Uterus transplantation combined with in vitro fertilisation (IVF)  as a treatment for infertility caused by an absence or malfunction of the uterus is advancing. About 50 transplantations have been conducted worldwide and at least 14 children have been born—9 of them by women taking part in a Swedish research project on UTx-IVF. The Swedish research protocol initially stated that the potential recipient must ‘have her own donor’ who is preferably related to the recipient. But what does it mean to ask someone for a uterus? What challenges does this question instigate? And what norms may it enact? In this article, I explore how 10 women—who have considered, and sometimes pursued, UTx-IVF—describe their experiences of searching for a donor. I aim to show how an analysis of such accounts can help us unpack some of the specific relational and gendered dimensions of UTx-IVF and by doing so enrich discussions of risks, benefits, care and support in UTx-IVF. Drawing on research in social sciences and medical humanities that has demonstrated how assisted reproductive technologies and organ donation can provoke social and familial conundrums, with respect to such topics as embodiment and identity, I present three patterns that describe different dimensions of the interviewees’ quest for a uterus donor. I discuss the negotiations that took place, how expectations unfolded and how entanglements were managed as the interviewees considered asking someone for a donation. Such an examination, I suggest, contributes to make care and support more attuned to the experiences and entanglements that UTx-IVF entails for those pursuing it. This will become increasingly important if (or when) UTx-IVF becomes part of general healthcare. To conclude, I problematise responsibilities and relational challenges in medical innovation, and in this way provide insights into how the ethical debate over UTx-IVF can broaden its scope. During the past 20 years, research in uterus transplantation has advanced rapidly. Since the late 1990s, Swedish researchers have systematically investigated the possibility of uterus transplantation combined with in vitro fertilisation (IVF) , at the forefront of endeavours to find a medical cure for uterine-factor infertility (UFI).In UTx-IVF, organ transplantation intersects with assisted reproductive technology (ART) as the procedure aims to enable gestational and—in cases so far—genetic motherhood. As such, it is—in contrast to several other forms of organ transplantation—not vital for the recipient but falls within the category of life-enhancing transplantations. Furthermore, UTx-IVF is temporary as the uterus will be removed after a determined period of time.In this article, I explore 10 Swedish women’s accounts of considering, and in some cases pursing, UTx-IVF. The Swedish research project on UTx-IVF initially involved live donorsTaking these questions as my starting point, I examine in particular how the interviewees describe their experiences of searching for a donor. By investigating the considerations and concerns that precede UTx-IVF from the perspectives of potential recipients, I aim to show how an analysis of live related uterus donation can help us unpack some of the specific relational and gendered dimensions of UTx-IVF. In doing so, I also seek to enrich discussions of risks, benefits, care and support in ethical debates, and the clinical settings of UTx-IVF.The advancements in UTx-IVF have initiated debates concerning live versus deceased donorsIn this article, I seek to contribute to filling a part of the persisting knowledge gap with respect to the experiences of women who are positioned as or who finds themselves to be ‘in need’ of a uterus. By analysing accounts of women considering UT-IVF, it contributes with perspectives from women who find themselves, or who are positioned as, being ‘in need’ of a uterus. As such, the article enriches our understanding of social expectations on motherhood and of gendered dimensions in UTx-IVFIn recent decades, ART and organ transplantation alike have become ordinary parts of healthcare. At the same time, these developments bring new questions about their potentially unsettling and far-reaching consequences, questions that are relevant also to UTx-IVF, as this form of transplantation specifically aims to enable the birth of a child.Feminist and anthropological scholars have analysed the ways in which ART renders visible, and at times challenges, beliefs about kinship, and how it enables new forms of reproductive choice, agency and new forms of female solidarity. They have, at the same time, demonstrated how ART on the one hand may foster new forms of domination, control and subordination—for example, through the trafficking in human organs and bodily services—and on the other hand may foster resistance.et al, be perceived as having an impact on the relationship by the recipient but go unnoticed or unrecognised in studies of donors’ perspectives.Similarly, live organ donation calls for relational negotiations as it involves a non-therapeutic, risky procedure being performed on a healthy individual (the donor), who—in addition—often has a close relationship with the recipient .et al state as they draw on Callon, ‘profoundly involved in kinship, mortality, bodily relations and immunological relations’.Focusing on the embeddedness of economic markets Michel Callon expands on the complex relationships in organ donation as he uses the case of postmortem organ transfer to describe the concepts of entanglement and disentanglement.between a donor—generally dead—and a recipient—generally in danger of death—when the organ is entangled in the body of a potential donor and through him in his family or circle of friends?Organ transfer requires, Callon argues, successful disentanglement. However, this is not easy. It requires, that the organ is ‘transformed into a good free of all attachments’, which—in turn—necessitates that the transfer takes the form of a gift that ‘reconciles circulation and entanglement’. In some contexts, Callon suggests with reference to the work of Fox and Swazey, concerted and systematic efforts have been made to disentangle organs by attempting to transform them ‘in something which makes them more like goods than gifts’. However, Callon continues, the more investments made to disentangle an organ from a donor, for example, by listing its relations of attachment, the ‘more the ties proliferate and multiply’.Much work in medical humanities and social sciences relatedly demonstrates the complexities of organ donation. And, as Scheper-HughesThe material analysed in this article consists of interviews with 10 women, 26–37 years of age, who had discovered in their teens that they did not have a uterus. Six of them took part in one interview. Out of the remaining four interviewees, three took part in three interviews and one of them took part in two interviews. These women were all being evaluated for transplantation at the time of the first interview or shortly thereafter. This gave me the opportunity to follow their transplantation journey for a longer period.The interviewees were all Swedish citizens and they all presented themselves as heterosexual. At the time of the interviews, some of the interviewees had only just started to consider transplantation; some were being evaluated for eligibility for transplantation, and some had undergone transplantation. All of them had considered the possibility of adopting and/or arranging for a surrogate mother abroad. In general, they described adoption as a time-consuming process fraught with uncertainties, while their descriptions of surrogate arrangements centred on the high cost. They also described the difficulties of ensuring that an arrangement would feel morally acceptable. These descriptions of alternative routes to parenthood need to be understood in light of Swedish regulations of surrogacy and adoption practices. Although surrogacy is not specifically regulated in Swedish law, it is in practice forbidden since only single women and couples who include a woman who can carry and give birth to an intended child can access fertility treatment.The interviewees were recruited in several ways: following distribution of advertisements in networks that I had previously established with women living with a congenital absence of the uterus and the vagina; through my professional website at the university; in social media; in networks of which women with UFI were members and by contacting directly women with UFI who had shared stories about their lives in traditional or social media. The advertisement stated that the aim of the project was to explore how UTx-IVF was experienced by women who had undergone or were considering UTx-IVF, their expectations on the procedure and their reflections on embodiment and the risks and emotions in relation to UTx-IVF. It also specified that I wanted to obtain women’s experiences and perspectives in their own words, and included information on what participation involved.The 10 women recruited were informed that they could end their participation at any time without having to explain their reasons for doing so; that collected data would be treated confidentially, and that documents with identifying information, such as consent forms, were to be kept in secure conditions at (information removed during review). They were also informed that they would receive a copy of any scientific publications, along with a summary of the same. They all gave their informed consent to participate. The interviews used a semi-structured interview-guide organised around overarching themes. The questions were open-ended and intended to enable the interviewees to describe their experiences and to provide a context that allowed a conversation to take place between me as the interviewer and the interviewee. Each of the interviews covered all of the themes in the interview guide, but since the interviewees were encouraged to tell their story the order of the questions differed. Furthermore, the specific questions were refined and reformulated in light of insights gained from the interviews.The interviews took place at a location chosen by the interviewee; two preferred to meet in my office, three in a private room at a public library and five in their homes. During the interviews, I asked the interviewees to describe what it was like to live with UFI, their experiences of and/or thoughts on UTx-IVF and their expectations for the future. In particular, I tried to facilitate the interviewees’ narrations of UTx-IVF in light of their embodied histories of living without uterus and vagina and the embodied dimensions of their relations to family and friends.When planning and conducting the interviews, I strived to stay reflexive and sensitive to how my position as a researcher—its situatedness and embodied particularities—always impacts the relationship between my interviewee and myself as a researcher.I conducted all interviews in Swedish and they were all audio-recorded. Qualitative research has underscored the importance of also considering the situatedness and interpretative elements of transcription.I subsequently used an inductive thematic approach to analyse the considerations and concerns that my interviewees described as preceding UTx-IVF.In the analysis, I identified three patterns that together formed an overarching storyline of the core considerations and entanglements at stake in the women’s search for a uterus donor. In my presentation of these patterns below all the quotations have been translated by me and all names have been replaced by pseudonyms.The research questions that guided the research project of which this article is part developed from my previous research on women’s experiences of living with a congenital absence of vagina and uterus.The fact that it was necessary to bring your own donor when looking to participate in the Swedish research project on UTx-IVF was well-known to most of the interviewees. Most of them had considered this requirement long before they actively began to investigate the possibility of having a transplantation. But whom do you ask for a donation? What must be considered?The first pattern formed around the ways in which the interviewees told of how they initially approached their mother in their search for a uterus. In most cases, the interviewees said that their mother stated that she would obviously donate, if medically allowed to. This pattern, I suggest, teased out relational expectations that play out when faced with the task of finding a uterus donor, and the challenges that arise when such expectations are not met.The second pattern detailed the interviewees’ consideration of whom to ask when one’s mother could not, or would not, donate. This pattern spelled out expectations on women’s life trajectories and reproductive bodies in general, and described anticipated relational contingencies. In this way, it demonstrated how the question of donation is not always confined to the one asking and the one being asked, but can become a concern that is distributed across the relational entanglements of the prospective recipients and donors.The third pattern concerned accounts that described what had happened when the quest for a donor came to an end in cases in which the mother could not or would not act as donor. It told of experiences of unexpectedly being offered a uterus and moving on to transplantation; of the potential donor not being medically accepted for donation and of not finding a donor. Specifically, this pattern detailed the ways in which the interviewees had continued to search for a donor, and ultimately how they had (or tried to) move on.Together, the three identified patterns form an overarching storyline of core considerations and entanglements at stake in the women’s quest for a uterus donor.I’d be happy to, why not? …]The quotation above, from Eva about her mother’s response when asked about donation, is typical: most of the interviewees told of how their mothers had stated that it was obvious to say ‘Yes’ when asked about donating their uterus. While the interviewees pondered on the risks, most of them said that their mother seemed sure that they wanted to donate, a pattern also seen among parents who are asked to donate a kidney.Because of course you think about that [the risks] too, about mom and all that. But mom was so sure about this the entire time. She just said: “I’ll do it, 100%. You don’t even have to think about it”, you know. She just said: “You don’t even have to think about my risks, because I’ve already thought about them, *you know*.Most of the interviewees also said that, despite the risks, it felt obvious for them to ask their mother. In many cases, they stressed that they had talked to their mother about the possibility of donation when they had found out that they did not have a uterus, and long before investigating transplantation. However, many also stressed that it did not feel important to obtain a uterus from their mother as such. One of them, Emma, had not seriously investigated the possibility of UTx-IVF when we met the first time, but saw it as a future possibility.Well, my mother said very early on that “I’ll do this”, you know. So I feel that I’ve always known that there is an alternative. But I don’t think… it’s not… If you think about it only in theory, I don’t think it matters that much. Because it is not something that you keep afterward. As I’ve understood it. They will take it out. When *you are done*, you know. So it feels more as a… as means for it to work out well, rather than a question of it feeling right.feeling right, but a matter of feasibility—of simply making it all ‘work out well’. For her, the knowledge of future disentanglement decreased the importance of who would become her donor. Her story suggested that this however might be something that she would consider more carefully if future disentanglement was not required. Furthermore, Emma stressed that since her mother had offered to donate early on, she had always known that this was an alternative. Hence, the proximity of a potential donor provided comfort and reassurance of a future in which her infertility could be managed.In order to transfer a uterus from one body to another it needs—to use Callon’s conceptualisation—to be physically disentangled from the body of the donor and then re-entangled in the body of the recipient. However, before the disentanglement of the uterus from the donor’s body can take place, it must have been agreed that the uterus will be disentangled a second time—from the body of the recipient. This ephemeralOccasionally, the question of a donation illuminated more explicit expectations on the mother-daughter relationship. Such expectations were most apparent in Melinda’s story of her mother’s response when approached with the question of donation. Melinda described how she had hoped that her mother would donate, but her mother had declared quite early on that she would not want to. It was at this point, Melinda emphasised, that ‘one of the greatest rifts between us started to grow’. Melinda felt, she explained, that her mother had not ‘taken on that “motherly” responsibility’ when Melinda was growing up.And when she said that [that she would not donate], then I realized that: “Shit, where is the love between child [sic]… and daughter?”. Because if I had had a child then I would have given a kidney, anything. You would do anything for your child.When her mother considered things like cosmetic results and menopause, Melinda felt ‘Well, she can’t have the right kind of love for her child”. Her mother’s response had fostered an embitterment in Melinda and even if her mother since then had asked for forgiveness and offered to donate, Melinda was still sure about her stance. ‘I don’t want anything from her!’ she underscored, adding that it would feel a lot better to have a uterus from a deceased donor. Melinda had been told to let go of that thought and to be grateful, but she was adamant; ‘I don’t want anything from her inside of me’.Indeed, the way in which Melinda described her own reaction to her mother’s response was an exception in my material. Interviewees in general stated that they understood any hesitation from their mother and emphasised that their mother had been more assertive about wanting to donate than the interviewee about receiving. Nevertheless, I find Melinda’s story to be important because it illustrates what failed expectations can lead to. In Melinda’s case, the mother-daughter relationship was expected to constitute a relational entanglement in which  disentanglement (from the uterus on her mother’s part) was taken for granted. When this expectation was not met, it resulted, as Melinda put it, in a ‘rift’ and an ‘embitterment’, which made a relational re-entanglement seem impossible and made a future physical entanglement through transplantation seem unthinkable.The ‘obviousness’ of mother-to-daughter donation that accounts in the first pattern expressed could, at first glance, be seen as shaped by two facts: that it was required that you bring your own, preferably related, donor when seeking to take part in the research on UTx-IVF in the Swedish context, and that your donor should have had successful pregnancies and not want any more children. In light of these requirements, which limited from the onset the recipients’ choices and options one’s mother may stand out as one’s primary donor candidate when searching for a donor in the Swedish context. However, several of the interviewees said that they had talked with their mothers about donation long before being aware of these requirements, which indicates that the obviousness of mother-to-daughter donation is not simply a matter of matching the requirements. While few of the interviewees explicitly elaborated on the reasons that mother-to-daughter donation is considered to be obvious, most of them did stress that it was not important, as such, to have their mother as a donor. Hence, the obviousness was not construed as a matter of maintaining bio-intimacy by keeping donation ‘in the family’, which Kroløkke and NebelingInstead, Emma’s and Melinda’s stories illustrate two other ways to understand the obviousness. In light of the ephemeral character of UTx-IVF, Emma’s story exemplifies how the obviousness can be construed as a matter of feasibility and proximity. It is possible that the knowledge that the organ is only temporary, and is not given to ensure survival but to enable gestational and genetic parenthood mitigates the concerns about anticipated contingencies with respect to embodiment, relationality and subjectivity that occur in other forms of organ donation.Similar to other reproductive transfers between related subjectsIt said that you were supposed to get the uterus from a relative and then you started thinking: “Okay, if it’s me, who will give me one?” and then: “Oh my god, are you supposed to ask… or are they supposed to offer?” or … you know: “What if you are putting their life at risk, those who donate their uterus?”. You know there were lots of those questions, I think. Lots of them.Ellen’s reflections above exemplify considerations of ‘whom’ and ‘how’ to ask for a donation that the interviewees emphasised as they told of their search for a donor. Central to these considerations was the idea that potential donors had to be ‘past the stage of having children’, which made the interviewees reluctant to ask sisters and friends who were about the same age as themselves. Mira, for example, explained that she had not told many friends about her condition since she was ashamed and she would, therefore, feel uncomfortable asking them. And it would be impossible to ask her sister:I can’t ask my sister, because she hasn’t started a family yet. She has to have the chance to do that first.They had not talked about this, Mira explained, but she had recently started to think about why her sister had not had children despite being in a stable relationship and having a permanent job. It feels as if she is waiting for me, Mira said. She continued:I can’t ask her to volunteer. Because then…I’ll deprive her of something.Mira’s reasoning showed how women of the same age as the interviewees were considered to be unapproachable as potential donors since donation would deprive them of the opportunity of pregnancy and a ‘normal’ life trajectory. In describing this ‘unapproachability’, the interviewees thus also drew on certain assumptions about the plans and desires of women of the same age when it comes to pregnancy and children. These assumptions, in turn, convey normative notions of how the life-course of young women is expected to be organised, making possible what Judith Halberstam calls a ‘reproductive temporality’Related to how they emphasised that certain persons would be unapproachable, the interviewees emphasised, although in some cases implicitly, the reproductive purpose of the uterus. Victoria, for example, explained that to her, ‘that that’s the only thing that it (the uterus) is made for: children’. Mira reflected on the perspective of potential donors:…it’s complicated to donate too, you can’t just…I think. But at the same time, I believe that many who could imagine themselves in this situation [of being in need of a uterus] would still think: “Well, you know, I don’t need it anymore, so why would I keep it? Then I might just as well donate it, if it’s possible”. That’s what I’d think, anyway. If there was a match with someone.and that the uterus loses its meaning when a woman has passed reproductive age. When you are past the stage of having children, you are ‘done with’ your uterus, and thus it is possible that it is taken for granted that you are a potential donor. This way of reasoning also echoes ideas of function found in the medical discourse on uterus donation, where it is argued, for example, that—in contrast to other forms of live organ donation—the uterus has ‘exhausted (its) function for the donor, and its loss does not alter any present or future physiological function’.The interviewees’ emphasis on the importance of considering the reproductive temporality of potential donors—by underscoring that donors had to be ‘past the stage’ of having children—illustrates, I suggest, expectations on the life trajectory of women in reproductive age. The interviewees’ accounts express assumptions about a desire for pregnancy and  children, While uterus donation through such discourses becomes positioned as a rather simple matter of giving away an organ no longer in use, the interviewees indicated at the same time that it might not be such a simple matter after all. This became apparent as they described their difficulties in asking for a donation and the difficulties of potential donors in responding to such a request. Anna mentioned both the physical risks for the donor and relational contingencies that could emerge from the question of donation. She had not, so far, found a uterus that she would ‘feel good about having’ and she had not had anyone tell her “Hi, you can have mine”. She explained that she did try to raise the question with one family member but, Anna noticed, ‘she wasn’t really ready to go through with it’. Anna had also asked her mother.And she [her mother] was OK with it, but then [a family member] started to influence me: “What if something happens?” and “Is it worth it?”, and then I felt guilty and…and then I told her: “No, I don’t want to go through with it”.Donation, this account illustrates, may not be obvious to everyone and the risks may be considered to outweigh the possible benefits. Furthermore, in showing how the question of donation became a concern that involved not only Anna and her mother but also other family members, it illustrates how the question of donation can become a concern that involves others with whom the interviewee is intimately entangled. The management of entanglements that the question of donation instigated was thus not confined to the recipient-donor relationship, but distributed across the intimate entanglements of which they were part.Like Anna, other interviewees emphasised that a uterus is not something that you are offered on a daily basis. Sara, for example, said that it is not ‘like you go around asking “Could you consider being my donor?”’ However, two close relatives had indeed offered to donate as soon as they found out that Sara was looking for a uterus. They both said, ‘Take mine!’, Sara recalled, but pointed out that: ‘That’s an easy thing to say’, and that one of them was ‘terrified’ of transplantation. As Sara’s mother had offered to donate at an early stage, Sara had never followed up on her relatives’ offer. Like Anna, Sara expressed concern about risks, although in her case she emphasised the relational risks more than the physical ones.But… because I don’t want her [her mother] to feel… guilty. And I don’t think she will, *because she is so fascinated by the whole thing*. What she is afraid of is that she will not be…approved. So that she’ll disappoint me. But she could never disappoint me! But I don’t think that she sees that, herself. And I can understand that, in a way.While Sara elsewhere made it quite clear that her mother had always expressed a willingness to donate, she indicates in this account that the offer was accompanied by certain relational riders, such as the risk of guilt and disappointment. Hence, the main issue was not what transplantation might do to the recipient’s or the donor’s body, but what a failed transplantation would do to the already established relational mother-daughter entanglement.Although the first pattern comprises accounts that positioned it as obvious and fairly uncomplicated to disentangle the uterus from the donor’s embodied self, the examples of the second pattern, I suggest, illustrate that physical risks for the donor as well as emotional risks—such as troublesome feelings of guilt and responsibility for the organ after transplantation—were taken into account when considering potential donors. While Anna’s account shows how these concerns were distributed and negotiated within the family, Sara’s account reveals a worry that feelings of guilt and disappointment would disrupt her relationship with her mother, and thus impede relational re-entanglement post-transplantation.The reproductive function of the uterus was often emphasised as the interviewees considered whom they felt it was possible to approach with the question of donation. Yet, as the interviewees described their deliberations, it became clear that not everyone for whom having children is no longer relevant is approachable. It might prove not to be easy to disentangle from the uterus, and some might find donation truly terrifying. To ask someone close to you for a uterus—be it your mother or someone else—requires considerations not only of the physical risks but also of the effect of donation on the already close relational entanglement between the one asking and the one being asked. As the very question of donation and the considerations that come with it may involve others with whom the one asking and the one being asked are entangled, the question of donation requires efforts to mitigate anticipated disruptions of established entanglements. Hence, it was—again—entanglements that preceded, rather than resulted from, donation that required management.I was told that “Yes, you could very well be a candidate [for UTx-IVF], but you do need to find… to have a donor”. So the clock was ticking for me. Really. It was very stressful. We had kind of explored all possibilities.Like Bella, in the account above, several of the interviewees expressed that a failure to find a donor had been, or would be, stressful. Some of those who had been actively looking for a donor had continued to search after failing to find one among their closest relatives. They frequently mentioned that they had hoped that there was a register for potential donors, or at least a way in which women prepared to donate could express their interest.Since UTx-IVF still only is performed as part of research in Sweden, structures available for other kinds of organ donation, such as donor registries, have not been established. At the same time, the fact that UTx-IVF was only performed as research might have allowed for flexibility with respect to the requirements. Bella, for example, who even had looked into the possibility of placing an advertisement in the newspaper in order to find a donor, was eventually approached by an acquaintance who volunteered to investigate the possibility of becoming her donor. Also Mira, who had been quite confident that one of her family members could become a donor, later found out that none of them would be accepted as donors for medical reasons. When Mira had been informed of this, she mentioned it to an older friend who immediately said that she was willing to investigate if she could become Mira’s donor. Mira recalled her friend emphasising:“And if it turns out that we match then, then I would like to donate”.L: Oh, what did you think about that?Mira: *Eee… what did I think…*L: Or felt?Mira: It, it… I think it was more like… “Really, do you know what you are getting yourself into?” Eee… And this… it is not… it is really not… it is really not just… it not a tiny thing, you know. Its… you’re not just giving some blood…but it is… you’re really taking something out from your body. But she’s been… all this time she’s been very aware of what it is that she has done. And, you know, have been reading up on everything. […] That’s what she said. “So I want to do this”. And that’s been quite nice for me, because I’ve never asked her. While mom…with her it’s been more…taken for granted that she would donate. […] Well she’s…she’s *a fairy godmother really*. Because if she hadn’t volunteered, I don’t know where I would have found someone.Bella’s and Mira’s stories demonstrate how access to transplantation, when it was required that one brings one’s own donor, became to some extent a matter of chance, but it still depended also on established relationships in which one felt comfortable enough to share one’s story. Both of them had happened to share their story with the right person at the right time, and their search for a donor thus resulted in unexpected entanglements involving a donor who was not a relative and for whom donation was not taken for granted. Mira’s story further demonstrated that in some cases it might be preferable to have another donor than your own mother. While there may very well be strong medical reasons for having your mother as a donor, on a relational level it may feel easier to be offered a uterus from someone who is not ‘taken for granted’ as a donor. Then, Mira indicated, you can feel more certain that it is something that the donor has considered carefully. By this, I do not suggest that a mother’s decision to donate a uterus to her daughter is never carefully thought through. Mira’s example, however, shows that being offered a uterus by someone not so close demonstrates that the obviousness of mother-to-daughter donation is not always easy. Hence, being offered a uterus from someone not as close may reduce the suspicion that the decision to donate had been a decision without reflection, rather than one that was well thought through.For some of the interviewees, the quest for a uterus came to an end for one of several possible reasons: it was not possible to enter the research project at the time, they decided to pursue another route to parenthood, or because they failed to find a donor. Emma, who—as part of the first pattern—emphasised that she had always assumed that her mother would be able to donate, eventually discovered that her mother would not be accepted as a donor because of her previous medical history.Emma: So we had to send them [the medical records] to them, just to check, basically. And we said that we do understand what this means, we can read it ourselves. But they confirmed it quite quickly. That it wouldn’t work. If you don’t have someone else who could consider donating. But…we haven’t, at the moment. So it ended pretty quickly too. At the same time as it was a bit drawn out.To find out that she could not have a donation from her mother was ‘as tough as hell’, Emma said, especially because her partner and she felt ‘that our premises were really good’. They thought, Emma said, that ‘this will work out fine, for sure, because we’re young and fertile and my mom is in good shape’.So it felt like: “We’ll fix this!”, perhaps. Or yes. But then I got really sad, when we found out. Or I’m still really sad, but now it’s like another phase, in a way. Back then, it was more the initial shock.Emma’s account describes the difficulty she had when she found out that the person she had taken for granted to become a donor would not be accepted. The realisation that transplantation was not an option, at least not at that time, took Emma back to square one and the feelings she had had as a teenager when she found out about her condition. She started therapy to try to deal with her experiences and once again figure out how to live without a uterus. While Emma did not describe the result of the failure to access transplantation as a disentanglement of her and her mother’s relationship, it did indeed disrupt an expected life trajectory and thus had an impact on her everyday life. The sorrow that she described suggests that support is needed to undergo the process of transplantation, and to manage the disruption to one’s expected trajectory that can occur when one is not accepted for transplantation.The resolutions that the third pattern highlighted did not necessarily involve transplantation and the birth of a child. Instead, the third pattern involved descriptions of different resolutions to the interviewees’ quest for a uterus donor. Bella’s and Mira’s stories told that when they had exhausted all alternatives to find a donor among closest family and friends, the search became a matter of whom they felt they could, or happened to, share their story with. However, it should be kept in mind that several interviewees were, for different reasons, still seeking resolution. Some of them had decided to actively pursue other routes to parenthood; others were still considering whether to continue to pursue UTx-IVF. Previous researchThe third pattern, thus, illustrated support in different ways. On the one hand, in demonstrating how finding a donor might become a matter of chance, Bella’s and Mira’s accounts showed how support could appear unexpectedly when sharing one’s story. It also showed how this support, in their cases, ultimately resolved their search for a donor. On the other hand, Emma’s account detailed the need for support not to find a donor but to deal with the realisation that there was no donor to be found. Hence, Emma’s account underscored the need for healthcare to offer support and care also for those who are not accepted for transplantation, who have not found resolution and when the lack of resolution brings struggles and pain from the time of diagnosis to life.In many respects, my analysis of the interviewees’ quest for a donor echo findings from previous research on the relational complexities and contingencies of live, related, organ donation. It shows that there is a risk of pressure and emotional burden on the donor and recipient alike,When discussing the obviousness of mother-to-daughter donation as it is expressed in the interviewees’ accounts, some particular aspects of UTx-IVF and the Swedish context must be kept in mind. As noted above, in the Swedish context UTx-IVF is only conducted as research. There is, at the moment, no donor registry, and a woman who wants to undergo UTx-IVF has had to bring a donor for whom the period of having children is over and to whom she is related.However, when considering the ‘obviousness’ of mother-to-daughter donation in more detail, it also becomes clear how it expresses expectations of what a mother ‘should’ be willing to do for her child and the relational conundrums that can arise when such expectations are not met. In the above analysis, this was brought out through an emphasis of the reproductive functionality of the uterus which positioned the uterus a container for carrying a child. That is, when the period of having children is over for a woman, it might be considered that she no longer needs or wants a uterus. The quest for a uterus can thus be seen to rely on norms about motherhood that signal expectations about responsibilities in the relational entanglement between mother and daughter, and on norms about female embodiment which signal that a person who has passed reproductive age no longer needs a uterus. The analytic patterns specifically revealed how these norms shape considerations of whom to ask for a donation, what response to expect when doing so, and contribute to position mother-to-daughter donation as ‘obvious’.By this, I do not mean to dismiss that many women might indeed feel that they do not need their uterus anymore and that it thus may be obvious for them to donate. Women might also want to volunteer for non-directed uterus donation if given the opportunity. A survey of Swedish women’s attitudes to ARTs, for example, demonstrated a preference for UTx-IVF over surrogacydo when discussing the ethics of UTx-IVF. By this, I do not mean that issues discussed in the ethical debate over such topics as risk-benefit, priority-setting and reproductive liberty should be set aside. Instead, I suggest that we can develop them further by taking into account participants’ experiences of risks and benefits and how they intertwine with societal and gendered norms and expectations, enacted for example through discourses that emphasise the reproductive functionality of the uterus. In this manner, ethical discussions can become more sensitive to how norms of motherhood and reproductive functionality—when expressed in ways that position uterus donation as obvious and the uterus as a body part that can be easily spared—shape how UTx-IVF is approached.The ‘obviousness’ of mother-to-daughter donation identified above can also be seen to obscure the many meanings and emotions connected to the uterus, expressed for example by those who are born without one, and who thus seek UTx-IVFFinally, my intention in this article has not been to argue for or against the development of UTx-IVF, but to—in line with Scheper-HughesIn the Swedish context, it remains to be decided whether this requirement will be maintained if (or when) the procedure comes to be offered as part of the general healthcare system, not solely in a research context. Likewise, international discussions of live versus deceased donation in UTx-IVF continue and the specific regulation of UTx-IVF, for example, with respect to the provision of donors, remains to be decided in several countries. Until such issues are resolved, the contingencies raised in the analysis above show that it is a matter of urgency to examine what the requirement of bringing your own donor entails in terms of creating stress for potential recipients, and how it contributes to disparities in access to transplantation. I suggest that by taking seriously the occurrence and anticipation of such relational conundrums and the management of entanglements that may proceed and follow donation the ethical debate on UTx-IVF can become more attuned to the experiences of those whom UTx-IVF is intended to help. In doing so, it can reach beyond discussions of  complications associated with the transplantation process


Aim: The purpose of this study was to determine the prevalence of healed plaque and its characteristics under optical coherence tomography (OCT) through a formal systematic review, meta-analysis, and meta-regression.Methods and Results: Thirteen studies were selected from MEDLINE, EMBASE, Cochrane, and online databases. The overall incidence of healed plaques was 40% (95% CI: 39–42), with 37% (95% CI: 35–39) in patients with acute coronary syndrome (ACS) and with 46% (95% CI: 43–49) in patients with stable angina pectoris (SAP). The incidence of healed plaque among culprit plaques  was nearly two times higher than that among non-culprit plaques . The incidence of thin cap fibroatheroma (TCFA), plaque rupture, microvessel, macrophage accumulation, and calcification was significantly higher in the healed plaque group. Meta-regression revealed an association between smoking (P = 0.033) and healed plaque rupture. Gender (P = 0.047) was independently associated with macrophage accumulation, and mean low-density lipoprotein cholesterol (LDL-C) was independently associated with microvessel.Conclusions: In summary, with a total incidence of 40%, the incidence of healed plaques under OCT was higher in SAP than in ACS, and higher in culprit plaques than in non-culprit plaques. Higher incidence of TCFA, plaque rupture, microvessel, macrophage accumulation, and calcification was found in the healed-plaque group. Smoking, gender, and mean LDL-C level were associated with healed-plaque characteristics. Healed plaque is a type of coronary atherosclerotic plaque that is characterized by infiltration with inflammatory cells, endothelial cells, and smooth muscle cells, and its formation may be associated with a stable lesion-contained thrombus. The newly synthesized type III collagen in the early healing stage, which is rich with proteoglycan and loosely aligned, is eventually replaced by type I collagen in the late healing stage. Therefore, most of the thrombotic substances in different stages have a layered structure after plaque rupture. Thus, the most prominent feature of healed plaques is a layered structure of organized thrombus and/or collagen –3.In terms of pathophysiology of the healed plaque, previous autopsy studies have shown a high incidence of healed plaques, ~61–73% in the culprit and non-culprit plaques . In addiOptical coherence tomography (OCT) is an intravascular imaging technique allowing a detailed view of the coronary artery wall structure. OCT can identify macrophages in atherosclerotic plaques, and its high resolution can detect thin cap fibroatheroma (TCFA), plaque rupture, and macrophage accumulation in most of the layered plaques , 9. HealHealing of an atherosclerotic plaque is a dynamic process that occurs after plaque rupture, which could prevent thrombus, promote plaque renovation, and restore vascular integrity. However, the clinical significance of plaque healing remains a controversial issue. Plaque healing may help atherosclerotic patients avoid ACS, but it can lead to chronic coronary syndrome . In addiWe conducted a systematic review, meta-analysis, and meta-regression to evaluate the prevalence of healed plaques and their characteristics under OCT observation.We carried out this study in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The protocol of this meta-analysis was registered at PROSPERO, International Prospective Register of Systematic Reviews [CRD42020186412], and this conformed with the meta-analysis of observational studies in epidemiology guidelines .Three independent researchers  searched MEDLINE, EMBASE, and Cochrane databases to identify potentially relevant studies from the inception of databases to Sep 20, 2021. The incorporating keywords including “healed,” “layered,” “healing,” and “healings” were searched and combined with headings from medical subject and Emtree including “Atherosclerotic Plaque,” “Optical Coherence Tomography,” and “Wound Healing” or “Healing” –3.in vivo OCT of coronary arteries conducted in clinical patients; (2) human studies including OCT examination and evaluating the characteristics of coronary plaques; (3) studies considering factors influencing healed plaque's morphology. The exclusion criteria were as follows: (1) duplicate reporting, conference abstract, or review; (2) studies that mentioned healed plaque but did not subgroup the data into healed plaque group and non-healed plaque group; (3) studies that could not explain factors influencing healed-plaque morphology.Three independent researchers  discussed the retrieved studies after reading their own title and/or abstract, with differences solved with consensus. The inclusion criteria were as follows: (1) Longitudinal, cross-sectional, and interventional studies reporting baseline data to assess characteristics of healed plaques were considered. Moreover, studies had to have been peer-reviewed and published in English to be included, and the assessment of the study quality was based on the Newcastle-Ottawa scale, as shown in Two independent researchers (FXX and GQY) reviewed the titles and abstracts of all studies independently. The full texts of all potentially qualifying articles were assessed. To extract relevant information from 13 included studies, a standardized form was used. Two independent researchers (FXX and GQY) evaluated the risk of bias for the finally included 13 studies in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Disagreements were resolved by discussion among the researchers until they reached accordance.I2 value was <50%. Otherwise, the random effects model was used. Original data were first converted by the double arcsine method to ensure their compliance with the normal distribution. The inverse variance method was used to calculate the pooled incidence of healed plaque and 95% CIs. Subgroup meta-analyses were conducted for categorical variables [classification of CAD (ACS v. SAP) and type of plaques (culprit vs. non-culprit)] (I2 ≥ 50%), subgroup analyses were performed to investigate potential moderators of the effect. As previously reported  < 0.05 was considered statistically significant. All data were analyzed using Stata/MP version 15  and Review Manager 5.3.Continuous variables were shown as mean ± standard deviation (SD). Values for categorical variables were listed as odds ratio (ORs) with 95% confidence interval (CI). The meta-analysis was implemented using the fixed-effects model when the ulprit)] , 19. Forreported , meta-rereported . P-valueA total of 369 potential studies were screened. Among them, 13 studies were identified for inclusion and further evaluation, and then two were excluded because they did not distinguish between healed and non-healed plaques. The complete process of identification and exclusion of studies is described in detail in the PRISMA flowchart . A totalI2 > 95%). On the one hand, the heterogeneity may have been driven by the variable estimation of healed-plaque morphology in the included studies and specific characteristics that introduced a degree of heterogeneity into the analysis. The specific definitions of each characteristic in healed plaque in every study are listed in To analyze the prevalence of healed plaques, we performed a single-arm meta-analysis. In the general population, the incidence of healed plaques was 40% (95% CI: 39–42). Stratified by the manifestations of disease, the incidence of healed plaques was 37% (95% CI: 35–39) in the patients with ACS and 46% (95% CI: 43–49) in patients with SAP. Moreover, at the level of plaques, the incidence of healed plaques among culprit plaques  was higher than that among non-culprit plaques  . HeterogA total of 13 studies reported the morphological differences between healed plaque and non-healed plaque. Potential sources of heterogeneity were explored by subgroup analysis through traditional classification, including the type of CAD (ACS vs. SAP) and the type of plaques (culprit vs. non-culprit) from the included studies.P < 0.05) was generally higher in the healed plaques, whereas the microvessel and calcification were higher only in culprit group. MLA was lower in healed plaques, but AS was higher than that in non-healed plaques only in the culprit group. Lesion length was also greater in healed plaques only in the culprit group. In the ACS and SAP subgroups, the incidence of TCFA was higher in healed plaques. MLA was lower in healed plaques, while AS showed the opposite trend , and gender  was associated with heterogeneity in macrophage accumulation (P = 0.047) (P = 0.034) (P > 0.05).In the meta-regression, we did not find the potential source of heterogeneity in the culprit or non-culprit data. Regarding the characteristics of healed plaque, we observed that in the entire population smoking was associated with heterogeneity in healed-plaque rupture (= 0.047) , 5. Rega= 0.034) . HoweverThe results of the funnel plot for characteristics of healed plaque are shown in To our knowledge, this is the first meta-analysis to evaluate OCT-based prevalence, describe the morphology, and explore the influencing factors of healed plaques. Our main findings were as follows: (1) The incidence of healed plaques in the overall population was 40%, with a higher incidence in SAP subgroup and at culprit sites. (2) Higher vascular fragility was reflected in higher incidence of TCFA and macrophage accumulation in healed plaques; the burden of healed plaques was heavier in patients with culprit plaques and ACS, as reflected in higher AS and longer lesion length. (3) Traditional cardiovascular risk factors including smoking, gender, and levels of LDL-C were associated with the characteristics of healed plaques.According to our analysis, the incidence of healed plaques was different between ACS and SAP subgroups. While Shimokado et al. reported that OCT detected healed plaques in 77% of SAP patients' target lesions , OkamotoCracked plaques are characterized by a thin fibrous cap, a large lipid-filled necrosis core, and persistent inflammation . The thiMacrophage accumulation was measured in 92.3% of the included studies, and it showed significant differences between healed plaque and non-healed plaque in the whole population, SAP group, and in culprit plaques. There is certain evidence that macrophages are a driving force in all stages of atherogenesis, from the earliest lesions to the formation of complex plaques ; moreoveIn the ACS and SAP subgroup analysis related to microvessel, higher heterogeneity was found in the SAP group. The mean level of LDL-C was related to heterogeneity in microvessel among SAP patients in meta-regression. On the basis of the microvessel formation, inward growth is a common feature during thrombus organization, and it is more common in healed plaques . ImportaIn the clinical therapeutic interventions, Kurihara et al. found that stents had limited dilation and more eccentric lumens in non-healed plaques after PCI in patients with ACS compared with healed plaques. Afterward, they found that the presence of healed plaques in culprit vessels was an independent predictor of revascularization rate during a 2-year follow-up , 27. In Our study obtained novel results by including the recent studies and correct data. Besides, we conducted subgroup and meta-regression analyses to explore the relationship between the characteristics of healed plaque and important clinical variables; meanwhile, we have listed the OCT images of the healed plaque and atherosclerotic patterns in The original contributions presented in the study are included in the article/XF, QG, and YZ developed the initial idea of this study. XF and QG conducted a comprehensive search of three databases and took responsibility for selecting the study and extracting data. XF analyzed the data and drafted the article. QG and YZ carefully examined this manuscript. All authors agreed with the ideas presented in the article and have made their contributions to research design, interpretation of results, and ideas for writing articles.This study was supported by grants from National Key Research and Development Program of China (2017YFC0908800), Beijing Municipal Health Commission (Grant Nos. PXM2020_026272_000002 and PXM2020_026272_000014), and Natural Science Foundation of Beijing, China (Grant No. 7212027) to YZ. QG was supported by Natural Science Foundation of Beijing, China (Grant No. 7214223).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Two types of MP were used: hypothermic MP (HMP) and normothermic MP (NMP). Three studies evaluated HMP, and 32 evaluated NMP. Independent of the system, MP resulted in clinical outcomes comparable to traditional SCS. However, NMP seemed especially beneficial for high-risk cases and donation after circulatory death (DCD) hearts. Based on currently available data, MP is non-inferior to standard SCS. Additionally, single-centre studies suggest that NMP could preserve the hearts from donors outside standard acceptability criteria and DCD hearts with comparable results to SCS. Finally, HMP is theoretically safer and simpler to use than NMP. If a machine malfunction or user error occurs, NMP, which perfuses a beating heart, would have a narrower margin of safety. However, further well-designed studies need to be conducted to draw clear conclusions.Currently, static cold storage (SCS) of hearts from donations after brainstem death remains the standard clinically. However, machine perfusion (MP) is considered an approach for donor organ management to extend the donor pool and/or increase the utilization rate. This review summarizes and critically assesses the available clinical data on MP in heart transplantation. We searched Medline (PubMed), Cochrane, Embase, and  Heart transplantation is the most effective method used to treat end-stage heart disease. Currently, static cold storage (SCS) of hearts from donations after brainstem death (DBD) remains the standard practice. SCS combines cardioplegia and hypothermia, which can significantly reduce the energy demand of the donor heart . HoweverMachine perfusion (MP) is considered an ideal approach for donor organ management to extend the donor pool and/or increase the utilization rate. Perfusion can supply the metabolic need of the myocardium, thus minimizing irreversible ischemic cell injury and death. Several heart perfusion systems, which are either hypothermic MP (HMP) or normothermic MP (NMP), have successfully preserved animal and/or human hearts . The lonWell-designed machine perfusion can theoretically expand the donor pool in different ways. A prolonged safe preservation time allows to utilize remote donor hearts and functional assessment allows to utilize some of the DCD and high-risk donor hearts. Pediatric heart transplantation may have an extra benefit since pediatric donor shortage is even worse, and long transport time occurs more frequently.Despite the growing number of human donor hearts preserved with MP, it remains controversial whether MP is superior to SCS. In this systematic review, we summarize and critically assess all available clinical data on MP of adult donor hearts, highlighting its therapeutic potential as well as the current limitations and shortcomings.ex vivo perfusion, ex vivo reperfusion, heart perfusion, cardiac perfusion, non-ischemic heart preservation, perfusion preservation, antegrade perfusion, and machine perfusion. Ongoing clinical trials were searched in clinicaltrials.gov using the term of heart transplantation for condition or disease in combination with preservation or perfusion for other terms. Only original publications in English were considered. All questions regarding the literature search and article selection were resolved by discussion between two independent reviewers. All references listed in the selected articles were screened for any further publications that were not identified in the initial search.This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The literature search consisted of two parts: searching for published studies and searching for ongoing clinical trials (inception to 27 June 2020). Published studies were searched in the Medline (PubMed), Cochrane, and Embase databases. The following searching terms were used in combination with AND or OR: heart transplantation, organ perfusion, Articles reporting the outcome of MP in donor hearts during primary adult heart transplantation were included. Reports that met any of the following criteria were excluded: 1) irrelevant topics, 2) duplicated data, 3) non-English language, 4) not transplanted, 5) not human, 6) pediatric, or 7) reviews, editorials, and letters to the editor.The initial search yielded 3,446 potentially relevant records. 2O. All four hearts were transplanted after a total preservation time of 6, 7, 12, or 15 h. Only one patient survived after 16 months with normal heart function  and a higher cost  compared with the OCS recipient . In nineThe OCS was used for DCD hearts in 11 studies  17–20, , 36–39. Five clinical trials are currently recruiting patients  41–45).–45.41–45Despite encouraging results, considerable challenges still need to be overcome before sound conclusions can be drawn regarding MP for heart preservation. Existing literature in this field is limited. Most of the studies were non-randomized and retrospective, and half of the publications were conference abstracts. The total number of transplantations using MP was low, especially for HMP. A clear advantage of MP has not been observed in randomized controlled studies. Although NMP has shown its superiority in high-risk cases in non-randomized single-centre studies, high-quality clinical trials still need to be conducted.in situ  , 7. MoreA challenge emerged during literature collection because the same data on MP transplantation has been used repeatedly in different conference abstracts and papers. Such examples can be found in publications from the groups of Rojas S., et al, Nilsson J., et al, Yeter R., et al, Chew, H., et al and García Sáez, D., et al. When the same data have been used in a series of publications, we included only the latest the publications and when only part of the data has been used with different study design, we included all these publications to avoid missing data , 33. ConIn summary, the machine perfusion in the form of either HMP or NMP, has emerged a potentially beneficial method for heart preservation. Based on the currently available data, when preserving a regular human donor heart, MP seems to yield clinical outcomes comparable to traditional SCS. However, HMP seems especially beneficial for high-risk cases and DCD hearts. Compared to NMP, HMP seems to be less complex, which may make it more feasible and safer, and this is an excellent advantage for the transportation of donor hearts. In future studies, we believe it’s important address the efficiency of MP for donor hearts with isolated risk factors, such as prolonged preservation time, hearts from higher age donors, or low ejection fraction. Additionally, it is also essential to develop an ideal perfusion medium for different types of MP and a system for pediatric transplantation considering the more significant donor shortage.


Spinal cerebrospinal fluid (CSF) leakage is frequently encountered clinically after lumbar puncture or spontaneous events. Although some patients recover without treatment or after intensive hydration, some require an epidural blood patch (EBP). The risks of nonresponsive hydration remain unknown. Therefore, we identified the risk factors for patients with spinal CSF leakage nonresponsive to hydration.We retrospectively reviewed patients diagnosed with spinal CSF leakage between January 2010 and March 2021. Clinical data, including patient age, sex, etiology, and radiological indications in magnetic resonance imaging, were compared between patients who were responsive and non-responsive to hydration.P = 0.01), had a higher percentage of spontaneous intracranial hypotension , had more spinal CSF leakage , and had a higher percentage of dural sinus engorgement . Spontaneous intracranial hypotension  and having ≥9 spinal CSF leakages , as indicated by magnetic resonance myelography, are considered risk factors for noneffective hydration.Of the 74 patients with spinal CSF leakage, 25 were responsive to hydration and 49 required EBP. Patients who were nonresponsive to hydration were older (39.27 vs. 34.32 years, Patients with spinal CSF leakage who have spontaneous intracranial hypotension and those with ≥9 spinal CSF leakages are considered at risk for noneffective hydration. EBP should be considered early in these patients. Spinal cerebrospinal fluid (CSF) leakage is usually encountered in clinical settings. The major etiologies include post-dural puncture headache (PDPH) or a spontaneous event , 2, withThe possibility of spinal CSF leakage must be carefully excluded in patients with orthostatic headaches. A definitive diagnosis relies on standard radiological findings; definitive CSF leakage can be determined using spinal magnetic resonance myelography (MRM) –8 to indAlthough patients can spontaneously recover after bed rest, SDH with brain herniation or sinus thrombosis , 15 are In this study, we identified the risk factors for patients with spinal CSF leakage who were nonresponsive to hydration.. Patients who were referred for MRI studies due to orthostatic headache and were diagnosed with spinal CSF leakage between January 2010 and March 2021 were recruited to our study. Their etiologies include PDPH and spontaneous intracranial hypotension (SIH). During hospitalization, the patients received intravenous fluid hydration at 3 L per day for three consecutive days. Targeted EBP was administered if the patients were nonresponsive to hydration . Due to the retrospective design, the need for informed consent was waived by the Institutional Review Board of Taichung Veterans General Hospital140B. DueThe etiology, age at symptom onset, sex, headache score measurement using the visual analogue scale upon presentation, duration between symptom onset and MRI examination , and hospitalization duration were collected from medical records for analysis.3, matrix size = 320 × 320 px, and field of view = 200 mm. Fat suppression was employed, and generalized auto-calibrating partially parallel acquisition imaging reconstruction with an acceleration factor of 2 was used. Images were acquired volumetrically in the coronal plane of the cervical-to-thoracic and thoracic-to-lumbar regions of the spine parallel to the spinal curve with some overlapping.A 1.5-T MRI scanner  was used. All patients received whole-spine MRM and spine and conventional brain MRI simultaneously upon presentation. Conventional brain MRI included axial spin-echo T1WI (repetition time (TR)/ echo time (TE), 500/10), axial fast spin-echo T2-weighted images (TR/TE 3200/115), and Gd-enhanced spin-echo T1WI images in the axial, sagittal, and coronal planes. Three-dimensional volumetric interpolated breath-hold examination and Gd-enhanced T1WI focusing on C-T spine level were also obtained to determine if spinal epidural venous engorgement was present. Whole-spine MRM was performed with 3-dimensional sampling perfection and optimized contrast using variable flip-angle evolution (3D-SPACE) sequences. The MRM parameters were as follows: TR = 3000 ms, TE = 560 ms, isotropic voxel size = 0.9 mmQualitative brain MRI parameters were evaluated. Pituitary hyperemia was defined as the convex shape of the pituitary gland. Venous engorgement appeared as a convex upper surface of the sinus confluence on the midline of the sagittal view of post-contrast T1WI. Diffuse pachymeningeal enhancement was defined as the presence of continually enhanced dura matter. The presence or absence of SDH was also recorded.The number of abnormal spinal CSF signals along each spinal neural sleeve on MRM was recorded as the number of spinal CSF leakages. For example, if abnormal spinal CSF signals were present on MRM at both C2–3 and C3–4, the number of CSF leakages was four. Spinal epidural fluid accumulation was defined by the number of vertebral bodies where the abnormal epidural fluid was on MRM. All imaging findings were interpreted by an experienced neuroradiologist (H.C. Chen).Patients were classified into two groups based on response to treatment. Patients who could not tolerate their clinical symptoms after hydration and who underwent target EBP were defined as having noneffective hydration. Patients who could tolerate their clinical symptoms and did not have symptom recurrence within 1 month were defined as having hydration effectiveness.P < 0.05 were included in a multivariable logistic regression using the forward method. All tests were two-tailed, with statistical significance defined at P < 0.05.All data were analyzed using SPSS software . Demographic data and MRI indications were compared between the hydration-effective and hydration-noneffective groups. Kolmogorov–Smirnov tests were used to verify whether the continuous variables were normally distributed. Age, headache scores, onset-diagnosis interval, number of spinal CSF leakages, and levels of spinal epidural fluid accumulation were not normally distributed and were, therefore, analyzed with nonparametric Mann–Whitney tests. Fisher’s exact test and the chi-square test were used for nominal variables. We used the receiver operating characteristic (ROC) curve to calculate the threshold for the number of CSF leakages. The risk factors for noneffective hydration were analyzed using univariate logistic regression, quantified as odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Those factors with From January 2010 to March 2021, 74 patients were diagnosed using MRM due to at least one spinal CSF leak. At total of 25 patients (33.78%) recovered after hydration without further EBP. The other 49 patients (66.22%) could not tolerate their symptoms and underwent EBP treatment.No considerable difference was observed with respect to sex, headache score, and onset–diagnosis interval between the hydration-effective and hydration-noneffective groups. Compared with the hydration-noneffective groups, the hydration-effective groups were younger and had a higher percentage of PDPH relative to SIH Table .Table 1DSubstantially greater numbers of spinal CSF leakage in the MRM and percentage of dural sinus engorgement were found in the hydration-noneffective group Table . The cutThe multivariable analysis results for the risk factors for hydration non-effectiveness are summarized in Table Because SIH is a risk factor for noneffective hydration, we further evaluated the parameters in patients with SIH Table . No subsA 22-year-old woman was admitted for posterior mediastinal schwannoma surgery. Four days after surgery, the patient complained of an orthostatic headache with nausea and vomiting. Anesthesia-related spinal CSF leakage was suspected. The MRI and MRM images showed CSF leakage into the left C5-T1 neural sleeves Fig. a with poIn this study, we determined that patients with SIH and those who have ≥9 spinal CSF leakages on MRM are at risk of hydration non-effectiveness. These patients also had longer hospitalizations.The mean numbers of spinal CSF leakages for patients with PDPH and SIH in our study were 6.54 and 11.41, respectively. No statistically significant differences between these two groups and the number of leakages have been reported in the literature , 19. TheAccording to the literature on post-lumbar puncture CSF leakage, not all patients are symptomatic or have clinically relevant symptoms . PatientIn patients with SIH, EBP is commonly required for treatment . AlthougNotably, the levels of epidural fluid accumulation were not considerably different between the two groups. In our study, nearly all patients had posterior epidural fluid accumulation. Patients usually remained in the supine position, and the extravasated CSF extended to the surrounding epidural space along the potential epidural space. Compared with the levels of abnormal epidural fluid accumulation, the number of spinal CSF leakages at neural sleeves may reflect disease severity more accurately. The supposition that anterior, compared with posterior, epidural fluid accumulation may more accurately reflect the severity of spinal CSF leakage has also been reported in the literature .In terms of treatment efficacy assessment, this study evaluated the effectiveness of hydration using symptom improvement. Although symptom improvement is subjective, it is commonly used to clinically evaluate hydration efficacy , 24. In Our study had several limitations. First, we used the treatment effect as the endpoint for patients receiving EBP. Patients may be sensitive to headaches and have different expectations regarding the treatment effect. Therefore, the clinical response and decision to receive further EBP may be subjective. Second, although PDPH is an independent factor predicting responsiveness to hydration treatment, further subgroup analysis focusing on PDPH patients was not performed due to the small sample size. The incidence of post-dural puncture CSF leakage is not as low as that of SIH, but patients with this condition are usually not referred to imaging studies due to good response to treatment or even spontaneous recovery. Studies with a prospective design that recruited larger sample sizes with scheduled imaging assessments may provide clearer findings.The number of spinal CSF leakages indicated on MRM is an efficient predictor of the effectiveness of hydration in patients with spinal CSF leakage. Patients with risk factors can receive EBP earlier to shorten the disease course and hospitalization.


Blood biomarkers represent a major advance for improving the management, diagnosis, and monitoring of Alzheimer's disease (AD). However, their context of use in relation to routine cerebrospinal fluid (CSF) analysis for the quantification of amyloid peptides and tau proteins remains to be determined.We studied in two independent cohorts, the performance of blood biomarkers in detecting “nonpathological” (A−/T−/N−), amyloid (A+) or neurodegenerative (T+ /N+) CSF profiles.1–42/Aβ1–40 ratio and phosphorylated tau (p-tau(181)) were independent and complementary predictors of the different CSF profile and in particular of the nonpathological (A−/T−/N−) profile with a sensitivity and specificity close to 85%. These performances and the corresponding biomarker thresholds were significantly different from those related to AD detection.Plasma AβThe use of blood biomarkers to identify patients who may benefit from secondary CSF testing represents an attractive stratification strategy in the clinical management of patients visiting memory clinics. This could reduce the need for lumbar puncture and foreshadow the use of blood testing on larger populations.The online version contains supplementary material available at 10.1007/s00702-022-02474-9. Detection of Alzheimer's disease (AD) with high sensitivity and specificity is key for the management of patients. Diagnosis can include detection of amyloid and tau biomarkers in the cerebrospinal fluid (CSF), which is one of international guidelines’ criteria  that has not yet been directly addressed is in relation to CSF testing performed in a routine clinical setting. The question is whether blood biomarkers can be used to decide the need for further CSF analysis. Thus, the objective here is to evaluate the performance of blood biomarkers in detecting a “nonpathological” (A−/T−/N−) CSF profile, rather than a specific pathological profile as seen in AD or brain injury. Note that the notion of “nonpathological” does not refer here to the globality of the CSF analysis which includes many other biochemical, immunological or microbiological analyses, but is restricted to the results of the amyloid and tau biomarkers. The results of this study suggest that blood markers can predict the presence of nonpathological CSF profile and could thus be decisive in whether or not to perform a LP.The Barcelona cohort included 150 participants from the Sant Pau Initiative on Neurodegeneration (SPIN cohort) ] were measured using Fujirebio Lumipulse or Innotest assay as described  above the cutoff and values of tau (N) and p-tau(181) (T) below the pathological cutoffs. We also identified amyloid (A+/A−) and tau-neurodegeneration (N+T+/N−T−) CSF profiles.CSF Aβ1–42 and Aβ1–40: “Neurology 3-Plex A”  and “Neurology 4-plex E Advantage kit”  in the Simoa platform (Quanterix) and an IP-MS approach from Shimadzu . The accuracy of the blood-based assays to discriminate nonpathological amyloid and tau CSF profile was evaluated using receiver operating characteristic (ROC) curve analysis and calculation, using the area under the curve (AUC) as a measure of diagnostic accuracy. Comparison of ROC curves to test the statistical significance between assay values derived from the method of DeLong et al.  for the 1–40 and Aβ1–42, individually, show variable but low accuracy for nonpathological profiles detection .We first tested the performance (AUC) of blood biomarkers to distinguish a nonpathological (A−/T−/N−) from a pathological CSF profile represented by the other A/T/N situations Table . Plasma 1–42 and total tau (p < 0.05) in Montpellier cohort. In Barcelona cohort, AUCs obtained for p-tau(181), Aβ1–42(Q3) and Aβ1–42(IP-MS) were similar (Table p = 0.022).To assess the value of combining biomarkers, we first tested the correlation between the different factors and observed that Aβ1–42, Aβ1–40, Aβ1–42/Aβ1–40 on the one hand, and tau, p-tau(181) on the other hand, were correlated together . We therefore selected as independent variable Aβ1–42/Aβ1–40 and p-tau(181)  that had the best AUCs. Combining biomarkers requires a stepwise approach , p-tau(181) and logistic regression combining these three parameters were very close and pairwise comparison of the different AUCs was significant only in Montpellier cohort between Aβ1–42/Aβ1–40 and logistic regression (Supp Table 3).In both cohorts, plasma levels of total tau were comparable between nonpathological and pathological CSF profiles, while elevated plasma p-tau181) was associated with a pathological CSF profile (Supp Table 1). Plasma p-tau(181) showed an AUC of 0.865 in Montpellier and 0.773 in Barcelona to discriminate a nonpathological (A−/T−/N−) CSF profile (Table 81 was as1–42/Aβ1–40 (measured with Quanterix Q3). However, the AUC of logistic regression was higher than that of p-tau(181) alone (p = 0.002). In this cohort, the highest Youden index was obtained when performing the logistic regression, reaching a sensitivity of 85.0% and a specificity of 86.7% for the detection of nonpathological amyloid and tau CSF profiles.The highest Youden index in this context was obtained when performing the logistic regression, reaching a sensitivity of 85.2% and a specificity of 83.6% for the detection of nonpathological amyloid and tau CSF profiles. In the Barcelona cohort Table B, pairwi1–42/Aβ1–40 ratio was comparatively lower, especially for the T+/N+ profile.We also studied the performance of biomarkers to identify two specific pathological situations with amyloid , amyloid (A+) or neurodegenerative (T+/N+) CSF profiles. The main interest of the detection of a nonpathological (A−/T−/N−) profile lies in the fact that this information can be taken into account in the decision to perform a LP or not. Using different analytical approaches and in two independent cohorts, we show that plasma p-tau181) and Aβ81 and Aβes Table , but herWith performances close to 85% sensitivity and specificity for the detection of nonpathological (A−/T−/N−) CSF profiles, one can really consider the results of blood biomarkers, which would then condition the subsequent need for a LP. Importantly, the biomarker cutoff decision points will likely be different than for AD detection. Such an approach could help clinicians in the decision to add other diagnostic tests (such as imaging), depending on the clinical evaluation of the patient. Depending on the prevalence of AD as well as that of other diseases modifying CSF amyloid and tau concentrations in a cohort, the reduction in the need for LP could be well over 50%, significantly reducing the cost of management of these patients and limiting invasive and unnecessary medical procedures. In conclusion, blood amyloid and tau biomarkers perform well in detecting nonpathological amyloid and tau CSF patterns. The importance and value of this “prediction” are linked to the exclusion of pathologies that vary these biomarkers (AD but not only) and to the decision to perform a LP or not. Blood biomarkers can therefore represent the first step in the patient's management strategy, to determine whether or not other diagnostic examinations by more invasive or more expensive means are necessary.Supplementary file1 (DOCX 28 kb)Below is the link to the electronic supplementary material.


We assess 43.3% of patients with GOS 2-1 and only 27.5% of patients with GOS 5-3 with low values of the coefficient of energy balance (KEB < 15.0) in days 0–3 after the hemorrhage as a trend to immediate intensive inflammation in the CNS of patients with poor outcomes. We consider significantly higher concentration of total protein of patients with GOS 2-1 in days 0–3 after hemorrhage (p = 0.008) as the evidence of immediate simultaneously manifested intensive inflammation, swelling of the brain and elevation of intracranial pressure.Extravasation of blood in the central nervous system (CNS) represents a very strong damaged associated molecular patterns (DAMP) which is followed by rapid inflammation and can participate in worse outcome of patients. We analyzed cerebrospinal fluid (CSF) from 139 patients after the CNS hemorrhage. We compared 109 survivors (Glasgow Outcome Score (GOS) 5-3) and 30 patients with poor outcomes (GOS 2-1). Statistical evaluations were performed using the Wilcoxon signed-rank test and the Mann–Whitney U test. Almost the same numbers of erythrocytes in both subgroups appeared in days 0–3 ( Hemorrhage in the central nervous system (CNS) is associated with a high risk of severe impairment of CNS or even the death ,2,3. DesHemorrhage in the CNS induces a local inflammatory response. Dumont et al. refer inflammation in response to subarachnoid blood as a plausible candidate pathway leading to cerebral vasospasm . Wang reOur previous effort was to detect predominantly purulent inflammatory complications of bacterial origin in the CNS after hemorrhage using basic analysis of the CSF . This reThe typical presentation of hemorrhage occurring within the CSF are erythrophages with freshly phagocytosed or decolored erythrocytes, siderophages and hematoidin crystals ,17,18,19The presence and composition of immunocompetent cells in the CSF was evaluated in our study. The presence of lymphocytes and monocytes is usually indicating slight serous inflammation which is typical for the posthemorrhagic clean-up reaction. The predominant presence of innate immunity cells, such as neutrophils, is indicating the inflammatory reaction to adverse consequences of hemorrhage within the CNS, especially vasospasms, re-bleeding and bacterial neuroinvasion ,18,19,20We used parameters of basic biochemical analysis of the CSF. These are concentrations of total protein, energy parameters and a measurement of catalytic activities of aspartate aminotransferase (AST) in the CSF ,21,22,23Concentration of the total protein in the CSF usually correlates with permeability of the blood-cerebrospinal fluid barrier. Nevertheless, high concentrations of the total protein in the CSF of patients after the CNS hemorrhage is very often influenced by impairment of the CSF circulation ,24.The AST catalytic activity in the CSF is reliable and easily accessible parameter of the CNS tissue injury .−1).[glucose] = molar concentration of glucose in the CSF (mMol·L−1).[lactate] = molar concentration of lactate in the CSF  are typical for very intensive inflammation with oxidative burst of professional phagocytes (neutrophils and macrophages) and ROS production–e.g., in the case of purulent inflammation ,37.We selected 139 patients with two analyses of their CSF in this retrospective study. The first analysis was done in between the 0 to 3 day and the second one in between the 7th to 10th day after the CNS hemorrhage. On days 0–3 the perioperative collections of the CSF were completed with the purpose of cranial decompression, improvement of surgical conditions and gaining of input information about the CSF compartment. All takings were made using lumbar puncture or drainage.The patients were clinically evaluated during hospital discharge using the Glasgow Outcome Score (GOS). We divided these patients into two subgroups—109 survivors (GOS 5-3) and 30 patients with poor outcome (GOS 2-1) .Furthermore, we present CSF findings in two considerably different control groups of patients—500 patients with normal CSF findings and 109 patients with purulent inflammation in the CNS.g) and the concentrations of total protein, glucose, lactate and AST catalytic activities were determined. The rest of the supernatant was temporarily stored in refrigerator at +4 °C to +8 °C for potential future analysis.CSF samples were repetitively obtained via external CSF drainage into a test tube without anticoagulation agents and immediately transported for laboratory examination. Immediately after receiving the sample, we evaluated the cell count and permanent cytological smear developed using a cyto-centrifuge method was made. Another part of the sample was centrifuged . Olympus BX40 microscope  was used.We analyzed molar concentrations of glucose in the CSF using the hexokinase method, molar concentrations of lactate in the CSF using the lactate–oxidase and peroxidase, mass concentrations of total protein in the CSF using the turbidimetric method with benzetonium chloride and catalytic activities of AST in the CSF using the IFCC  method with a Cobas 6000 analyzer . We calculated the KEB for each case ,37.p values < 0.05 were considered as significant.Concentrations of total protein, glucose and lactate, KEB values, numbers of nucleated cells and erythrocytes, the percentage of neutrophils and AST catalytic activities in the CSF are presented in Immediately after the CNS hemorrhage the numbers of erythrocytes in the CSF were almost the same in survivors and patients with poor outcome. Significant differences between these subgroups were apparent in days 7–10. While number of erythrocytes in the CSF of survivors significantly decreased, their number in patients with poor outcome was insignificantly higher .The increase in the number of leukocytes in the CSF on days 0–3 and on days 7–10 after the CNS hemorrhage in both subgroups of patients was approximately the same. It is significant in survivors and insignificant in patients with poor outcome .Relative count of neutrophils in the CSF of both subgroups of patients on days 0–3 and 7–10 after the CNS hemorrhage were approximately the same .The elevation of total protein in the CSF immediately after the CNS hemorrhage was significantly higher in patients with poor outcome compared to survivors. On days 7–10 their values were approximately the same. The decrease of concentrations of total protein in the CSF during this time was significant in both subgroups of patients .Significantly higher concentrations of glucose in the CSF were found in patients with poor outcome compared to survivors on days 0–3 and 7–10 after the CNS hemorrhage. They significantly decreased in time in both subgroups of our patients .Immediately after the CNS hemorrhage the concentrations of lactate in the CSF were significantly higher in patients with poor outcome compared to survivors. They significantly decreased over time to similar values on days 7–10 after the CNS hemorrhage .Decreased KEB values in the CSF presented the higher extent of anaerobic metabolism in the CSF compartment in survivors and patients with poor outcome. They were neither significantly different in both subgroups of patients nor in time after the CNS hemorrhage .Immediately after the CNS hemorrhage AST catalytic activities in the CSF were similar in survivors and patients with poor outcome. Their significant increase was apparent in both subgroups between the days 0 and 3 and the days 7 and 10 after the CNS hemorrhage. The growth of AST catalytic activities was higher in patients with poor outcome .We found apparently more causes with low KEB values (<15.0) and apparently less causes with moderate KEB values (15.0–28.0) in patients with poor outcome compared with survivors immediately after the CNS hemorrhage .The differences between frequencies of patients of both subgroups divided in accordance with their KEB values were not significant on days 7–10 after the hemorrhage .While frequencies of survivors and patients with poor outcome with AST catalytic activities more than 30.0 IU/L in the CSF immediately after the CNS hemorrhage were almost the same, on days 7–10 frequency of patients with poor outcome was significantly higher .The CNS hemorrhage is a very serious brain injury with a high risk of persistent neurology deficits or even the death. Many variables can influence the outcome of patients. We focused on the CSF monitoring of these patients over several days and divided them into two subgroups in accordance with the severity of their impairment—survivors (GOS 5-3) and patients with poor outcomes (GOS 2-1). All these patients were followed during the first 3 days and on the second occasion between the 7th to 10th day after the CNS hemorrhage.Some authors recognize the amount of bleeding in the CNS as one of the important factors of its prognosis ,7. In thCNS hemorrhage and its consequent complications are evoking damaging local inflammatory response in the CNS ,6,7,8,9.Slightly decreased KEB values in patients with GOS 2-1 compared to patients with GOS 5-3 immediately after the CNS hemorrhage represents a trend to higher intensity of inflammation in patients with poor outcome. In addition, we found 43.3% of patients with poor outcome and only 27.5% survivors with very low KEB values under 15.0 . AnaerobElevation of total protein in the CSF immediately after the CNS hemorrhage is simultaneously influenced by many variables—amount of extravascular blood, inflammatory response and disorder of the CSF circulation to name some of them. It seems that the inflammatory reaction in the CNS immediately after the hemorrhage plays the key role. Inflammation is accompanied by a higher increase in the permeability of the blood-brain barrier (BBB) and presence of proinflammatory mediators in the CNS. It results in swelling of the brain, increase of intracranial pressure (ICP) and impairment of blood circulation in the brain and circulation of the CSF. In addition, inflammation in the CNS increases risk of vasospasms and secondary cerebral ischemia ,5,7,8,24Elevation of total protein in the CSF is found in both subgroups of our patients. It is significantly higher in patients with poor outcome . The conConcentrations of glucose in the CSF of patients with poor outcomes compared with survivors were significantly higher in days 0 to 3 after the CNS hemorrhage . SignifiAST catalytic activity in the CSF is recognized as a useful parameter to detect CNS tissue injury. However, its values in survivors and patients with poor outcome were not significantly different immediately after the CNS hemorrhage . Only a Extravasation of blood in the CNS parenchyma represents a very strong DAMP (damaged associated molecular patterns) which is followed by rapid inflammatory response and other pathologies which can cause worse outcome of patients.The battery of our tests to monitor the CSF in patients after a CNS hemorrhage comprises the absolute count of leukocytes and erythrocytes, the differential cell count, concentrations of total protein, glucose and lactate, the calculation of the KEB values and catalytic activities of AST. We compared these parameters in two subgroups of patients after a CNS hemorrhage—in survivors (GOS 5-3) and in patients with poor outcome (GOS 2-1).We found two key adverse prognostic factors. The first one is the persistence of bleeding or re-bleeding in the CNS. The second ones are the low KEB values (<15.0) and increased total protein concentration in the CSF both representing trend to the very intensive early inflammatory response in the CNS, brain swelling, elevation of intracranial pressure and impairment of the CSF circulation. Subsequently increased AST catalytic activities in the CSF of patients with poor outcome reveal more profound structural tissue injury in their CNS.