the character and spokespersons address situations associated with work and how they communicate about their experiences, the analysis identifies lessons about professions and professionalism. Lessons about Professions and Professionalism First, the discussion of lessons about professionalism focusses on the material markers of being a scientist. How do the professionally defined objects, places, and activities signify Luciana’s belonging to the STEM sphere? At the Space Camp, the kids wear space and science clothes, and Luciana receives an official Space Camp flight suit upon check-in. The camp participants move from their habitats, with bunk beds for six campers, to the habitat common area, with screens streaming news from the international space station, and to the mission floor, with spacecrafts, greenhouses, and training equipment. Luciana finds her sense of belonging to the Space Camp through items signifying connections to space explorations. She wears a dress of “the colors of the nighttime sky—blue, red, purple, orange” (Teagan 4) and the star-shaped necklace. She also packs her “favorite pajamas from the planetarium” (Teagan 11) and “a pillow with the solar-system pillowcase” (Teagan 2). The items make her feel comfortable upon her arrival at the camp. The STEM-style objects can stimulate desires to purchase the toys and outfits, such as the lunar habitat, space suit, galaxy-patterned dress for the doll, or science kit, available from the American Girl brand. In addition to the merchandise and branded items, the projects completed by the camp participants are indicative of their professional belonging: The campers perform soil experiments and design robots. The narrative refers to specialised terms (types of rocks and rockets), equipment (goggles, beakers), and scientific routines (wearing safety goggles, labelling samples) to create a world focussed on science. These details show Luciana’s familiarity with the camp space and speak to her abilities needed to complete the activities. The videos posted on YouTube provide additional illustration to the narrative. The spokespersons in the promotional videos as well as guests and hosts in the TV studio during the reveal wear blue overalls and walk through the NASA Centre (“A Day in the Life of Luciana”; “Meet American Girl’s 2018”). These descriptions and demonstrations create excitement about space exploration and make the STEM fields seem attractive and available. However, the price tag of almost $1,500 in 2023 (“Space Camp”) for camp participation keeps the dream of flying to Mars a distant reality for families. The financial barrier, obviously, does not appear in the texts promoted by the American Doll brand. Such silence indicates that each family needs to decide for themselves to what extent they can participate in the world of STEM, and such considerations reinforce class-based stratifications. Further, the discussion focusses on the ways of thinking associated with professionalism. Adams argues that professionalism offers epistemologies that define "what is sayable, what is knowable, what is included, and what is excluded" (332). In other words, professionalism implies a system knowledge necessary for success in the neoliberal economy (Adams; Cheney and Ashcraft). What skills and epistemologies emerge in the texts associated with Luciana Vega? The set-up of Luciana’s story establishes her responsibility for the success. She participates in a week-long space camp without her parents and friends. Even though she has an opportunity to develop her interests and meet new friends, the narrative suggests that Luciana must push back her longing for her family and her worries about the adoption of her new sister to emphasise the camp projects and her dream to be an astronaut. The discourse about work and life balance is significant for the neoliberal feminist analysis because those who are successful can do it all (Rottberg; Thornton). Luciana takes responsibility for adapting to the camp environment and controlling her own development. Luciana’s competitive record illustrates her drive. She obtains an acceptance to join the camp after two rejections, and this achievement communicates her resilience and perseverance necessary for a neoliberal subject (Rottberg). Teamwork, leadership, and creativity are core skills expected from workers in the contemporary economy. Creativity defines neoliberal femininity as it aligns with passion, energy, and stamina (Rottberg; Thornton). Creativity is Luciana’s quality. Alex, one of the trainers, confirms her reputation by saying, "we need creative future astronauts just like you" (Teagan 6). Luciana’s ideas, however, may cause mistakes, as it happens during the building of a rover because she ignores the expectations about the rover’s weight. As the narrative develops, the team needs Luciana’s ideas, especially in designing a robot from junk parts, and the team acknowledges Luciana’s contributions. They note that Luciana has pretty good ideas and that making mistakes is normal. Ella, one of the teammates, concludes that "it’s the person who thinks a little differently from the rest who has the greatest chance of making a difference in this world" (Teagan 133). Even though Luciana’s creativity leads to various results, it is essential for her success as a professional. In addition to creativity, Luciana develops her teamwork and leadership skills. These qualities are required for the success of the camp mission and future professional endeavours. Alex, the camp trainer, says that "for an astronaut team is everything" (Teagan 118). To compete in the robotics challenge, Luciana becomes the captain of one of the teams, and she encourages her team to work in a cohesive and productive manner. The team chooses the name Red Rover by brainstorming and voting, yet the team fails to collaborate in the rover-building challenge because Luciana does not rely on the knowledge of her teammates. Red Rovers get disqualified from the competition, but Luciana leads her team in continuing their experiment, building a successful robot, and even helping the team whose project the girls have damaged. As a result, the team members develop a strong friendship bond and receive an award for building a unique robot. Luciana’s leadership is meaningful for professional aspirations in the neoliberal style because it juxtaposes her character against the other participants of the camp, which promotes the emphasis on taking responsibility for mistakes. Creativity, teamwork, and leadership permeate the simple activities inspired by the 2018 Doll of the Year: making star-shaped cookies, creating a purple hair streak, and organising a space-themed party (AG Life). The short episodes follow the style of videoblogs or reality TV shows created by and for teens and tweens. The five hosts are girls of Luciana’s age who perform activities and share knowledge in an easy-going manner imitating a conversation. Faber and Coulter critique girls’ digital production as an embodiment of neoliberal ideologies built on playful authenticity and the affective glamourisation of entrepreneurial logics. Making star-shaped cookies, creating a purple hair streak, and organising a space-themed party represent science and space exploration only by association, similar to the pyjamas from the planetarium or the star-shaped necklace. Together with the claims for expertise in the STEM sphere and the emerging skills required for success in professional spheres, Luciana experiences difficulties, such as the imposter phenomenon and work harassment. Imposters exhibit doubt in their achievements, think of their success as fraud, and diminish their success (Parkman). In the story, Luciana completes a difficult docking manoeuvre with her team successfully, yet she concludes that the task has been “barely” (Teagan 151) completed. She compares herself to other kids: “my belly was starting to turn. I hadn’t expected there to be so many genius kids here. Did they all want to be astronauts like I did?” (Teagan 29). Luciana doubts her leadership abilities and questions her creativity, suggesting that her existing skills are not enough. In one of the episodes, she almost gives up her captain role, hinting at a potential burn-out situation. She particularly struggles to build connections with Ella, one of her team members, yet she develops a relationship with her after a few trials. These experiences illustrate the challenging process of finding self and connecting with others in a professional context. The creators of Luciana Vega attempt to send a positive message to future experts in the field by welcoming diverse individuals. Luciana states that “astronauts come with hair in all shades and sizes and colors” (Teagan 32). However, the positive message is muffled because it serves as a reaction to a comment by another camp participant, James, who shares that he never saw astronauts with purple hair. The focus on the signature purple hair streak as a sign of diversity exemplifies a simplistic approach to intersectionality and diversity, a common criticism of the American Girl dolls (Marcus; Valdivia; Zaslow). In addition, the exchange about the purple streak in the girl’s hair highlights gender dynamics in the contemporary workplace, pointing at the possibility of workplace harassment. James adds that “it’s the like mom law” (Teagan 32), thus offending Luciana. In organisational contexts, harassers make offensive jokes and engage in insults, making the workplace environment hostile (Griffin), and Luciana encounters this experience. James clashes with Luciana and her team members throughout the narrative. What is important here is not only the professional rivalry that emerges in the narrative and is normalised in competitions, but the reactions that Luciana practices. She ignores the hurtful comments made by James during the spacewalk simulation exercise, yet she shares her resources to help him complete the task. Luciana’s team supports James’s team in the robot design task and transfers sponsorship to the boys’ team. Even though the story line introduces diversity to the workforce, it falls short of addressing instances of potential workplace harassment with force. Luciana seems not yet equipped to address the hostility exhibited by the fellow camp participant. She prioritises teamwork and camp mission at the expense of her own well-being. These emphases contributing to the gendered professional capital (Rottberg) essential for neoliberal progress. Conclusion The lessons about professions and professionalism offered by the American Girl are complex, if not contradictory. The presence of Luciana Vega in the competitively selected camp is promising, yet the STEM field remains difficult to access. The character experiences the imposter phenomenon even if she has extensive knowledge of science. Science-themed clothes, books, and accessories as well as science-inspired activities may promote an interest in the field. Teamwork, leadership, and creativity establish markers of professionalism and provide resources for cultivating professional epistemology. The current generation of girls and the future generations of women receive exposure to difficulties in developing leadership and teamwork skills and potential work harassment but may learn to address them through self-improvement or individual development. These lessons emphasise empowerment in the neoliberal frame of reference typical of the American Girl dolls. References “A Day in the Life of Luciana at Space Camp | Luciana Vega: Girl of the Year 2018.” American Girl. YouTube, 2 Feb. 2018. <https://www.youtube.com/watch?v=SXgHWZScSwo>. “American Girl”. Mattel. 1 Feb. 2023 <https://corporate.mattel.com/brand-portfolio/american-girl>. “Meet American Girl's 2018 Girl of the Year: Aspiring Astronaut Luciana Vega.” Good Morning America. YouTube, 2 Dec. 2017. <https://www.youtube.com/watch?v=8maWJDIBr6c>. “Space Camp”. US Space and Rocket Center. 14 Apr. 2023 <https://www.spacecamp.com/space/camp>. “Who She Is, Hair & Science Diys, & Space Party!” American Girl. YouTube, 29 Dec. 2017. <https://www.youtube.com/watch?v=wIPP6kg-4bg>. Adams, Kiely Flanigan. "The Discursive Construction of Professionalism". Ephemera 12.3 (2012): 327-343. Ahuja, Sumati. “Professional Identity and Status: An Ethnography of Architects in Professional Service Firms”. Dissertation. Sydney: University of Technology Sydney, 2018. <https://opus.lib.uts.edu.au/handle/10453/129461>. Barbour, Joshua B., Shelbey L. Rolison, and Jared T. Jensen. "The Politics of Inclusion and Exclusion among Professions and Professionals". Organizing Inclusion, Moving Diversity from Demographics to Communication Processes. Eds. Marya Doerfel and Jennifer Gibbs. Routledge, 2020. 135-155. Caza, Brianna Barker, and Stephanie Creary. "The Construction of Professional Identity". Perspectives on Contemporary Professional Work. Eds. Adrian Wilkinson, Donald Hislop, and Christine Coupland. Edward Elgar, 2016. 259-285. Caza, Brianna Barker, Heather Vough, and Harshad Puranik. "Identity Work in Organizations and Occupations: Definitions, Theories, and Pathways Forward". Journal of Organizational Behavior 39.7 (2018): 889-910. Cheney, George, and Karen Lee Ashcraft. "Considering 'the Professional' in Communication Studies: Implications for Theory and Research within and beyond the Boundaries of Organizational Communication." Communication Theory 17.2 (2007): 146-175. Doshi, Vijayta, Paaige K. Turner, and Neharika Vohra. “Challenging the Discourse of Leadership as Knowledge: Knowing and Not Knowing.” Management Communication Quarterly 35.2 (2020): 2020. Faber, Tamar, and Natalie Coulter. "'Let’s Go Make Some Videos!': Post-Feminist Digital Media on Tween-Coms." Television & New Media (2023). Forman-Brunell, Miriam. “Interrogating the Meaning of Dolls.” Deconstructing Dolls: Girlhoods and the Meanings of Play. Ed. Miriam Forman-Brunell. Berghahn Books, 2021. 1-11. Foss, Katherine A. "Pink or Blue?" Beyond Princess Culture: Gender and Children's Marketing, Ed. Katherine Foss. Peter Lang, 2019. 3-30. Griffin, Cindy L. Beyond Gender Binaries: An Intersectional Orientation to Communication and Identities. U of California P, 2020. Kuhn, Andreas, and Stefan C. Wolter. "The Strength of Gender Norms and Gender‐Stereotypical Occupational Aspirations Among Adolescents". Kyklos 76 (2023): 101-124. Machin, David, and Theo Van Leeuwen. "Toys as Discourse: Children's War Toys and the War on Terror." Critical Discourse Studies 6.1 (2009): 51-63. Marcus, Lisa. "Dolling Up History." Deconstructing Dolls: Girlhoods and the Meanings of Play. Ed. Miriam Forman-Brunell. Berghahn Books, 2021. 12-34. Marshall, Elizabeth. "Consuming Girlhood: Young Women, Femininities, and American Girl." Girlhood Studies 2.1 (2009): 94-111. Parkman, Anna. "The Imposter Phenomenon in Higher Education: Incidence and Impact." Journal of Higher Education Theory & Practice 16.1 (2016): 51-60. Rosner, Molly. Playing with History: American Identities and Children’s Consumer Culture. Rutgers UP, 2021. ———. “The American Girl Company and the Uses of Nostalgia in Children’s Consumer Culture.” Jeunesse: Young People, Texts, Cultures 6 (2014): 35-53. Rottenberg, Catherine. “Women Who Work: The Limits of the Neoliberal Feminist Paradigm.” Gender, Work, and Organizations 26 (2019): 1073-1082. Rybas, Natalia, and Sergey Rybas. "Where the Inner Star Leads." Beyond Princess Culture: Gender and Children's Marketing. Ed. Katherine Foss. Peter Lang, 2019. 73-95. Scharff, Christina. "Gender and Neoliberalism: Young Women as Ideal Neoliberal Subjects." The Handbook of Neoliberalism. Eds. Simon Springer, Kean Birch, and Julie MacLeavy. Routledge, 2016: 217-226. Solly, Meilan. “Why American Girl Dolls Are Starring in Viral History Memes.” Smithsonian Magazine, 15 July 2022. <https://www.smithsonianmag.com/smart-news/why-american-girl-dolls-are-starring-in-history-memes-180980424/>. Strickland, Ashley. “New American Girl Doll Is an Aspiring Martian Astronaut.” CNN, 10 Jan. 2018. <https://www.cnn.com/2018/01/10/health/luciana-vega-american-girl-astronaut-trnd/index.html>. Teagan, Erin. Luciana. New York: Scholastic, 2018. Thornton, Davi. "Transformations of the Ideal Mother: The Story of Mommy Economicus and Her Amazing Brain." Women's Studies in Communication 37.3 (2014): 271-291. Valdivia, Angharad N. "Living in a Hybrid Material World: Girls, Ethnicity and Mediated Doll Products." Girlhood Studies 2.1 (2009): 73-93. Zaslow, Emilie. Playing with America’s Doll. New York: Palgrave Macmillan, 2017.

Face and object recognition is a challenging problem in the field of computer vision. It deals with identifying faces or objects form an image or video. Due to its numerous applications in biometrics, security, multimedia processing, on-line shopping, psychology and neuroscience, automated vehicle parking systems, autonomous driving and machine inspection, it has drawn attention from a lot of researches. Researchers have studied different aspects of this problem. Among them pose robust matching is a very important problem with various applications like recognizing faces and objects in uncontrolled scenarios in which the images appear in wide variety of pose and illumination conditions along with low resolution. In this thesis, we propose three discriminative pose-free descriptors, Subspace Point Representation (DPF-SPR), Layered Canonical Correlated (DPF-LCC ) and Aligned Discriminative Pose Robust (ADPR) descriptor, for matching faces and objects across pose. They are also robust for recognition in low resolution and varying illumination. We use training examples at very few poses to generate virtual intermediate pose subspaces. An image is represented by a feature set obtained by projecting its low-level feature on these subspaces. This way we gather more information regarding the unseen poses by generating synthetic data and make our features more robust towards unseen pose variations. Then we apply a discriminative transform to make this feature set suitable for recognition for generating two of our descriptors namely DPF-SPR and DPF-LCC. In one approach, we transform it to a vector by using subspace to point representation technique which generates our DPF-SPR descriptors. In the second approach, layered structures of canonical correlated subspaces are formed, onto which the feature set is projected which generates our DPF-LCC descriptor. In a third approach we first align the remaining subspaces with the frontal one before learning the discriminative metric and concatenate the aligned discriminative projected features to generate ADPR. Experiments on recognizing faces and objects across varying pose are done. Specifically we have done experiments on MultiPIE and Surveillance Cameras Face database for face recognition and COIL-20 and RGB-D dataset for object recognition. We show that our approaches can even improve the recognition rate over the state-of-the-art deep learning approaches. We also perform extensive analysis of our three descriptors to get a better qualitative understanding. We compare with state-of-the-art to show the effectiveness of the proposed approaches.