The influence of first author sex on acceptance rates of submissions to Anaesthesia Cases

More than 50% of medical students and 45% of practising doctors are female in the UK. In the specialty of anaesthesia, 32% of consultants are female. However, compared with males, females are under-represented as authors of articles published in high-impact journals. We investigated the proportion of female first authors by examining the case reports submitted to Anaesthesia Cases since its inception in 2013. We defined authors by their sex (male or female), that is, biological characteristics, rather than their gender. There were a total of 802 submissions to Anaesthesia Cases over 4.5 years. Sixteen submissions were excluded and of the remaining 786 submissions, 279 were accepted and 507 rejected, an acceptance rate of 35.5%. Twenty (2.5%) authors’ sex could not be identified. The overall proportion of female first authors was 37.1%. The proportion of female first authors of accepted case reports was 42.1% and females were first authors of rejected case reports in 34.4%. We found that, compared with previous studies on female sex and gender bias in publishing, there was a relatively high proportion of female first authors publishing in Anaesthesia Cases and female first authors were more likely to be accepted than male first authors. Authorship is considered to reflect career success and there continues to be sex/gender inequity that must be tackled at all levels, from application to medical school, through research funding, journals and Editorial Boards.     

Revisiting liver transplant immunology: from the concept of immune engagement to the dualistic pathway paradigm.

Ever since the demonstration that allografts are rejected through immune reactions of the host, clinical therapies for organ allografts have relied on immune suppression to prevent these destructive events. A growing body of clinical and experimental data suggests that allografts elicit multiple, interactive immune responses. The result is not inevitably graft rejection, and "spontaneous" acceptance of fully allogeneic liver grafts occurs in rodents without immunosuppression. A spectrum of results range from spontaneous acceptance without immunosuppression to rejection with immunosuppression. The "dualistic pathway paradigm" aims to reconcile apparently conflicting observations in liver transplantation and proposes that: (1) immune engagement between the host and the allograft is instrumental in both rejection and acceptance; (2) there exist in all mammalian species congruent interactive pathways of immune activation whereby the fate of the allograft is determined by the quantitative results of these interactions; (3) the dualistic effect of immunosuppressive drugs on pathways of immune activation, conferring the capacity for favorable or unfavorable graft outcome should be investigated in experimental models in which organ allografts are spontaneously accepted. In conclusion the design of clinical strategies based on this research may contribute to protocols resulting in allograft acceptance without chronic immunosuppression.     

Medical Research Publication: An Insider’s Guide

Most original scientific articles submitted to high-impact medical journals are not accepted for publication. Reasons for rejection are diverse, and tips and pearls to improve chances for acceptance are manifold. Four essential points could maximize the chance that submission of a scientific article will result in acceptance and publication. First, before initiation of a study, it is valuable to state a hypothesis detailing what one expects the study to show. Second, the conclusion should be based exclusively on, and not overreach, the results. If researchers start with a hypothesis, describing the conclusion is simple; the results either do, or do not, support the hypothesis. Third, the methods must address the purpose of the study. This sounds obvious, but poorly designed methods can fatally flaw the study, so methods should be written before initiation of a study, and this is the time to seek expert advice regarding whether one’s methods could be improved. Fourth, a prospective power analysis will ensure the study includes a sufficient number of patients to avoid failure to detect a difference between study groups due to an insufficient sample size (β error). In summary, before starting a study: state the hypothesis, write the methods, perform a power analysis, and conscientiously review these 3 essentials with both expert mentors and a statistician. Finally, this will mitigate against fatal methodological flaws, and the results of the study will clearly support the study hypothesis—or not—resulting in a definitive conclusion. In the end, authors following these essential guidelines could have improved odds of having their research submissions accepted for publication in a prestigious peer-reviewed medical journal such as Arthroscopy or Arthroscopy, Sports Medicine, and Rehabilitation.     

CD25+CD4+ regulatory T cells develop in mice not only during spontaneous acceptance of liver allografts but also after acute allograft rejection

BACKGROUND: Liver grafts transplanted across a major histocompatibility barrier are accepted spontaneously and induce donor specific tolerance in some species. Here, we investigated whether liver allograft acceptance is characterized by, and depends upon, the presence of donor reactive CD25CD4 regulatory T cells. METHODS: CD25 and CD25CD4 T cells, isolated from CBA. Ca (H2) recipients of C57BL/10 (B10; H2) liver and heart allografts 10 days after transplantation, were transferred into CBA. Rag1 mice to investigate their influence on skin allograft rejection mediated by CD45RBCD4 effector T Cells. RESULTS: Fully allogeneic B10 liver allografts were spontaneously accepted by naive CBA.Ca recipient mice, whereas B10 cardiac allografts were acutely rejected (mean survival time=7 days). Strikingly, however, CD25CD4 T cells isolated from both liver and cardiac allograft recipients were able to prevent skin allograft rejection in this adoptive transfer model. Interestingly, CD25CD4 T cells isolated from liver graft recipients also showed suppressive potency upon adoptive transfer. Furthermore, depletion of CD25CD4 T cells in primary liver allograft recipients did not prevent the acceptance of a secondary donor-specific skin graft. CONCLUSIONS: Our data provide evidence that the presence of CD25CD4 regulatory T cells is not a unique feature of allograft acceptance and is more likely the result of sustained exposure to donor alloantigens in vivo.     

Reducing transplant evaluation costs by early identification of unsuitable patients

Many patients undergo a full transplant evaluation and are rejected for transplant on the basis of the test results. Some of these patients could be identified earlier in the evaluation process, thus reducing the cost of undergoing a full evaluation. Subjects in this study were 117 patients who had undergone a heart transplant evaluation over a 6-month period. The rates of acceptance, rejection, deferral, and those deferred and later listed were monitored: 53% were accepted, 17.1% rejected, 18.8% deferred, and a further 11.1% were deferred and then later listed. Of the group that was rejected, 45% were rejected on the basis of the cardiopulmonary exercise test and deemed too well for transplant. Other reasons for patients being rejected were obesity, psychological or social issues, and as a result of other diagnostic testing. The transplant evaluation process can be modified so that the cardiopulmonary exercise test is performed first, which would reduce the ultimate cost of a transplant evaluation from $11,330 to $680. The cardiopulmonary exercise test has become an intrinsic part of the cardiac evaluation process and is a strong indicator of a patient's suitability for transplant.     

The role of passenger leukocyte genotype in rejection and acceptance of rat liver allografts

BACKGROUND: Although graft-resident passenger leukocytes are known to mediate acute rejection by triggering direct allorecognition, they may also act in an immunomodulatory fashion and play an important role in tolerance induction. Our purpose in the current study was to utilize rat bone marrow chimeras to evaluate the role of the genotype of passenger leukocytes in both acute rejection and tolerance of liver allografts. METHODS: The fate of livers bearing donor-type, recipient-type, and third-party passenger leukocytes was evaluated in the MHC class I and II mismatched rejector combination ACI-->LEW and the acceptor combination PVG-->DA. RESULTS: We report that although treatment of ACI liver donors with lethal irradiation does not lead to prolongation of graft survival in the ACI-->LEW strain combination, ACI livers bearing recipient-type (LEW) or third-party passenger leukocytes (BN) are rejected at a significantly slower rate. We confirm that lethal irradiation of PVG donor animals leads to abrogation of tolerance induction with acute rejection of their livers by DA recipients. However, the majority of PVG livers carrying donor-type (PVG), recipient-type (DA), or third-party (LEW) passenger leukocytes are accepted for >100 days. These DA recipients develop immune tolerance to the donor parenchyma (PVG). CONCLUSIONS: Our findings demonstrate that long-term acceptance of liver allografts and tolerance induction is not dependent on the presence of donor-type passenger leukocytes and can be achieved with organs carrying donor-type, recipient-type, or third-party passenger leukocytes. The importance of the MHC framework on the surface of passenger leukocytes as a critical regulator of the immune response after transplantation of chimeric organs is substantiated by the delayed tempo of rejection of ACI livers bearing recipient-type or third-party passenger leukocytes in the ACI-->LEW strain combination.     

The graft helps to define the character of the alloimmune response

Introduction: In mice, kidney and liver allografts may be spontaneously accepted, whereas cardiac and skin allografts in the same strain combinations are rapidly rejected. The reasons for this dichotomy in murine response outcomes remains to be determined. Methods and results: When DBA/2 (H-2d) cardiac allografts were placed in C57BL/6 (H-2b) recipients, they were rejected within 10 days, unless the allograft recipients were transiently treated with gallium nitrate (GN), at which time the allografts were accepted for > 150 days. The cardiac allograft rejector mice displayed DBA/2-reactive DTH responses, whereas the cardiac allograft acceptor mice displayed both TGFbeta- and IL10-mediated inhibition of DTH responses. In contrast, DBA/2 kidney allografts placed at the same location in C57BL/6 mice were spontaneously accepted without immunosuppression. These kidney allograft acceptor mice displayed TGFbeta-mediated, but not IL10-mediated inhibition of donor-reactive DTH responses. Conclusions: In the DBA/2-> C57B1/6 strain combination, cardiac allografts induce pro-inflammatory immunity and allograft rejection, while kidney allografts induce anti-inflammatory immunity and allograft acceptance despite the fact that both organs display the same strong MHC disparities and are implanted at the same location. Anti-inflammatory immunity and allograft acceptance are displayed by cardiac allograft recipients when they are transiently treated with select immunosuppressants. Thus, multiple immune response options are available to the organ allograft recipient, and the choice is determined, to some degree, by the allograft, itself.     

Acceptance of murine thyroid allografts by pretreatment of anti-Ia antibody or anti-dendritic cell antibody in vitro

A new method for thyroid allografts in mice was established. Thyroids of C67BL/6J mice were treated with collagenase, and the follicles were isolated using a Percoll density gradient technique. These follicles were treated with anti-Ia antibody (Ab) or anti-DC Ab plus complement in order to eliminate DCs. The follicles were then mixed with agarose and transplanted under the left renal capsule of BALB/c mice. One hundred days after transplantation, acceptance of the grafts was verified by both histological study and the incorporation of 125I into the grafts. Allografts treated with C were rejected, whereas allografts treated with Ab plus C were accepted. When nontreated thyroids of C57BL/6J mice were grafted under the right renal capsule of BALB/c mice that had accepted DC-depleted thyroids of C57BL/6J mice, the nontreated thyroids were rejected. These findings indicate that DCs play a crucial role in the rejection of mouse thyroid allografts, and that the depletion of DCs permits allografts to be accepted without inducing donor-specific tolerance. Our method presented here may be developed as a viable strategy for the treatment of patients with congenital or acquired hypothyroidism.     

MHC-identical heart and hepatocyte allografts evoke opposite immune responses within the same host

BACKGROUND: Purified allogeneic hepatocytes are highly antigenic and elicit immune responses that are not easily controlled. However, it is not clear whether hepatocytes are not capable of protective immune mechanisms or whether they are not to protection by immune mechanisms that permit long-term survival of other allografts. The purpose of the current study was to determine whether donor-matched allogeneic hepatocytes are protected from rejection in mice that have been induced to accept heart allografts. METHODS: Transient treatment with anti-CD4 monoclonal antibody (mAb) or gallium nitrate (GN) was used to induce acceptance of heterotopic FVB/N (H-2(q)) heart allografts by C57BL/6 (H-2(b)) mice. Transgenic hA1AT-FVB/N hepatocytes were sequentially transplanted into C57BL/6 mice that had accepted FVB/N heart allografts more than 60 days (heart acceptor mice), CD8 depleted C57BL/6 heart acceptor mice, or B-cell knockout (BCKO, H-2(b)) heart acceptor mice. Hepatocyte survival was determined by the detection of secreted transgenic product hA1AT by enzyme-linked immunosorbent assay (ELISA). RESULTS: FVB/N hepatocytes were rejected by day 10-14 posttransplant, while FVB/N heart allografts continued to function in C57BL/6, BCKO, and CD8 depleted heart acceptor mice. When FVB/N hepatocytes and heart allografts were transplanted into C57BL/6 or BCKO mice under short-term cover of anti-CD4 mAb or GN, hepatocyte rejection occurred by day 10 posttransplant, while most heart allografts survived for more than 60 days. CONCLUSIONS: Hepatocyte rejection does not appear to interfere with the of mechanisms that permit heart allograft acceptance. However, immune responses to allogeneic hepatocytes are not to regulation by mechanisms induced in heart acceptor mice. The simultaneous rejection of FVB/N allogeneic hepatocytes and continued acceptance of FVB/N-matched heart allografts is independent of host CD8+ T cells and humoral immunity.