Subsequent Rejection Research Articles

Heart Transplant Rejection in the Setting of Glyphosate Herbicide Exposure; A Case Report

Glyphosate is a common herbicide utilized worldwide with known exposure related toxicities. Numerous adverse effects related to glyphosate exposure have been documented, specifically in non-human models, however literature is lacking on cardiotoxic effects specific to heart transplant patients. Rejection is the most common post-transplant complication and the diagnosis of such is vital in order to guide immediate and appropriate treatment. In addition to the endomyocardial biopsy, noninvasive genetic testing can aid in rejection diagnosis and distinguish between cell-mediated and antibody-mediated rejection. We describe a case of glyphosate exposure in a post orthotopic heart transplant and the subsequent heart transplant rejection, patient’s clinical course, treatment, and follow up.

The Architecture of Learning: Space, Time, and Pedagogy in the Open Space School

This article considers the open space schools of the 1960s and 1970s as both a spatially distinctive architectural typology and the environmental component of child-centered learning. Emphasis is placed on, but not limited to, the United States in the 1960s and 1970s, a period of hostility to conventional children’s education in terms of both pedagogy and spatial setting. The impact of this context is examined. The initial embrace and subsequent rejection of the open space school by the mid-1970s are contrasted with the more receptive response in western Europe and especially the Scandinavian countries. In the latter setting, this approach has been embraced by both public and private sectors, and is described along with the open space school’s instrumentalization into globalized capitalism by the 2000s, when the very characteristics that the open space school and its pedagogy sought to inculcate in its students (digital technology-literate, collaborative, independent problem-solvers) were seen as the skills needed by an emerging class of “knowledge workers” on whom the globalized corporations of the contemporary world depend.

Early state socialism and eugenics: Premarital medical certificates in Czechoslovakia, East Germany, and Poland in the aftermath of World War II

The article discusses the immediate post-war persistence and subsequent rejection of eugenics in East-Central European socialist states, exploring the case of premarital medical certificates. Building our analysis on published and archival sources, we show that immediately after the war, policies formulated at the governmental level were informed by eugenic ideas in medical expertise. Premarital medical certificates were aimed at combatting contagious diseases and thus securing a healthy population. Their legal status varied: in Poland, they were formally introduced; in the Soviet Occupied Zone and East Germany, Nazi law was abolished, but local officials still advocated for the introduction of certificates; and in Czechoslovakia, medical certificates were planned but not introduced. Despite these differences, after a short period between 1949 and 1950, the attempts to put a measure into practice ended in all three countries. We argue that the communist takeover and consolidation of power played a decisive role. After 1950, premarital medical certificates were not discussed again in Czechoslovakia or East Germany; in Poland, the debate re-emerged in 1959–60 during political liberalization.

Analysis of extremely low water hammer pressures of draft tubes for double units in pumped storage power stations under successive load rejection conditions

With large-scale integration of intermittent energy into power systems, the operating conditions of pumped storage power stations (PSPSs) change frequently, thereby intensifying the risk of load rejections. For multiple units sharing a water conveyance system, when one or more units reject the load, other units also reject the load after a few seconds; this is defined as successive load rejection (SLR). During SLR conditions, pumped storage units produce extreme water hammer pressures, jeopardizing the safe operation of PSPSs. This study reveals the generation mechanism of extremely low draft tube pressure (DTP) during SLR, and clarifies the generating unit and corresponding occurrence moment characteristics of the minimum DTP. The results indicated an extremely low DTP, attributed to the sharp decline in the discharge owing to increased rotational speed in unit's S-shape region and the hydraulic interference owing to the increased discharge of the other unit. When the guide vane closing time (GVCT) was short, the minimum DTP occurred in the subsequent load rejection unit (SLRU) near the first peak of its rotational speed, with the discharge of initial load rejection unit (ILRU) in the rising stage. Conversely, for a large GVCT, the minimum DTP occurred in the ILRU near the second peak of its rotational speed, with SLRU discharge in the rising stage. Finally, engineering measures to improve the extremely low DTP were proposed. Overall, the findings underscore crucial engineering insights for ensuring the safety of PSPSs under extreme conditions.

The Effects of COVID-19 in Kidney Transplantation: Evidence From Tissue Pathology.

The biological effects of SARS-CoV-2 infection in transplanted kidneys are uncertain with little pathological information. This single-center, prospective observational study evaluated kidney transplant biopsies from recipients of deceased donors with COVID-19, current recipients contracting SARS-CoV-2 Omicron variant in 2022, against prior BK virus (BKV) infection and uninfected (without SARS-CoV-2 or BKV) samples, as respective positive and negative comparators (n = 503 samples). We demonstrated nonvirus tubular injury in implanted tissue from infected donors and prevalent recipients with mild acute COVID-19 and acute kidney injury, excluding direct viral infection as a cause of kidney damage. COVID particles were absent in 4116 ultrastructural images of 295 renal tubules from 4 patients with acute COVID-19. No viral cytopathic effect, viral allograft nephropathy, or SARS-CoV-2 RNA was detected in acute tissues, nor in 128 sequential samples from infected donors or recipients with COVID-19. Following recipient COVID-19 (mean 16.8 ± 12.0 wk post-infection), the biopsy-prevalence of rejection was 33.0% (n = 100 biopsies) versus 13.4% for contemporaneous uninfected controls (n = 337; P < 0.001). Prior COVID-19 was an independent risk factor for incident rejection using multivariable generalized estimating equation adjusted for competing risks (odds ratio, 2.195; 95% confidence interval, 1.189-4.052; P = 0.012). Landmark and matched-pair analyses confirmed an association of SARS-CoV-2 with subsequent transplant rejection, with a similar pattern following BKV infection. Transplantation from COVID-19+ deceased donors yielded good recipient outcomes without evidence of viral tissue transmission. Acute kidney injury during COVID-19 was mediated by archetypical tubular injury and infection correlated with an increased risk of subsequent rejection.

Subclinical rejection and allograft survival in kidney transplantation: protocol for a systematic review and meta-analysis

IntroductionSubclinical rejection (SCR) refers to the presence of acute rejection without accompanying kidney allograft dysfunction. The impact of SCR on long-term graft survival remains a subject of ongoing debate.Methods and...

Development of a novel 3D perfusable vascular graft model to elucidate the mechanisms for congenital heart disorders.

Pediatric heart transplantation is hampered by a chronic shortage of donor organs. This problem is further confounded by graft rejection. Identification of earlier indicators of pediatric graft rejection and development of subsequent strategies to counteract these effects will increase the longevity of transplanted pediatric hearts. Heart transplant reject is due to a complex series of events, resulting in CAV, which is thought to be mediated through a host immune response. However, the earlier events leading to CAV are not very well known. We hypothesize that early events related to ischemia reperfusion injury during pediatric heart transplantation are responsible for CAV and subsequent graft rejection. Identification of the molecular markers of ischemia reperfusion injury and development of subsequent therapies to block these pathways can potentially lead to a therapeutic strategy to reduce CAV and increase the longevity of the transplanted heart. To accomplish this goal, we have developed a perfusable vascular graft model populated with endothelial cells and demonstrated the feasibility of this model to understand the early events of ischemia reperfusion injury.

Mycophenolate Dose Reduction in Tacrolimus-based Regimens and Long-term Kidney Transplant Outcomes in Australia and New Zealand.

Mycophenolate dose reduction (MDR) is associated with acute rejection and transplant failure in kidney transplant recipients (KTRs). The optimal dose to prevent rejection and reduce complications remains poorly defined in tacrolimus-based regimens. We assessed adult KTRs from 2005 to 2017 initiated on mycophenolate mofetil 2 g/d, tacrolimus, and prednisolone from the Australia and New Zealand Dialysis and Transplant Registry. KTRs with rejection within the first 30 d posttransplant were excluded. The primary outcome was time to first rejection between 30 d and 2 y posttransplant. Mycophenolate dose was modeled as a time-varying covariate using Cox proportional hazards regression. Secondary outcomes included assessment of early MDR to <1.5 g/d within the first 6 mo posttransplant and subsequent patient and death-censored graft survival. In the primary analysis, 3590 KTRs were included. Compared with mycophenolate dose of ≥2 g/d, both 1.0-<1.5 and <1 g/d were associated with an increased risk of rejection during the 2 y posttransplant (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.29-2.16; P < 0.001 and HR 2.06; 95% CI, 1.36-3.13; P = 0.001, respectively) but not 1.5-<2 g/d (HR 1.20; 95% CI, 0.94-1.53; P = 0.14). Early MDR to <1.5 g/d occurred in 45.3% of KTRs and was an independent risk factor for death-censored graft failure (HR 1.32; 95% CI, 1.05-1.66; P = 0.016) but not death (HR 1.18; 95% CI, 0.97-1.44; P = 0.10), during a median follow-up of 5.0 (interquartile range, 2.6-8.5) y. Early MDR was a risk factor for subsequent rejection and graft failure in KTRs receiving contemporary tacrolimus-based regimens.

#1474 COVID-19-infection in kidney transplant recipients during the omicron surge, a sigh of relief

Abstract Background and Aims The COVID-19 pandemic had a profound impact on global health, particularly affecting high-risk individuals such as solid organ transplant recipients (SOTRs). SOTRs have an elevated risk of severe COVID-19 disease and increased mortality. Kidney transplant recipients (KTRs) vaccinated with mRNA-based vaccines exhibit a lower response rate and shorter half-time of the serologic conversion. However, the percentage of serologic response improves with increasing number of vaccine doses. Studies also indicate that KTRs with prior COVID-19 infection demonstrate a more robust immune response post-immunization compared to COVID-19 naïve patients. Factors such as age, immunosuppressive regimen, eGFR, time since transplantation also impact vaccination response. This study aims to investigate COVID-19 infection outcome and vaccination response among KTRs during the Omicron surge. Method This study is a retrospective single-center cohort study at the Department of Nephrology and Transplantation at Skåne University Hospital in Malmö, Sweden. KTRs infected with COVID-19 during the Omicron surge were included (January 2022 until August 2023). Results 97 KTRs diagnosed with COVID-19 were included of whom 91 were vaccinated. In average, three doses of COVID-19-vaccine had been given to the patients. 67 KTRs showed seroconversion, 28 remained seronegative and the status of the remaining 2 KTRs was unknown. There was a significant association between lack of antibody production and mycophenolic acid (MPA) treatment (P = 0.019, Chi2 test), however the significance was not retained in a multivariate logistic regression analysis. Among the seroconverted (n = 67), 61 experienced mild infection, 5 moderate infection and 1 severe infection, according to the WHO clinical progression scale. In the seronegative group (n = 28), 25 had mild infection while the remaining three had moderate infection. The median time for viral clearance was examined in 79 KTRs and was 23 days (IQR 18-31). Immunosuppression was adjusted in 34% (n = 33) of cases. 2.1% (n = 2) of KTRs experienced graft rejection post infection. Conclusion While most patients experienced a mild infection, unlike during the first surges of the pandemic, the observed subsequent graft rejections emphasize the complexity of COVID-19´s potentially immunologic triggering effect and risk of graft loss in KTRs. The correlation between MPA treatment and a lower degree of serologic conversion after vaccination underscores the need for personalized immunologic follow up and treatment regimen in KTRs.

Optimising referral letters for the dental practitioner.

Referrals are defined as 'a process in which a health worker at one level of the health system, having insufficient resources (drugs, equipment, skills) to manage a clinical condition, seeks the help of a better or differently resourced facility at the same or higher level to assist in patient management'. Within the UK, the NHS dental service is divided into nationally defined levels of care, which provide treatment based upon complexity and patient modifying factors. Having a sound knowledge of these levels will help general dental practitioners (GDPs) make appropriate and efficient onward referrals to the correct service.This article aims to outline the key information required for all strong GDP referrals, as well as highlighting information that may be specific to each speciality. This is with the hope of creating a key list for GDPs to use on clinic when writing referrals to reduce the incidence of missed information and subsequent rejection. The article also aims to outline the levels of NHS dental care and what factors and treatments are suitable for each to aid GDPs during their referral decision-making process.

Novel traceable CRISPR-Cas9 engineered human embryonic stem cell line (E1C3 + hSEAP + 2xKO + pCD47), has potential to evade immune detection in pigs

Here we present the generation of a human embryonic stem cell line with the potential to escape immune rejection upon transplantation to an alternate species, in this case sus scrofa. For in vivo detection the cells were modified by CRISPR-Cas9 to express human secreted alkaline phosphatase. To avoid immune recognition and subsequent rejection by host, genes encoding hB2M and hCIITA were knocked out and the porcine gene for CD47 was introduced. Upon editing and subsequent culture, cells maintained molecular and phenotypic pluripotent charactaristics and a normal karyotype supporting viability and functionality of the engineered cell line.

Impact of Raw Milk Quality on Dairy Products &amp; Payment Systems

The trend of microbial quality of raw milk is affected by the seasonal variation in in milk production practices and ambient temperature with the season. A payment system, which includes testing for selected parameters, with subsequent rejection and/or penalties or bonuses, is considered functional to improving raw milk quality. In addition to the minimal legal requirements, milk may be graded (and paid) according to its “quality,” usually measured according to composition (fat, protein, lactose, other solids, free fatty acids), hygienic quality. Psychrotrophic microbes, particularly Pseudomonas spp., are found in the microbiota of chilled milk because they can grow at temperatures below their optimal growth temperature. Psychrotrophic counts ranging from 105 to 108 CFU/ml in refrigerated raw milk affect cheese quality, since the synthesized thermoresistant enzymes affect the nutritional value, sensory properties and texture. Therefore, stringent measures must be implemented throughout the dairy supply chain to ensure the microbial quality of raw milk is maintained at safe levels, thus safeguarding the integrity and safety of dairy products for consumers.

CMV Infection and Lymphopenia: Warning Markers of Pneumocystis Pneumonia in Kidney Transplant Recipients.

Pneumocystis pneumonia (PcP) remains life-threatening in kidney transplant recipients (KTR). Our study investigated risk factors one-year before PcP. We conducted a monocentric, case-control study including all KTR at the Dijon University Hospital (France) with a diagnosis of PcP between 2005 and 2022 (cases), and matched control KTR with no history of PcP (3 controls/case). Among all 1,135 KTR, 57 cases (5%) and 169 matched-controls were included. PcP was associated with 18% mortality. Compared to controls, cases were older, with a higher immunological risk, and CMV infection was more frequent in the year preceding the occurrence of PcP (23% vs. 4%; p < 0.001). As early as 1 year before PcP, lymphocyte counts were lower and serum creatinine levels were higher in cases, but immunosuppressive regimens were not significantly different. Multivariable analysis identified lymphocyte count, serum creatinine level, being treated by immunosuppressive therapy other than anti-rejection drugs, and CMV infection in the year preceding the time PcP as independently associated with the occurrence of PcP. PcP was associated with an increased risk of subsequent chronic rejection (27% vs. 3%; p = 0.001) and return to dialysis (20% vs. 3%; p = 0.002). The occurrence of CMV infection and a low lymphocyte count could redefine the indications for continuation or reinitiation of anti-Pneumocystis prophylaxis.

Polyinosinic: polycytidylic acid induced inflammation enhances while lipopolysaccharide diminishes alloimmunity to platelet transfusion in mice.

Alloimmune responses against platelet antigens, which dominantly target the major histocompatibility complex (MHC), can cause adverse reactions to subsequent platelet transfusions, platelet refractoriness, or rejection of future transplants. Platelet transfusion recipients include individuals experiencing severe bacterial or viral infections, and how their underlying health modulates platelet alloimmunity is not well understood. This study investigated the effect of underlying inflammation on platelet alloimmunization by modelling viral-like inflammation with polyinosinic-polycytidylic acid (poly(I:C)) or gram-negative bacterial infection with lipopolysaccharide (LPS), hypothesizing that underlying inflammation enhances alloimmunization. Mice were pretreated with poly(I:C), LPS, or nothing, then transfused with non-leukoreduced or leukoreduced platelets. Alloantibodies and allogeneic MHC-specific B cell (allo-B cell) responses were evaluated two weeks later. Rare populations of allo-B cells were identified using MHC tetramers. Relative to platelet transfusion alone, prior exposure to poly(I:C) increased the alloantibody response to allogeneic platelet transfusion whereas prior exposure to LPS diminished responses. Prior exposure to poly(I:C) had equivalent, if not moderately diminished, allo-B cell responses relative to platelet transfusion alone and exhibited more robust allo-B cell memory development. Conversely, prior exposure to LPS resulted in diminished allo-B cell frequency, activation, antigen experience, and germinal center formation and altered memory B cell responses. In conclusion, not all inflammatory environments enhance bystander responses and prior inflammation mediated by LPS on gram-negative bacteria may in fact curtail platelet alloimmunization.

Enhanced alloresponse to platelet transfusion due to immune dysregulation following ablative chemotherapy in mice.

Alloimmunization is common following platelet transfusion and can result in negative outcomes for recipients such as refractoriness to subsequent transfusions and rejection of transplants. Healthy people do not receive blood transfusions, and the diseases and therapies that result in a need to transfuse have significant impacts on the immunological environment to which these alloantigens are introduced. Ablative chemotherapies are common among platelet recipients and have potent immunological effects. In this study, we modeled the impact of chemotherapy on the alloresponse to platelet transfusion. As chemotherapies are generally regarded as immunosuppressive, we hypothesized that that they would result in a diminished alloresponse. Mice were given a combination chemotherapeutic treatment of cytarabine and doxorubicin followed by transfusion of allogeneic platelets, and compared to controls given no treatment, chemotherapy alone, or transfusion alone. Alloantibody responses were measured 2 weeks after transfusion, and cellular responses and growth factors were monitored over time. Contrary to our hypothesis, we found that chemotherapy led to increased alloantibody responses to allogeneic platelet transfusion. This enhanced response was antigen-specific and was associated with increased CD4+ and CD8+ T cell responses. Chemotherapy led to rapid lymphocyte depletion followed by reconstitution, non-specific activation of transitional B cells with the highest levels of activation in the least mature subsets, and increased serum levels of B cell activating factor (BAFF). These data suggest that ablative chemotherapy can increase the risk of alloimmunization and, if confirmed clinically, that additional measures to protect these patient populations may be warranted.

Abstract 14448: Graft Loss and Rejection Following COVID in Pediatric Heart Transplantation - A Pediatric Heart Transplant Society (PHTS) Propensity Matched Analysis

Introduction: While short-term outcomes following COVID among pediatric heart transplant (HT) recipients have been described, graft outcomes including the risks of subsequent graft loss and rejection following COVID are unknown. Hypothesis: We sought to determine the overall trends of post-HT survival during the COVID pandemic and determine if there was an increased risk for subsequent graft loss and/or rejection following post-HT COVID. Methods: All pediatric recipients of first HT between 1/2003-6/2022 in the Pediatric Heart Transplant Society ( PHTS) database were included. To assess if early post-HT survival changed during the COVID pandemic, 2-year HT survival was compared among those who underwent HT in 2014-2016, 2017-2019, and 2020-2022. To compare the risks of graft loss and rejection (acute cellular and/or antibody-mediated) between those with vs without post-HT COVID, a 1:2 (COVID vs non-COVID) propensity-score matched analysis using multiple pre-HT and post-HT factors (including exact matches for HT year and time post-HT) and Kaplan Meir analysis were performed. Patients with COVID within 3 months post-HT were excluded. Results: The 2-year post-HT survival was similar among patients who underwent HT across the 3 eras (Fig 1A). Among the overall 6634 patients (n = 888 [13%] with post-HT COVID), 861 patients with post-HT COVID and 1716 without post-HT COVID were included in propensity-score matching. There was no difference in the risk of subsequent graft loss (Fig 1B) or rejection (Fig 1C) among those with vs those without post-HT COVID. Conclusions: No differences were observed in early pediatric post-HT survival during the COVID pandemic compared to the immediately prior era. Post-HT COVID did not increase the risks of subsequent graft loss or rejection. Longer-term follow up is necessary to look at other potential post-HT COVID outcomes, such as coronary allograft vasculopathy.

The Impact of Subclinical T Cell-Mediated Rejection on Subsequent Rejections and Allograft Survival in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

The Impact of Subclinical T Cell-Mediated Rejection on Subsequent Rejections and Allograft Survival in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

¿Qué fue lo que ocurrió con el control difuso en la Administración Pública Peruana?

Diffuse administrative control was the subject of intense debate during the brief period in which it was in force in Peru. This paper aims to address the main concepts that led, initially, to authorize the public administration to exercise this power. The reason for this was to provide greater legal certainty to individuals by guaranteeing that their processes would be resolved under the protection of the constitution when a legal norm violated their fundamental rights. In addition, I seek to recount the different stages experienced by the diffuse administrative control in the judgment of the judges of the Constitutional Court TC; from its initial complete denial, through an increasingly perceptible acceptance until reaching the consolidation and subsequent rejection. Finally, we try to elucidate the questions that the last phase left regarding the questionable decision to leave without effect a binding precedent without proposing a new one to replace it; thus concluding, with a critical opinion of the authors that, in their own opinion, the final decision of the Constitutional Court in relation to the administrative diffuse control is considered irregular, almost arbitrary.

Does ozaki procedure have a future as a new surgical approach for aortic valve replacement? a systematic review and meta-analysis.

In 2014, Ozaki et al. introduced the neo-cuspidation (Ozaki procedure), a new valve from the pericardium, to reduce or even prevent the risk of chronic autoimmune inflammation and subsequent rejection or valve degeneration. Thus, the authors aimed to assess the safety and efficacy of the Ozaki technique in treating aortic valve diseases. A comprehensive search was performed via PubMed, the Cochrane Library, Scopus, and the Web of Science up to 20 February 2022. Random-effects meta-analysis models were employed to estimate the pooled mean and SD or event to the total of the Ozaki procedure. Relevant records were retrieved and analyzed by OpenMeta analyst software. A total of 2863 patients from 21 studies were finally included in our analysis. Ac. Ozaki technique showed statistical significance in terms of mean cardiopulmonary bypass time of 148mins (95% CI 144-152.2, P<0.001), mean aortic cross-clamp time of 112.46mins (95% CI 105.116, 119.823, P<0.001), reoperation with a low risk of 0.011 (95% CI 0.005, 0.016, P=0.047), conversion to aortic valve replacement with a low risk of 0.004 (95% CI -0.001, 0.008, P=0.392), finally ICU stay (days) and hospital length of stay (days) with a mean of 2.061 days (95% CI 1.535, 2.587, P<0.001) and 8.159 days (95% CI 7.183-9.855, P<0.001), respectively. The Ozaki procedure provides a safe surgical technique with low mean cardiopulmonary bypass time and aortic cross-clamp time; moreover, a mean of 2-day-postoperative hospital stay was observed with the Ozaki procedure with a low risk of conversion to aortic valve replacement, reoperation, ICU and hospital stay, and death.

Graft rejection in paediatric congenital heart disease.

Congenital heart disease (CHD) affects around 1.35 million neonates worldwide per annum, and surgical repair is necessary in approximately 25% of cases. Xenografts, usually of bovine or porcine origin, are often used for the surgical reconstruction. These xenografts elicit an immune response due to significant immunological incompatibilities between host and donor. Current techniques to dampen the initial hyperacute rejection response involve aldehyde fixation to crosslink xenoantigens, such as galactose-α1,3-galactose and N-glycolylneuraminic acid. While this temporarily masks the epitopes, aldehyde fixation is a suboptimal solution, degrading over time, resulting in cytotoxicity and rejection. The immune response to foreign tissue eventually leads to chronic inflammation and subsequent graft failure, necessitating reintervention to replace the defective bioprosthetic. Decellularisation to remove immunoincompatible material has been suggested as an alternative to fixation and may prove a superior solution. However, incomplete decellularisation poses a significant challenge, causing a substantial immune rejection response and subsequent graft rejection. This review discusses commercially available grafts used in surgical paediatric CHD intervention, looking specifically at bovine jugular vein conduits as a substitute to cryopreserved homografts, as well as decellularised alternatives to the aldehyde-fixed graft. Mechanisms of biological prosthesis rejection are explored, including the signalling cascades of the innate and adaptive immune response. Lastly, emerging strategies of intervention are examined, including the use of tissue from genetically modified pigs, enhanced crosslinking and decellularisation techniques, and augmentation of grafts through in vitro recellularisation or functionalisation with human surface proteins.