Veterinary team members encounter a wide range of ethically challenging situations (ECS) in their work. Inability to resolve ECS in accordance with their values may negatively impact the wellbeing of veterinary team members. We sought to determine the types of ECS described in published ethical vignettes in the veterinary literature. We performed a strategic literature search, followed by a thematic analysis of vignettes published in the veterinary literature from 1990–2020. We identified 567 published vignettes in 544 publications. In the majority of vignettes, the protagonist was a veterinarian (61.6%) and the most common categories of animal involved were dogs (28.0%), livestock in general (10.8%), and cattle (10.6%). The primary type of ECS was coded for each scenario, generating 29 themes. These findings extend knowledge about types of ECS that may be encountered by veterinary team members. These themes can help to inform curricula and better prepare veterinary team members to navigate ECS. They may also highlight factors that contribute to ECS that can be addressed on a broad scale, such as through regulation, continuing professional development, or stakeholder education. Knowing that others may experience similar ECS may help veterinary team members feel part of a moral community. Ethically challenging situations (ECS) are encountered frequently in veterinary settings ,6,7,8,9.Reflecting on ECS may reveal systemic factors that can be addressed on a broad scale. This may involve changes in legislation or regulation, development of continuing professional development (CPD) or stakeholder education, cultural change, changes in practice and protocols, or other initiatives. For example, surveys of ECS have identified client financial limitations as an ECS commonly encountered by veterinary team members ,2,3,9. TThe Canadian Veterinary Journal [In Practice [Vignettes or case scenarios are commonly used in medical  and vete Journal  and In PPractice , invite We sought to explore published ethical vignettes to gain insight into the types and range of ECS that may be encountered by veterinary team members.To identify published vignettes, a strategic search was performed in Web of Science , PubMed, and Google Scholar, carried out between 14 January 2021 and 7 February 2021. Search terms utilised were:  AND (case OR dilemma OR scenario OR vignette) AND . The search was limited to articles published between 1 January 1990 to 31 December 2020, in English. Vignettes that were not available as full texts via Google were sourced via the University of Sydney library or interlibrary loan. Those that were not available as full texts via these sources, or not in English, were excluded.Web of Science and PubMed entries were exported or manually entered into Endnote for sorting. Duplicates were removed. The remaining Endnote entries were filtered by title and abstract screening, followed by full-text screening to determine whether the article fulfilled inclusion criteria . Google interpretive activity undertaken by a researcher who is situated in various ways, and who reads data through the lenses of their particular social, cultural, historical, disciplinary, political and ideological positionings”  [Rigorous qualitative research is acknowledged to be “context-bound, positioned and situated” . In othemphasis) . To thismphasis) ,36.The first author is a companion animal veterinarian, practicing as a primary accession veterinarian within metropolitan, urban, and regional areas within Australia, and a lecturer in the Sydney School of Veterinary Science. In teaching veterinary ethics, she draws upon both published surveys documenting the ECS encountered by veterinary team members, as well as published vignettes, some of which she contributed. The latter appear in this analysis. Her interest in the types and stressfulness of ECS stems from personal experience and discussions with colleagues and DVM students.The second author is a veterinarian, lecturer in epidemiology and public health, and a researcher at the Sydney School of Veterinary Science. His veterinary practice experience is derived exclusively from government practices as a field veterinarian. He teaches research methodology to first-year DVM students and coordinates third-year DVM student research projects. The latter includes screening and checking research projects for ethics  approval and best research practice and advising students on approaches to researching veterinary topics.In Practice for 10 years and 100 issues. Some of these vignettes were submitted by readers, others were proposed by potential responders, and some were written by the second author. All of these vignettes appear in this analysis.The third author is a veterinarian, researcher, and lecturer in veterinary ethics at University College Dublin. She has a long-standing interest in veterinary ethics, starting as a student and continuing through practice and into teaching. She instigated and coordinated a vignette-based series, ‘Everyday Ethics,’ in the UK veterinary journal The Endnote library was exported into NVivo12 Plus . Data were analysed using principles of thematic analysis (TA) using an inductive approach aligned with codebook TA .The analytical process involved six stages. Firstly, the first author read each vignette at least three times to familiarise herself with the vignettes. Secondly, initial codes were generated. Each vignette was coded inductively for semantic themes, employing a realist approach without a pre-existing theoretical framework. An iterative approach was used. Each vignette was initially coded three times according to the role of the protagonist, the type of animal involved, and the primary ECS described. Where vignettes involved multiple protagonists or species, the vignette was coded according to the first mentioned. For example, if the vignette stated, “you are a veterinary technician…” or “Dr X is a veterinarian”, it was categorised according to the role “veterinary technician” or “veterinarian” respectively. If a vignette did not specify a role but referred to a protagonist who had made a diagnosis or performed surgery, the role was classified as “veterinarian”. If the vignette did not specify a role or posed an ethical challenge for which the role within a veterinary team was not relevant—for example, where a role was not specified and the vignette raised a general question whether a type of animal use is acceptable—the role was coded “not applicable”. Where there was no protagonist, the vignette was coded “not applicable” for the role. Where the vignette did not refer to any animal , it was coded “not applicable” for the animal category. Types of ECS were initially coded according to ECS identified in surveys, as shown in Thirdly, initial themes were generated. To facilitate initial coding of semantic themes associated with the type of ECS, we identified surveys and reviews focused on determining the type, frequency, and/or stressfulness of ECS encountered by veterinary team members. From each of these, we compiled a list of specific types of ECS, either directly from the survey where this was available, or in other cases, key ethical challenges identified. A codebook approach is often utilised with large datasets, providing structure that offers some efficiency in analysis . In addiThe list of codes was examined to identify clusters of codes and complex codes which were grouped together as themes deemed to best represent the data. Themes were reviewed for both internal coherence and distinctiveness from other themes. This involved regularly re-reading all coded extracts from each theme. Where extracts did not fit a theme, these were either reallocated to a more appropriate theme or allocated to a new theme. The first and third authors discussed coding and initial generation of themes.The fourth and fifth stages—refining themes and developing a thematic map, and defining and naming themes—were performed concurrently, and involved further discussion between all authors. The sixth and final stage involved construction of a table describing key ECS within each theme. We counted the number of vignettes coded for each theme, to indicate the prominence of themes relative to one another. While this is not typical of a TA approach , we chosWe identified nine publications, comprising seven surveys, one committee report, and one policy Delphi listing key ethically challenging situations encountered by veterinarians. Of these, seven listed specific or key ethically challenging situations, either in a questionnaire or as a summary see . The poln = 123) and Bavarian veterinary officers (n = 81) asked respondents to report the frequency of ECS in broader terms, notably: “1. I wasn’t sure what was the morally right thing in this situation; 2. I was sure what was the morally right thing to do, but I could not, or only partially, implement it; 3. My personal moral convictions contradicted the legal requirements; 4. No matter how I decided…there were always weighty moral reasons against this decision; 5. I knew what would have been morally right, but the implementation would have meant a considerable extra effort for me.” Because of the broad nature of these ECS in comparison to those listed the other publications, we did not utilise these in coding.Two surveys “deliberately refrained from giving concrete examples or a given definition of ‘morally challenging situations’” ,8. TheseWeb of Science  and PubMed searches returned 862 and 641 records, respectively, a total of 1503 records . A GooglCanadian Veterinary Journal  and In Practice , both publications aimed at veterinarians. The Australian Veterinary Journal accounted for another five vignettes (0.9%). Vignettes featured in journal articles that were designed for veterinary students and veterinarians accounted for 4.2% [Exploring the Grey Zone) [n = 27); Veterinary Technician , The Veterinary Nurse ; and Veterinary Nursing Journal . Vignettes were contributed by a combination of panels   , columninicians ,44), andinicians ,44, someinicians ,29, and inicians .n = 349). In addition, where the protagonist was a practice owner , veterinarian practice owners were specified in the majority  of these vignettes. The next most frequent category was “not applicable” .The role of the protagonist in each vignette is presented in n = 159), followed by livestock in general , cattle , cats , animals in general , and companion animals in general . Some cases did not feature an animal , for example those focused exclusively on collegial relations.The categories of animals featured are presented in Themes generated from the types of ECS described in the vignettes are described in Analysis of published veterinary ethical vignettes reveals that veterinary team members may encounter a broad range of ECS in their work. The fact that we identified 567 vignettes comprising 29 themes confirms that many ECS are not unique, which may give veterinary team members a sense of moral community .The sources of vignettes varied, and included panels, column or journal editors, journal readers, researchers, and book authors. It was not possible for us to determine the degree to which vignettes reflected the actual experiences of veterinary team members, if at all. Indeed, some vignettes were developed deliberately to provide an example of reportedly common scenarios  or to prA perspective missing almost entirely is that of the client, animal owner, or guardian. While vignettes serve a purpose in the education of veterinary team members about ECS they may encounter, the client—where featured—is almost invariably portrayed as the source of the ECS, or a barrier to its resolution, rather than as someone who may be experiencing ethical challenges themselves. In portraying clients in this way, there is a risk of failing to consider their perspectives and interests. One vignette describes a veterinarian’s assessment of a farm dog that they are called out to examine, and diagnoses a fractured left femur . In the After reading the ethicist’s response to the vignette, the owners of the dog depicted in the vignette wrote to the journal, ostensibly in defence of their veterinarian. However, their letter provides insight into the factors that impacted their decision making—not discussed with their veterinarian at the time—including their own assessment of the dog’s pain and beliefs about analgesia and animal welfare, and financial constraints they faced “as parents of five children and living solely on a farm income” . FurtherCompanion animals  and livestock  accounted for the majority of species or category of animal depicted in vignettes, probably because veterinary team members are most likely to encounter these groups of animals. The prevalence of companion animal-related vignettes may reflect the reality that, in most western countries, the majority of veterinary teams care exclusively or mostly for companion animals or small animals ,49,50,51Aside from the companion animal bond, companion animals may have featured more prominently in vignettes due to a broader spectrum of treatment options (introducing more variables to consider in decisions around euthanasia) , and ethn = 60) were more likely to feature dairy cattle  than beef cattle  or unspecified . This may reflect increasing public concerns about practices such as culling of male calves and the separation of calves and cows [Livestock featured heavily in themes such as “what forms of animal use are acceptable”, “ensuring food safety, food security and biosecurity”, “how to balance animal productivity with animal welfare”, and “slaughter and killing of farm animals”. Vignettes that featured cattle primarily  ,70,71,72The relative prevalence of these species may reflect the change in the focus of clinical veterinary practice in the 20th and 21st century. This focus shifted from the horse at the beginning of the 20th century, to the dairy cow, to companion animals from the middle of the 20th century to the present day .Animal categories including “sheep, goats and alpacas”, “wildlife”, “laboratory animals”, “laying hens” and “non dog and cat companion animals” featured in less than 5% of vignettes, while “fish”, “elk, moose, bison”, “primates”, “farmed mink and fox” and “farmed duck” featured in less than 1% of vignettes. This may reflect the relatively small number of veterinary team members working with these categories of animals, rather than reflecting the range of ECS they encounter. This aligns with a review of papers presented at the World Association for the History of Veterinary Medicine, which found that fish, wildlife and exotic species were among the least commonly discussed .Given concerns about the impact of occupational stressors on the wellbeing of veterinary team members ,79,80,81Veterinary team members support and often engage in animal use themselves . They also engage with colleagues and clients with diverse and dynamic views about what forms of animal use are acceptable. Numerous vignettes raised the question of what forms of animal use are acceptable, suggesting the need for veterinary team members to reflect on their own views and consider relevant evidence, for example, from animal welfare science. This is reflected in the OIE recommendations on Day 1 veterinary competences, which specify that veterinarians should “provide leadership to society on ethical considerations involved in the use and care of animals by humans”  .It is important to reflect on factors that may have influenced the development of themes presented here. For example, conflict between the interests of animals and the interests of their owners. Rollin stated that the “fundamental question of veterinary ethics” is “to whom does the veterinarian owe primary obligation—animal or owner?” . Tannenbboth their human clients and animal patients. Indeed, they are often called upon to serve as an advocate of both parties’ interests, even when these interests conflict. Thus, veterinarians will often speak out on behalf of the animal, telling the client how the animal feels or is likely to fare, and indicating what is or is not in its interests. At the same time, veterinarians are often asked to be advocates for their clients’ interests—to know, for example, what would make the pet owner happy, the racehorse owner wealthy, or the researcher successful.”“…veterinarians are expected to serve  (p. 146)However, the conception of ECS as occurring within this triadic relationship between veterinarian, client/owner, and patient overlooks the reality that veterinary team members rarely work in isolation, are often employed, and may not have ethical responsibility withcomplete decision-making autonomy. This predicament has been raised in the context of other professions, for example engineering, where engineers are expected to do what is right and prevent what they recognise as wrong. This may lead to conflict with colleagues and employers:“The engineer is usually working with a team, and he or she first has to persuade the collaborators to modify or even stop a project because of ethical concerns. Moreover, the engineer is dependent on the employment contract he or she has signed towards the employer. Through this contract the engineer becomes subject to directives, and thus renounces his or her personal autonomy as far as professional work is concerned, and he or she undertakes to keep secret any internal business information. So, on principle the moral responsibility of the individual engineer is cut by industrial law. Even if, meanwhile, in some countries refusal to work and whistle-blowing are legally accepted in cases of serious concern, the engineer involved is usually risking his or her career. Engineering ethics, in terms of individual responsibility, in the borderline case is forcing the engineer to play the moral hero, a role that is neither desirable nor realistic”.Yet the pervasiveness of the conception of the veterinarian as a “moral hero” in veterinary settings may explain why the majority of vignettes feature a veterinarian as the protagonist, why major surveys regarding ECS in veterinary settings have focused on veterinarians ,4,6,7,8,As an alternative to the veterinarian–client–animal triad, Durnburger talks about “a triangle within a square”: the triangle consisting of the veterinarian, animal, and client, situated within a square including politics and legal requirements, society and its expectations, other veterinarians in different roles , and veterinary officers  . It may Similarly, veterinary team members are guided in their daily work by codes of professional conduct and animal welfare legislation, but interpretation is not always easy, and laws and regulations are not uniformly enforced . AdditioVeterinarians and other veterinary team members, including registered veterinary nurses and animal health technicians, are required to make professional judgements and be able to justify these according to sound principles. According to the Royal College of Veterinary Surgeons “Day 1 Competencies”, veterinarians, for example, “must be able to think through the dilemmas they face when presented with conflicting priorities and be prepared to justify the decisions they make. As well as decisions relating to individual patients, animal groups, populations of animals and clients, veterinary surgeons must take account of the possible impact of their actions beyond the immediate workplace, for example, on public health, the environment and society more generally” .Canadian Veterinary Journal typically close with a question, in bold, posed as a single ethical dilemma. For example, “If the behaviour of caged rodents can never be representative of human behaviour, is such experimentation ever justified?”  [For pragmatic reasons, each vignette was only coded according to what the authors perceived as the primary ECS depicted, yet vignettes varied in complexity , with some depicting multiple, often overlapping ECS which could have been coded differently. For example, a vignette describing a “recently qualified veterinary nurse” who has “noticed that some of the procedures used in the practice do no concur with what she was taught”, specifically, procedures that the nurse feels are below the standard of what she was taught , was codal bold) .It is possible that published vignettes may not reflect ECS most commonly encountered by veterinary team members. This may be because veterinary team members have become desensitised to common ECS, or that they have established workable approaches to deal with common ECS . In mediOur search strategy omitted vignettes from the grey literature, a potentially rich source of ECS encountered by veterinary team members. Inclusion of grey literature, including newsletters, research and committee reports, conference proceedings and abstracts, dissertations and even online forums, may reduce publication bias . It is pThe majority of vignettes were published prior to the COVID-19 pandemic, during which veterinary team members encountered novel ECS including decisions about what counts as an essential veterinary service, conflict between the wellbeing of household members and professional role, and whether to perform non-contact vet visits . We onlyThematic analysis is not performed in an epistemological vacuum. A realist approach to thematic analysis assumes a predominantly unidirectional relationship between meaning, experience, and language. However, this may overlook the diverse sociocultural contexts and structural conditions that underpin these scenarios in the first place . Due to What counts as an ECS may vary between veterinary team members. The vignettes analysed in this study were presented as ethical challenges or ethical dilemmas, based on an underlying assumption that they would be experienced as such. However, one study found variation among veterinarians as to whether a particular scenario was experienced as ethically challenging (a ‘dilemma’) or not at all . WhetherWhile vignettes provide contextual factors that may complicate ECS, it is impossible to depict every iteration of an ECS that a veterinary team member may encounter. Durnburger found that a key dilemma faced by German farm-animal veterinarians was conflict between personal convictions and external constraints . We agreThe authors acknowledge that reliance on case-based teaching in ethics may overemphasise the weight of isolated decisions of individuals, while underplaying the broader institutional and social contexts that create and shape ethical challenges . It is i


Social scientific work has considered the promise of genomic medicine to transform healthcare by personalising treatment. However, little qualitative research attends to already well-established molecular techniques in routine care. In this article we consider women's experiences of routine breast cancer diagnosis in the UK NHS. We attend to patient accounts of the techniques used to subtype breast cancer and guide individual treatment. We introduce the concept of ‘diagnostic layering’ to make sense of how the range of clinical techniques used to classify breast cancer shape patient experiences of diagnosis. The process of diagnostic layering, whereby various levels of diagnostic information are received by patients over time, can render diagnosis as incomplete and subject to change. In the example of early breast cancer, progressive layers of diagnostic information are closely tied to chemotherapy recommendations. In recent years a genomic test, gene expression profiling, has become introduced into routine care. Because gene expression profiling could indicate a treatment recommendation where standard tools had failed, the technique could represent a ‘final layer’ of diagnosis for some patients. However, the test could also invalidate previous understandings of the cancer, require additional interpretation and further prolong the diagnostic process. This research contributes to the sociology of diagnosis by outlining how practices of cancer subtyping shape patient experiences of breast cancer. We add to social scientific work attending to the complexities of molecular and genomic techniques by considering the blurring of diagnostic and therapeutic activities from a patient perspective. •Molecular techniques are embedded within contemporary UK breast cancer care.•Routine diagnostic practices ‘split’ breast cancer into subtypes.•The diversity of diagnostic techniques can render diagnosis both partial and subject to change.•We capture these experiences from a patient perspective with the concept of ‘diagnostic layering’.•Gene expression profiling could finalise, but also prolong, diagnostic processes. Howeveribid). Indeed, a recent article in Nature's Breast Cancer journal suggests that this (ongoing) fragmentation demands that breast cancers be considered as rare diseases , Progesterone (PR) and human epidermal growth factor (HER2) have been used to classify breast cancer into subtypes. The development of hormone treatments and a targeted therapy, Herceptin, has led to defined treatment pathways for individual patients where they test positively for ER, PR and HER2 status . Moleculdiseases .Reflective of its heterogeneity, in the UK today a diagnosis of breast cancer is multifaceted, informed by factors including the presentation of symptoms, clinical imaging and laboratory analysis of tumour tissue. Pathology examinations occur at several time points, following one or more biopsies and surgeries to remove the cancerous and surrounding tissue. Alongside histological laboratory work to establish characteristics such as the tumour's size and whether it has spread to the lymph nodes (LN), the examination of the ER, PR and HER2 status of tumour tissue to determine molecular subtype is a routine aspect of breast cancer diagnosis in the UK. This provides an indication of the suitability of hormone treatments and Herceptin for each patient . In addiIn 2013 a genomic technique, gene expression profiling, was approved for use within the UK NHS for a defined group of patients with early stage ER/PR+, HER2-and LN- breast cancer . This catype DX test. This test analyses 21 genes in tumour tissue taken at surgery to develop prognostic information (the likelihood of cancer recurrence), and based on this an estimate of chemotherapy benefit. Today this test has been adopted across the UK NHS to inform chemotherapy decision-making. The addition of gene expression profiling to existing practices of subtyping reflects the fact that clinically and within the laboratory, the number of procedures and tests undertaken on breast tumour samples is increasing. As a consequence, diagnostic processes are becoming more divergent among individual patients , and more protracted. An important question for sociologists is how these wider approaches to molecularization for driving more individualised and precise diagnoses impact patients’ experiences of cancer.The first gene expression profiling platform approved for NHS use in the UK was the US-developed OncoAcross medical sociology, a number of scholars have considered personal experiences of breast cancer diagnosis e.g. , includitype DX testing as part of this process. We discuss experiences of well-established clinical diagnostic pathways to identify their specific cancer type, then turn to accounts of the Oncotype DX test. Contributing to literature on the sociology of diagnosis, we introduce the concept of ‘diagnostic layering’ to make sense of how the multitude of diagnostic processes in oncology, which in the UK today routinely draw on molecular and genomic techniques, shape patients' experiences of being diagnosed with breast cancer. First, we outline some of the sociological approaches to diagnosis that have informed our analysis.In this article, we explore women's accounts of being diagnosed with early stage ER/PR+, HER2-and LN- breast cancer, focusing on patients who have experienced Onco1.1In recent years, the study of diagnosis has become firmly established as a ‘sociology’, with in-depth examination of the procedures and experiences of diagnosis providing insight into the wider social and structural conditions within which it occurs , but alsOnce established, diagnoses can be acted upon through the establishment of a corresponding prognosis and treatment plan . DiagnosBy tracing diagnosis in practice, existing work has shown that diagnostic categories and procedures can be experienced by patients in varying ways; for example as disembodying in the case of medical technologies , but alsGenomic techniques have further reconfigured the relationship between diagnosis and treatment, and the wider healthcare systems within which these practices take place e.g. . TroubliDespite anticipations for genomic techniques to remedy diagnostic uncertainties, particularly in rare genetic diseases where patients seeking a diagnosis often hope these “advanced” tools “may bring their search to an end” : 442, thtype DX). Drawing on personal accounts we introduce the concept of ‘diagnostic layering’ as a heuristic device to make sense of how these processes of classifying breast cancer shape patient experience. Due to the numerous laboratory analyses now conducted on breast tumour tissue, patients receive information about their cancer in ‘layers’, as separate rounds of clinical information are relayed to them by their clinician. This can be over a period of many weeks. These layers aim towards a more refined diagnosis, as they work to ‘lump’ the suspected tumour as a cancer, and then ‘split’ the cancer into a distinct subtype and subsequently direct treatment. The concept of layering thus entails both of these activities, but additionally captures the temporality of these processes, which occur across various time points and may require repetition. As several layers of diagnostic information from diverse sources are collated to subtype breast cancer today, including histopathological, molecular and genomic analyses, we contend that diagnosis is temporally extended, as well rendered partial (incomplete) and subject to change (mutable). This can impact patients' expectations for diagnostic pathways and care. Despite anticipations for genomic testing to finalise the diagnostic process, patient accounts reveal a more complex picture. We show that the incorporation of these test results into treatment decision-making is not straightforward, but informed by diagnostic information derived from established tools, and powerful cultural imaginaries of cancer and chemotherapy.In this article, we draw on qualitative interview and observational data to explore these issues in the context of routine cancer care in a UK setting. We contribute to existing literature by considering the molecularization of breast cancer diagnosis, with specific reference to the identification of cancer markers and gene expression profiling  discussed treatment decisions in light of Oncotype DX results. Interviews with oncologists who had used the technique with their patients were also conducted, as well as observation of online discussions of Oncotype DX testing, with these findings presented elsewhere  and with the help of key oncologists and research nurses, we recruited and interviewed 18 patients who had received Oncolsewhere .type DX result, subsequent treatment decision-making and ongoing legacies of the result. Interviews lasted between 45 min to up to 2 h, were audio-recorded and transcribed verbatim. The four observations of consultations took place in June and July 2017. These involved a researcher being present at consultations where treatment decisions were discussed and formalised by patients following their Oncotype DX result. These lasted up to 1 h. Fieldnotes were taken by hand, before being typed and shared with the research team.Interviews with patients took place between June 2017–August 2019. Interviews were semi-structured and began by seeking a narrative account of the interviewee's symptoms, suspicions and their path to diagnosis. Interviews also covered engagements with gene expression profiling specifically, including how the technique was explained by their clinician, any independent research they had undertaken about the technique, how they made sense of their Oncoin vivo code that succinctly described participants' experiences of gradually gaining various levels of information about their cancer over time. After going back to the data with this theme in mind, we developed the concept of ‘diagnostic layering’ to convey the ways in which, from a patient perspective, molecular and genomic information shape experiences of contemporary breast cancer diagnosis. We also attended to how processes of diagnostic classification were further shaped for these participants in light of gene expression profiling; in ways that could both end but also extend the diagnostic process.Analysis drew on techniques of constant comparison cf.  and themtype DX testing. We show how this aspect of diagnosis became intimately connected to treatment, and related to this, how some women described this as a ‘final’ layer of diagnostic information. However, for others this information could introduce further uncertainties and extend diagnostic processes. We end by considering the implications of genomic techniques for patients' experiences of cancer diagnosis.In what follows, we present women's accounts of ‘diagnostic layering’, and discuss the implications of this for chemotherapy decision-making and wider experiences of cancer. In the first section we attend to how participants discussed well-established routine diagnostic procedures for breast cancer. We share experiences of several of the ‘diagnostic layers’ articulated by patients. These included provisional diagnoses of cancer at the breast clinic, the molecular classification of cancer following pathology results , and for some the re-casting of their cancers after further pathology. In the second section we attend specifically to personal accounts of Onco3Many participants’ experiences of diagnosis began with an embodied awareness of a lump in their breast, but for a minority this followed a recall after routine screening. At the time of our interviews patients had all been treated surgically, and had commenced or were due to embark on chemotherapy and/or radiotherapy following the results of gene expression profiling.For most interviewees, the initial labelling of suspicions about a lump or a blur on a mammogram as cancer took place in the breast clinic. The clinic, described by Dette as a “one-stop shop”, provided women with a mammogram, ultrasound and, if necessary, a biopsy on the same day. Valerie described her experience at the clinic as like a “conveyer belt”. The very experience of being in the clinic could serve as a form of diagnosis in itself. Several participants described a number of ‘cues and clues’ that led them to anticipate a diagnosis of cancer before being formally told cf. . These iAt the end of their visit, which for some lasted the entire day, a discussion with the oncologist at the breast clinic could represent a first layer of diagnosis for participants. Shortly after their final biopsy, a verbal indication of cancer could be communicated to women. For some this was unequivocal, coming as a shock for Bethany who exclaimed “how can she say that when they've not got the biopsy result?“. For others this was implied. Linda was told “don't be surprised” if the pathology report indicated cancer. All were told that more information would be available following the biopsy results, which could take up to two weeks.3.1Biopsy results provided a further strata of information to participants about their cancer; and in some cases it was not until this point that cancer was confirmed. The pathology report both confirmed a diagnosis of breast cancer (a ‘lumping’ of the tissue's characteristics as ‘cancerous’), but also provided information about the tumour's receptor status e.g. ER+, HER2- (the ‘splitting’ of their cancer into a particular subtype). In describing their diagnosis during interviews, almost all disclosed the receptor status outlined in this first pathology report, and some the size and grade of their tumour, appreciating that this information was specific to their cancer. The heterogeneity of breast cancer was therefore recognised by participants, gleaned not only from their pathology results but also from discussions with clinicians. In two consultations, we observed the oncologist explain to the patient that “breast cancer is a very big family of cancer” (Observation2 July 2017) and “breast cancer is not one cancer” (Observation1 July 2017)., and he's like, ‘whoa, whoa, what have you been told?’ Right, and I was like, ‘well, basically, in no uncertain terms, I had cancer, but it, the word wasn't used’ … And he went, ‘oh yes, you've got cancer’, he said, ‘but it's a good cancer’.So when I went in and he said, erm, ‘oh well, it's all good news’. So of course, I was like, ‘oh yes!‘, do you know what I mean?’ And he must've saw my faceCommonly encountered within interviews were reports of clinicians describing their subtype of the disease as a ‘good’ cancer. This was inferred through explanations of their cancer as “early stages” (Elisa), “treatable” (Lois) and “low risk” (Lillian), or in some cases women's cancers were explicitly described as ‘good’. Eve had attended the breast clinic and was informed that something “sinister” had been found on her ultrasound, leading to several biopsies later that day. During the discussion with the oncologist she was advised of possible scenarios and treatments, but unlike other participants had not been told to expect a diagnosis of cancer. Her next appointment was with a different clinician two weeks later. She recounted:JulieWhen they gave me the results of the oestrogen, the ER-positive, they said that was good because the tamoxifen would be very effective and so the consultant was “that's really good.” This way of communicating her first formal diagnosis discursively configures Eve's cancer subtype in a positive way, and as distinct from the widely accepted understanding of cancer more generally as ‘bad news’. A configuration of these women's cancers as good was also achieved beyond linguistic performance. As discussed by This layer of information largely configured our participants' cancers in ways that inspired relief and optimism. Significantly these positive interpretations of their cancer-type impacted upon anticipated treatment pathways, which were again largely discussed optimistically in the first instance, and without mention of chemotherapy. Dette was told in a “matter-of-fact” way that “it's very small, it's very early, you'll find out about radiotherapy but you have to have surgery first.” Similarly Elisa was told “yeah you have got [cancer] but early stages. So we'll just give you surgery then radium”.So I was HER2 negative so that helped. Erm, and then obviously whether it was in the lymph nodes or not. From the ultrasound they, they thought it wasn't, but they weren't gonna confirm that until results from the surgery.Others, however, were given a more tentative outlook, being told that treatment depended upon further factors that would only be resolved following surgery. Valerie was told about her molecular markers in a positive way, but that though appearing favourable there was uncertainty regarding lymph node involvement:Though tentative for several participants, such initial depictions of their cancer as ‘good’, and for some, easily treated, are significant. These impressions paved the way for the shifts in anticipated treatment pathways that were to come, as additional layers of diagnostic information emerged; each achieved through fresh configurations of socio-material practices.3.2As outlined above, initial biopsies taken at the breast clinic gave a degree of diagnostic information about our participants' cancers, and in some cases, indication for treatment. However, further pathology examination following surgery meant that for some, their ‘good’ diagnosis and related anticipations for treatment could be reconfigured.As in Valerie's extract above, surgery was presented to participants as the point at which uncertainties about treatment could be resolved. However in practice, surgery could result in initial understandings of the tumour being rendered obsolete, and in some cases the designation of their results as a ‘grey area’. This could require further intervention to generate an additional layer of diagnostic information. Some of these uncertainties, notably to do with the cancer's size, could be clinically acted upon. For six of those we interviewed, following breast conserving surgery to remove the cancerous tissue (a lumpectomy) it was discovered that the operation had not removed an adequate margin of cancer-free tissue around the tumour. These six women therefore underwent one or more re-excisions to remove all of the cancerous tissue, and re-establish the size of the tumour.I got the results from the surgeon and that was when he said “oh, your lymph nodes were clear and all the cancer's been removed” so that was a great boost, so that was super. But the cancer had moved from a grade 2 to a grade 3 category so it was worse than first expected.Other aspects of the cancer were also altered following diagnostic information from surgery, with ‘good’ cancers rendered potentially ‘bad’ cancers. In most instances this was due to confirmation of, or in three cases a shift in, the cancer's grade (rate of growth). This was the case for Lois:had expected chemotherapy, which was then called into question following surgery.The transformation of their cancer to a higher grade provoked a shift in language from clinicians. Women reported their doctors now using terms including “aggressive” , “high grade” (Zoe), and “fast growing” . In some instances surgery uncovered what was described as a “slight” or “tiniest” spread to lymph nodes, which was the case for Lillian, Jane, Julie and Alice. In situations such as these, where new or altered information about the tumour was introduced, anticipated treatment pathways were (again) rendered uncertain, and chemotherapy could be raised as a possibility where it had not existed before. Due to previous layers of information pointing to a ‘good’ cancer, Elisa, Dette and Lois had not anticipated being offered chemotherapy, with Chrissy also unsure as to why the treatment had suddenly been introduced when “the cancer had all gone from surgery”. Linda had not considered chemotherapy because of heart condition, which had compelled her clinicians to “try and avoid that”. The introduction of chemotherapy came as a “blow” for these women. The instability of diagnosis as related to treatment could work both ways, however, as two participants (Susan and Julie) incompleteness of diagnostic information described in the extracts above, which participants (and their clinicians) gained gradually in layers, interviewees therefore also pointed to the mutability of diagnosis, particularly following surgical intervention. Subsequent layers of information could both add to and refine existing understandings of the tumour and cancer type, but in some cases called previous layers into question. Paradoxically, though diagnosis is generally engaged upon with a view to fixing a disease classification, and discern treatment along with “a sense of where the road ahead may lead”  “that kills” (Susan), and which inspired painful recollections of the deaths of friends or family members. Though contemporary medicine has relieved some of the historic devastation caused by the disease and radical treatments , cancer It is within this context that where a clinician had so far guided them with regards treatment decisions, providing some solace in the face of these oncological uncertainties, unknowns suddenly became openly acknowledged. Further, the responsibility for addressing these could be passed to patients: in the absence of a recommendation from the prognostic algorithm, many interviewees had been asked to choose whether or not to proceed to chemotherapy. Lois described this as her oncologist “laying the decision at your door”, and along with others, experienced this as emotionally fraught. One patient observed in Observation2 July 2017 said that this placed her “between a rock and a hard place”, an idiom also used by Alice who elaborated further: “I didn't want to take a risk of not having chemo if I needed it. But I didn't want to have, take the risk of taking chemo if I didn't need it.” Below, we demonstrate how the layer of information provided by gene expression profiling could both attend to the emotional difficulties of this situation by solidifying a diagnosis and enabling a treatment decision, but also prolong the diagnostic process further by introducing additional contradictions and complexities.4.1type DX was represented by clinicians, and understood by patients, as having the potential to resolve clinical uncertainties surrounding treatment. In one consultation we observed the following exchange:type test result [i.e. with just the NHS Predict result], it might have appeared that the patient doesn't need chemo but with this result it shows the benefit … The consultant said NHS Predict gives you ‘a rough average’ but because breast cancer is a big group of diseases, this is ‘where Oncotype comes in’. Observation1 July 2017Because the patient is ‘so young’ [early 40s] the consultant predicted a good prognosis. She added that without the OncoOncoNHS Predict. The notion that gene expression profiling provided a level of refinement not available from other tools was echoed by interviewees. Both Julie and Bethany described the test as providing “more specific” information about their cancer. Bethany, who described Oncotype DX as a “state of the art” test, and “most advanced that's available” explained this in more detail:As far as I was concerned, this test, as it had been described to me, meant that this was very particular to me, in a way. You know, this was a sort of DNA profile of my tumour and, to some extent, milder extent, of me and therefore if that test said I needed [chemotherapy] then I would definitely have done it.Here, gene expression profiling is described as providing a more specific estimation of chemotherapy benefit, contrasting with the ‘rough average’ generated by Due to the fact that the test generated a recommendation based on analysis of her own tumour tissue, Alice discussed the test as providing “scientific fact”, which she contrasted with the “expertise” of her clinician. Julie noted that the result “will make me feel I'm not making a hunch decision, I'm making a decision based on actual science”. The fact that the test was “personalised”, gave Hazel “confidence” in the subsequent recommendation to forgo chemotherapy. This was echoed by Bethany who, again demonstrating an appreciation of the diversity of breast cancer, explained “it does make me feel more confident that this is about me and em, that attention is being paid to me and the sort of tumour I have”.type DX as providing a layer of information to inform their treatment decision which surpassed others. Though previous diagnostic techniques had of course also been personalised, involving molecular analysis and pathological examination of their tumour tissue, treatment recommendations had been more heavily developed from clinical judgement, assisted by tools such as the NHS Predict algorithm. Whilst such algorithms and Oncotype DX perform the same task – estimate recurrence risk to develop a chemotherapy recommendation – the fact that Oncotype DX's treatment recommendation was directly developed from their “DNA profile”, and thus “personalised”, marked the tool as distinct for some participants, and as inspiring a particular confidence.Due to its ability to provide a “personalised” recommendation, these interviewees portrayed OncoLoisSo by getting the test … then that gave us the second opinion really to say that no, I didn't need the chemo. AliceSo I had the test done, so I had the scientific back-up, almost, to say, yeah, you really won't benefit [from chemotherapy]. For these interviewees, the test result was represented as integral to their decision about chemotherapy. Those with a ‘low risk’ score described their result as allowing them to more confidently say no to chemotherapy:type DX results. Felicity represented the test as leaving her with no choice but to proceed with the treatment:I had, well, a score of twenty-seven, which was a no, no-brainer, really. That's, that's you at a high risk so … So in that way that was reassuring. [Laughs]. Do you know, in an awful way. In an awful way. It was like well, I was glad that it was such a definitive result.Similarly, those with a high risk score, despite some being disappointed that chemotherapy had been recommended as a treatment option, also welcomed their Oncotype DX as “definitive”, contrasting with previous clinical assessments of her tumour. Felicity had faced particular uncertainties around adjuvant chemotherapy having received hormone treatment prior to surgery, and had found chemotherapy decision-making “impossible”. She welcomed the Oncotype DX result, which squarely placed her at high risk, providing a clear recommendation for chemotherapy. For these participants, the fact that the test result directed treatment decision-making in this way distinguished it from previous layers. As well as being “definitive” in the sense of not able to be technically surpassed by other techniques (“state of the art”), the perceived finality of the Oncotype DX result can also be linked to the fact that it directly recommended a treatment. Due to their fears surrounding recurrence, but also of chemotherapy, the discernment of the ‘right’ treatment was an important outcome of the diagnostic process for interviewees. For the participants above, by successfully resolving uncertainties around treatment, no further ‘layers’ of diagnostic information were needed. Bethany, who earlier likened breast cancer diagnosis to a ‘process of elimination’, described the test as a ‘final diagnosis’:It just really meant that it was a very individualised, you know, that it was another layer, a bit like peeling an onion until you get to the final bit, you know, the final sort of diagnosis really.Here, Felicity describes the ‘layer’ of diagnostic information provided by Oncotype DX. Importantly, Bethany discussed this information as a ‘final’ layer because, due to the fact it was “individualised”, she could now make a decision about chemotherapy. Complementing Dette's earlier description of the diagnostic process thus far, Julie similarly proclaimed that the test acted as “a bit of a crystal ball, you know, and g[a]ve me something to actually make a decision on”.Here Bethany points to an alternative conceptualisation of diagnostic layering, where various components of information are gradually uncovered until the most refined is provided by Oncotype DX was therefore welcomed by many participants interviewed for this research. The test was seen to solidify diagnoses which had previously been experienced as fluid and changeable. It ‘finalised’ diagnosis in two ways; through its provision of ‘state of the art’ and personalised diagnostic information, which could not technically be surpassed, but also by clearly directing treatment, ending uncertainties surrounding this important aspect of their cancer care. Nevertheless, receiving the Oncotype DX score did not straightforwardly finalise the diagnostic process for every patient. As we now discuss, the introduction of the technique also had the potential to further unsettle paths to treatment, particularly in terms of its blurring of diagnosis and prognosis.In the context of uncertainty surrounding a feared treatment, Onco4.2type DX are presented as bringing finality, with clinicians often presenting such techniques as “the most comprehensive test” . Novel genomic techniques such as Oncove test” : 442. Hotype DX results conflicted with previous layers of diagnostic information. Where these contradictions arose, unlike in the extracts above the genomic result was not always taken at face value, but required further interpretation. During the earlier stages of diagnosis, Lillian had been told “on two or three occasions” that hers was a “low risk cancer”. However, Oncotype DX indicated that chemotherapy would be recommended for her. Having learned her result she decided that chemotherapy was “inevitable”, and welcomed the presentation of statistics and percentages alongside her score to help her make her decision. However, she also felt confused about her result, a feeling which lingered beyond her consultation:type.It's only when I got home and I looked at my notes, I almost couldn't marry the two things together. Him saying it's low risk but then me being a 29 on the OncoIn some cases, our interviewees’ Oncotype DX score placed her in the ‘high risk’ category. She discussed her confusion about this with her oncologist:‘You don't have to be terrified’ [the oncologist] said, ‘you, your prognosis is incredibly good.’ And this is what's difficult to understand, is why give me chemotherapy? And she said ‘it's just because we don't want you to get it again.’This was also the case for Dette, for whom the possibility of chemotherapy first arose following surgery. Despite being consistently advised that her cancer was “small” and “early”, her Oncotype DX test. This apparent contradiction is mitigated by the oncologist above through her distinction between Dette's cancer in the present (which had been successfully excised), and a possible cancer recurrence in the future. This demonstrates that the ambiguity of Oncotype DX as a prognostic or diagnostic tool, as well as having implications for practitioners  expectations for genomic techniques to resolve diagnostic uncertainties (In line with personalised medicine's aim to further refine diagnosis and treatment, it is likely that additional layers of diagnostic information derived from novel genomic techniques will become incorporated into routine cancer care. However, scientists now highlight the diversity of breast cancer even within individual patients, and as shifting over time . This catainties .ER developed the idea for this piece and wrote the article with JS. ER and CKC led qualitative data collection. SCB and AK devised the wider research project and secured funding. All authors were involved in developing and editing this article.We have no conflicts of interest to disclose.


This letter is a response to “Gender Dysphoria and Transgender Identity Is Associated with Physiological and Psychological Masculinization: a Theoretical Integration of Findings, Supported by Systematic Reviews” by Dutton and Madison , which r Dear Editor,The recent publication of “Gender Dysphoria and Transgender Identity Is Associated with Physiological and Psychological Masculinization: a Theoretical Integration of Findings, Supported by Systematic Reviews”  hypothesis of autism aetiology (e.g. Barbeau, Mendrek, & Mottron, Finally, therefore, the suggestion that trans people are “masculinised” based on the overlap with autism is no more valid than another of the authors’ assertions that a 2% difference in the rate of left-handedness between the sexes renders handedness a meaningful correlate of sex. A more parsimonious proposition is that autistic people are more likely to identify as trans due to differences in perception and cognition leading to a reduction in the likelihood that social conditioning will prevent them from becoming aware of their gender identity when it differs from the gender assigned to them at birth (Jackson-Perry, Considering these numerous scientific failures, Dutton and Madison  represen


Children with ME/CFS who are severely ill are bedbound and homebound, and oftentimes also wheelchair-dependent. Very seriously affected children are often too sick for doctor’s office visits, let alone school attendance. The most recent data estimate that 2–5% of children may be severely affected or bedridden. However, there is no recent research that confirms these numbers. The severely ill receive little help from their schools, and are socially isolated. This article outlines several suggestions for the type of education that students with ME/CFS should be receiving and develops a preliminary sketch of the web of resources and emergent techniques necessary to achieve these outcomes. Educators and clinicians focused on children suffering from mild-to-moderate ME/CFS have made significant strides in the past decade in supporting chronically ill students in achieving academic success. Classroom teachers and other education professionals are increasingly designing effective Individual Educational Plans (IEPs), creating supportive classroom learning environments, and modifying curricula to emphasize mastery over completion . Many trThe same cannot be said regarding the education of children whose ME/CFS symptoms are so severe as to render them housebound and/or bedbound. Despite sometimes heroic measures by family members, caregivers, and visiting teachers, children with ME/CFS often face spending years in social and intellectual isolation, devoid of challenging cognitive stimulation or the opportunity to learn new skills and information. Though estimates remain little more than guesses because bedbound students are rarely disaggregated in reported statistics, it is likely that thousands of children, adolescents, and young adults suffering from ME/CFS are essentially being “warehoused” in their own bedrooms ,7,8. Pen(1).delineate the impact of severe pediatric ME/CFS on student learning, and how that impact inherently limits the positive impact that even the most innovative K–12 educational programs can expect to achieve;(2).type of education that students with ME/CFS should be receiving, and the educational outcomes to be expected; andestablish an initial foundation—in philosophical and process terms—for the (3).develop a preliminary sketch of the web of resources and emergent techniques necessary to achieve these outcomes.This article seeks to accomplish three modest goals:Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by profound, medically unexplained fatigue including a range of sleep, pain, cognitive, neuroendocrine, and immune symptoms. Post-exertional malaise  and persistent generalized fatigue make school attendance irregular even in mild-to-moderate cases; the most common feature of pediatric ME/CFS observable in the classroom is the array of attention, concentration, and memory deficits known collectively as “Brain Fog” . ChildreMental health consequences are equally profound, as Boularzreg and Roach note, with catastrophism, pessimism, depression, and isolation, leading to “a substantial loss of self” because “adolescents with ME/CFS attach significance to attending school and hang-outs with friends, [and] when deprived of these events, the adolescent questions the meaning of life” . As one “Imagine having the flu, being severely jet-lagged, and having not slept for two days but without the sinus and lung congestion—that’s the closest I’ve found to a description of what this illness is like, but it understates it. I lack mental clarity; I mix up words, and I have memory problems and trouble focusing. I have an enormous need for sleep, which never refreshes. There is an overwhelming, permanent, and intense malaise” .A mother of two sons in their mid-twenties who have been homebound or bedbound for a decade reports that they often cannot be upright in bed, and that severe light, sound, and touch sensitivities restrict their use of computers. Their attention spans are often limited to irregular intervals 20 min long, and while “their intellect is not impaired, the [physical] resources available to apply that intellect are severely limited.”American public schools are chronically ill-equipped to educate such children, adolescents, and young adults ,15. EducMost innovations introduced to support the education of bedbound individuals suffering from severe ME/CFS have been technology-based. Robotics are intended to allow these students virtual access to live classrooms in a real-time, interactive three-dimensional setting . New kinThese innovations are intended as aides to making the existing patchwork system function, rather than rethinking the philosophy, organization, and objectives of educating bedbound students. They are sometimes perceived by school districts as comparatively inexpensive and not requiring significant investments of staff or resources, and often lump all bedbound students into a single category. A robotic telepresence is of extremely limited usefulness to a child with ME/CFS whose working attention span for active learning exists in irregularly spaced 20 min intervals, and who has enough issues with processing speed without having to operate a complex interface while trying to pay attention to a lecture or group activities. Many of the solutions to these issues are being pursued in hospitals, not schools .In fact, for decades, the most innovative work in educating bedbound students (and older patients as well) has originated in hospitals providing long-term care rather than the educational system. In 1942, Dr. Elena D. Gall of Hunter College established a continuing education program at Goldwater Memorial Hospital in New York City, which had a population of 1850 patients permanently confined to a hospital setting. Designed in 1937 by architect Isadore Rosenfield, who “was as concerned with the careful design of a patient’s bedside lamp as he was with the circulation patterns of the thousands of people who would use the facility each day,” Goldwater Memorial embodied an “unwavering patient-centric design approach” .Gall theorized that the patients “are thinking, intelligent individuals who still function on an intellectual level,” but that “agencies which offer continued education to interested adults did not reach out to people who were to be hospital bound for many years.” She created a continuing education program that was multigenerational, democratically run by the patients themselves, and focused on lifelong learning rather than specifically tied to credentialing within the public education system: “The patients, ranging from teenagers to elderly people, meet every Friday night in one of the recreation rooms of the hospital. Each year they themselves choose the area of interest for the term of study. One year it was English literature, another time it was world affairs. This year they decided on current events. They have their own roster of duly elected officers” ,34. ThisGall’s Goldwater Memorial program is a comprehensive model for the education of bedbound individuals that provides a potential alternative to our current patchwork approach. First and foremost, the model emphasizes supported lifelong learning based on individual interest for personal growth as part of a total patient-care package, largely decoupled from the credential and course-based emphasis of public education. Gall also insisted on creating what we would currently call “a community of learners” as a critical element . This reAdditionally, diverse elements outside American public education seem almost to have been crafted toward Gall’s model, or a close variant. There is a robust body of research on the “gamification of education,” with a significant subset focused on meeting the needs of special needs children. Gamification, although it has been variously defined since the first use of the term in 2008, generally refers to the practice of using elements of structure and rewards from digital gaming to support students in solving problems and remaining motivated, and experts constantly reiterate that “in gamification applications, students need not have to have toys, electronic devices, etc., and not always play games in order to learn” ,37. MateA second example addresses the criticality of establishing a learning community to provide long-term psychosocial support for bedbound students. There is an understandable tendency in American society—especially after a year spent dealing with the COVID-19 pandemic—to consider virtual support communities as the default option here. In the Kohzikode district of the State of Kerala in India, however, education professionals are exploring a different strategy, that of physically constructing “resource rooms” in the houses of chronically bedbound students “to help differently abled bedridden students develop social and other skills” . BesidesWhat makes these home-learning resource centers particularly innovative is that they are specifically linked to building social ties to a friendship peer group “from the school where the differently abled child is enrolled. They interact with the child during weekends or holidays to help them improve their skills. Resource teachers plan activities for the children keeping in mind their physical and mental condition” . This emIn terms of education, bedbound children, adolescents, and young adults suffering from severe ME/CFS currently exist in a lonely frontier at the borders of public education, long-term care, psychotherapy, technological innovation, and communities too often completely unaware of any obligation to citizens they never see. The problem is not that we do not know enough about the requisite elements to enrich these young people’s lives through education, but that there is currently no framework to coordinate and deploy the knowledge, skills, supports, and technologies which already exist. Not only does the model of best practices have to be built, but we—as a society—have to figure out who will be responsible for enacting it.There is reason to be hopeful, however. Slightly more than a decade ago we faced a similar state of affairs in supporting children with mild-to-moderate cases of ME/CFS to be educationally successful within the public schools. A broad coalition of researchers, clinicians, educators, parents, and volunteers coalesced to address that challenge, and they have made major progress. Students with ME/CFS increasingly find that schools are better prepared to teach them on their own terms. That process began with a few educators raising the issue, followed by a national dialogue among the concerned parties. Despite the loss of the Chronic Fatigue Syndrome Advisory Committee at the Department of Health and Human Services, which coordinated many of those early discussions, there are today a number of robust networks that cross disciplinary boundaries and are capable of initiating such conversations.


Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, converting to an aberrant and toxic metabolite, galactitol. Newborn screening and timely galactose-restricted diet can resolve acute symptoms and decrease fatalities. However, despite this, significant chronic, progressive morbidities remain which have a real impact upon daily life. To better understand the burden of disease, 20 in-depth qualitative interviews were undertaken with adult patients (n = 12), and their caregivers (n = 8), enrolled in the ACTION-Galactosemia trial, part of a clinical program designed to investigate the safety and efficacy of AT-007 (govorestat) in reducing toxic galactitol and long-term clinical outcomes in Classic Galactosemia.Interviews revealed the substantial burden of Classic Galactosemia on patients and families. Most adults were not able to live independently, and all required support with day-to-day activities. Short- and long-term memory difficulties and tremors were identified as the most frequently experienced and challenging symptoms. Other difficulties such as fine motor skills and slow/slurred speech contribute to the significant impact on daily activities, affecting ability to communicate and interact with others. Symptoms were first noticed in early childhood and worsened with age. Classic Galactosemia impacted all areas of daily functioning and quality of life, leading to social isolation, anxiety, anger/frustration and depression. This demonstrates the significant burden of disease and challenges associated with Classic Galactosemia.The impact on both patients and caregivers underscores the severity of the unmet medical need and the importance of pharmacological intervention to halt or prevent disease progression. Any treatment that could reduce symptoms or slow functional decline would ease the burden of this condition on patients and caregivers. GALT) gene mutation, and is the most common form of Galactosemia, occurring in 1/16,000 to 1/60,000 births worldwide  would ask a question with a normal 3–5 s turnaround, hers would be 10–15 s” Caregiver-03. During childhood this created challenges with learning and education, and in adulthood resulted in issues with key ADLs, functioning at work (if they were able to hold a job), and ultimately their ability to live independently. For example, one patient described the impact of his memory difficulties at work and how he would often ask people to repeat instructions, “[if] my boss tells me to do something in a specific order, and I might have to ask another time, like, once or twice, two more times at the most” Patient-07. This patient needed to rely on his boss to help him manage his short-term memory challenges. Other patients and caregivers also discussed patients needing support to deal with memory difficulties in their day-to-day lives, which was required by most patients. One patient also explained that his memory difficulties have impacts for his health, as he sometimes forgets to take his medication “I almost forgot to take the medication, and then I forgot to take the medication” Patient-11.Memory difficulties created many challenges for patients. Individuals experienced difficulties communicating, as they needed longer to process information in conversations and respond to questions, which impacted their interactions with others and ability to socialize. One caregiver explained that her daughter has a recall delay and requires additional time to answer questions ““I remember in school the kids would notice it [the tremor], and ask me about it… [as an adult] other people look at me funny, and uh, I don’t want that. I just explain to them that I have a tremor and they understand, but. So social, socially I think it has impacted me” Patient-05. As adults the tremors could be misinterpreted, with others thinking the individual was dealing with addiction  which heightened the social impacts and resulted in further emotional effects. This had a severe impact, as one patient highlighted when he explained: “if I could have a treatment that fixed one thing, I would want it to fix that [the tremor]” Patient-09.Tremors also led to an extensive burden on patients’ day-to-day lives, particularly with fine motor activities such as handwriting, which led to challenges during education and work as well as personal care such as brushing teeth. A wide range of activities were impacted, which affected the patient’s ability to live independently, and so tremors were felt to be important. Tremors also caused patients to stand out from others, which was felt as a child at school and as an adult when at work or socializing, as highlighted by one patient who explained: Ovarian failure, which was identified in female patients in puberty, resulted in considerable issues for these patients. During puberty this caused patients to stand out even more from their peers since they would not sexually mature and required hormone therapies. This was important to both patients and caregivers, since patients already stood out and had difficulties with social interactions, additional physically visible differences in appearance contributed additional burden. In addition, ovarian failure also resulted in infertility, which created an enormous emotional burden not only on the patients directly, but also upon the caregiver, who struggled not only with acceptance of a long-term progressive disease in their child, but also the loss of future grandchildren or generational continuity. For female patients, ovarian failure appeared to be one of the most important aspects of their Classic Galactosemia and had a substantial emotional impact often leading to feelings of depression and anxiety.As can be seen in the conceptual model, the impacts of Classic Galactosemia were substantial and upon all key aspects of HRQoL. Some impacts were more obviously related to specific symptoms, such as cognitive, speech and language, and motor impacts, and others were broader impacts affected by many or all symptoms together, such as physical, social, and emotional well-being. Classic Galactosemia was shown to limit ADLs, restrict ability to live and function independently, and impair overall HRQoL Fig. . Fig. 3F“He doesn’t really have friends in the sense that people have friends, you know” Caregiver-06. Caregivers highlighted that the types of social interactions expected of an individual the same age as the patient were not possible. This affected the patient’s ability to undertake day-to-day activities, function at school/work, and live independently, but also had an emotional impact: “I think part of that is me not really wanting to put myself out there because I do feel like I don’t fit in, so why would I want to go into this into situations where I'm inviting that” Patient-09. Although some patients can generally function on their own in terms of day-to-day activities and self-care, they may also feel isolated due to the social impacts of Classic Galactosemia.Although all patients discussed an impact on their ADLs, these were often managed by having a caregiver. Therefore, beyond this, the impact most frequently discussed was impacts related to social aspects of life, such as impacts on social interactions and relationships (n = 11/12 patients and 7/8 caregivers) that led to feelings of social isolation and were particularly important to patients as was reported to have a substantial impact on their day-to-day life. Patients and caregivers related difficulties with social interactions to Classic Galactosemia as a whole and to specific symptoms such as tremors and cognitive difficulties (such as short- and long-term memory difficulties and foggy brain) as well as slowed and slurred speech. For example, one caregiver of a non-verbal patient explained that he struggled interacting due to being non-verbal: “we did sign language in the beginning, you know, and by now, we as this family understand him, I understand him the best but most of the family can kind of understand him pretty well” Caregiver-06. For other patients their speech was extremely impacted to the point of being nonverbal. Across all levels, these speech problems had an impact on patients’ education, often requiring additional services such as speech therapy during school: “I just remember struggling so much in class and having to be pulled out to a different class, a different classroom setting to work on, you know, my wordings and my articulations of certain words like the letter R. And just, I remember not really understanding a lot in school” Patient-08. Difficulties with speaking and communicating were also linked to struggles with social interactions and feelings of isolation and frustration for patients since they could not easily be understood, and their difficulties impacted the way others perceived them. For example, 1 caregiver described: “I think, sometimes, when he speaks people have a tendency to not take him very seriously, because he has a difficult time communicating” Caregiver-07.Individuals also reported that Classic Galactosemia impacted their speech and language, which was associated with cognitive symptoms. Aspects of speech and language ranged from speech articulation (enunciation of words) to receptive and expressive language (ability to understand what is spoken to them and communicate thoughts). Difficulty speaking was described by n = 9/12 patients and 8/8 caregivers. Most patients and caregivers described difficulties with slowed speech and slowed speech response (receptive and expressive language), although many mentioned slurred speech (articulation). For some this can lead to challenges in communication that may require additional strategies, as one caregiver explained: Overall, most signs and symptoms of Classic Galactosemia were reported as first being noticed by the patients and caregivers in early childhood, except for ovarian failure which generally began around puberty for female patients. Although there is variation in the patient journey, typically, early symptoms were jaundice of the newborn, and growth issues. As the patient got older, other symptoms, such as tremor and cognition issues, were noticed. As time progressed these signs and symptoms typically appeared to worsen and had more of an impact on patients’ lives.Caregivers also discussed the services and evaluations used by patients during childhood and into adulthood. Services and evaluations frequently described as being used during childhood were speech and language therapy (discussed by n = 7/8 caregivers), occupational therapy (n = 5/8 caregivers), and services for learning differences (n = 5/8 caregivers). Other services each reported as being used were mental health services, physical therapy, and attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD) services. In comparison, the most frequent service described as being used by patients now (as an adult) were mental health services (n = 4/8 caregivers). Other services reported as currently being used during adulthood, each by only one caregiver, were: services for learning differences, physical therapy, ADD/ADHD services, vocational services, and life coach. It was also reported that most patients saw multiple specialists throughout their life; most frequently a geneticist and nutritionist/dietitian, each discussed by 7/8 caregivers. One caregiver also reported that her daughter saw a pediatric infertility specialist, and another caregiver explained that her son has seen a podiatrist because he needed aides to help with his walking due to his Classic Galactosemia.When looking at the identified signs, symptoms, and impacts experienced by patients overall there were no clear differences by gender . In addition, although the numbers were low there was no difference by genetic subtype or by GALT enzyme activity .The direct impact upon the patient was particularly evident for those who lived semi-independently in close proximity to family but did not have formal caregivers to support them in their day-to-day needs. Those with more severe symptoms not only lived with a caregiver but relied on the caregiver to perform functions that they struggled with or could no longer do, including ADLs. In these cases, a lot of the impact was felt on the caregiver. This highlights the substantial burden of Classic Galactosemia on patients’ lives and the impact this has on their ability to live independently. Classic Galactosemia thus had a wide-ranging impact upon both the patient and their family.“she’ll just… not think that she needs to go have a shower, or that sort of thing. It’s always been something that’s been… a slight issue. She’s always had to be encouraged to take care of her personal hygiene basically” Caregiver-10. Another stated: “he's not going to be able to drive or live independently, or go to college, or have a job” Caregvier-06. Most patients were unable to live independently and relied on a caregiver, a few were able to manage their symptoms and difficulties, with support, and were able to engage in work/some form of education program and live semi-independently. However, those living semi-independently still described the substantial support they needed from their caregiver or others to do this, and the fundamental difficulties Classic Galactosemia caused. For example, one caregiver explained that she still provides support for her son’s healthcare “I’m the one who took him [to doctor’s appointments]; finding the right health care resources, as he got to be an adult; because he doesn’t, well, he struggles with processing and how to find the right resources; so, as an adult, I had to help him navigate through the health care system” Caregiver-07.Patients and caregivers talked about the potential for, or current reality of, the impact of Classic Galactosemia on the patients’ ability to live independently. There are multiple ways that independent living was affected. For example, one caregiver explained her daughter needs reminders to take care of her personal hygiene because she will often forget Caregivers also highlighted the impact of caring for a child with Classic Galactosemia on their own lives, describing the fear and worry they experience related to the patients’ Classic Galactosemia and concern over who will provide support to the patient if they are no longer around to act as a caregiver. Caregivers also described the impact on their lives in terms of needing additional time and resources to support the patient. The most frequently discussed caregiver impacts were related to the emotional burden (n = 6/8) and the impact on the caregiver’s time and resources (n = 4/8) related to caring for someone with Classic Galactosemia.The findings from this analysis of qualitative data from patient and caregiver interviews revealed that Classic Galactosemia has a substantial impact on the lives of the patients, their caregivers and their families. This is depicted within the conceptual model that was developed to illustrate the lived experience of Classic Galactosemia, based upon the patient and caregiver voices in this study. Classic Galactosemia is associated with a high burden of disease consisting of symptoms spanning across emotional, social, motor, cognitive, physical, speech and language, and impacting core aspects of life such as education, work, social interactions and ADLs.In line with previous research, the current study identified tremors, cognitive impairments (difficulties with short- and long-term memory), ovarian failure, and difficulties with independent living as key symptoms and impacts of Classic Galactosemia , 11, 14.There was a range of experience and symptom severity for patients with Classic Galactosemia. Most patients interviewed were living at home with their caregiver and family, which is consistent with previous clinical literature . HoweverThe current study was undertaken with English speaking US-based White American patients only, which may limit representativeness of the findings. Thus, although significant cultural differences in the lived experience of Classic Galactosemia are not anticipated, it was not possible to confirm the absence of cultural differences. As participants were recruited though the Applied Therapeutics clinical trial the sample was restricted to those who engaged in that trial. All who had been or were currently enrolled in the trial were approached, and all except 1 participant took part, meaning that the interview sample was highly representative of the clinical trial population. Medical information on patients was not collected in this study. Therefore, it is not possible to confirm how the full range of severity of Classic Galactosemia is represented clinically. While genetic data indicate all patients in this study have a Q188R allele, with 8 patients homozygous, all subjects have GALT enzyme activity of 0.0 nmol/h/mg making potential differences in genetics less likely to impact the observed phenotype. Indeed, the qualitative data suggest that it is highly likely this interview study included patients representing the full spectrum of adult Classic Galactosemia severity. Future research should replicate this study with a larger, demographically diverse sample to confirm the current findings are representative comprehensively capture the full patient experience.The qualitative data from this study demonstrate the significant burden of disease and challenges associated with Classic Galactosemia across all core aspects of life. The impact on both patients and caregivers underscores the severity of the unmet medical need and the importance of pharmacological intervention.In-depth qualitative interviews were conducted with Classic Galactosemia patients, and their caregivers, who were currently taking part in/had completed the Part D Extension portion of the ACTION-Galactosemia clinical trial exploring the safety and pharmacokinetics of AT-007 (govorestat). All those taking part were invited for the interview.ACTION-Galactosemia clinical trial is a Phase 1–2 Dose-Escalating, 6-Part Study to Evaluate the Safety and Pharmacokinetics of Single and Multiple Doses of AT-007 (govorestat) in Healthy Adult Subjects and Adult Subjects with Classic Galactosemia (CG) or GALK-deficient Galactosemia. Part D and Part D Extension involved subjects who had a Classic Galactosemia diagnosis confirmed by evidence of absent or significantly decreased (< 1%) GALT activity in their red blood cells and by historical record of diagnosis of GALT deficiency , who have urine galactitol > 100 mmol/mol creatinine, and have no other significant health problems unrelated to Classic Galactosemia. To be eligible, patients also had to be male or non-pregnant, non-lactating female adults between the ages of 18 and 65 years. Patients were recruited for participation in the clinical trial via a selection of clinical sites across the US. No additional eligibility criteria were applied for this interview study other than a willingness to participate in the study and being sufficiently fluent in English to take part in an interview.Subjects in the clinical trial were entered into Part D Extension after approximately 1 month in the Part D treatment arm of the study (during which they received placebo or active drug) or they may have entered Part D Extension without participating in Part D. Part D Extension involved treatment or placebo for up to 3 months. Some subjects had completed Part D Extension over a year prior, or were no more than two months into participating in Part D Extension.Participants were recruited into this interview study by the clinical trial staff who shared information about the interviews and obtained informed consent. For patients and caregivers who provided consent, contact details were provided to Clinical Outcomes Solutions, an independent research company, who contacted the participants to schedule and conduct their interview. The interviews were conducted with participants either as they entered, during, or after completion of the Part D Extension.All interviews were conducted in the US using an online phone system due to the impact of coronavirus-19 (COVID-19). Interviews with patients and their caregivers were conducted separately. Interviews and analyses were conducted by trained qualitative researchers, independent from Applied Therapeutics and the clinical trial.A semi-structured discussion guide was used to explore the signs, symptoms, and impacts of Classic Galactosemia, to understand the burden of living with Classic Galactosemia for the patient, their caregivers and families, and to understand the impact on ability of the patient to live independently.Interviews began with some brief initial questions to establish rapport and open the conversation, followed by a series of questions to spontaneously identify signs, symptoms, and impacts, and then focused questions to explore topics of interest including probes to explore relevant issues not previously mentioned. Caregivers were also asked to provide some background information related to patients’ medical history and specific services and evaluations the patient may have used, to aid the understanding of the patient’s journey. Interviews lasted approximately 60 min and were conducted by trained qualitative researchers. All interviews were recorded and transcribed verbatim. No therapeutic interventions or treatments were administered as part of this study.All study documents for this study were approved by an independent review board as part of the main clinical trial documents. The study was conducted in compliance with Good Clinical Practice guidelines, including the International Conference on Harmonization Guidelines, and was consistent with the most recent version of the Declaration of Helsinki . All appTranscripts of the interviews were entered into NVivo 10 , a software package designed to facilitate the storage, coding, and analysis of qualitative data. They were coded using thematic analysis to identify any themes, patterns, or features of interest within the data.Saturation analysis was undertaken by dividing the study sample into 4 equal groups based on the chronological order in which they were interviewed. If a concept was discussed spontaneously or endorsed after probing, by at least 1 participant within a group, a check mark was added to the corresponding square. Saturation was considered met when no new themes or descriptions of concepts were identified in the final round of interviews.