An Update on Usage of High-Risk Donors in Liver Transplantation

The ideal management for end stage liver disease, acute liver failure, and hepatocellular carcinoma (HCC), within specific criteria, is liver transplantation (LT). Over the years, there has been a steady increase in the candidates listed for LT, without a corresponding increase in the donor pool. Therefore, due to organ shortage, it has been substantially difficult to reduce waitlist mortality among patients awaiting LT. Thus, marginal donors such as elderly donors, steatotic donors, split liver, and donors after cardiac death (DCD), which were once not commonly used, are now considered. Furthermore, it is encouraging to see the passing of Acts, such as the HIV Organ Policy Equity (HOPE) Act, enabling further research and development in utilizing HIV grafts. Subsequently, the newer antivirals have aided in successful post-transplant period, especially for hepatitis C positive grafts. However, currently, there is no standardization, and protocols are center specific in the usage of marginal donors. Therefore, studies with longer follow ups are required to standardize its use.

SARS-CoV-2 Viral Load Assessment in Lung Transplantation

In the era of COVID-19 pandemic, organ transplantation programs were facing serious challenges. The lung transplantation donor pool was extremely limited and SARS-CoV-2 viral load assessment has become a crucial part of selecting an optimal organ donor. Since COVID-19 is a respiratory disease, the viral load is thought to be more important in lung transplantations as compared to other solid organ transplantations. We present two challenging cases of potential lung donors with a questionable COVID-19 status. Based on these cases, we suggest that the cycle threshold (Ct) value should always be requested from the laboratory and the decision whether to proceed with transplantation should be made upon complex evaluation of diverse criteria, including the nasopharyngeal swab and bronchoalveolar lavage PCR results, the Ct value, imaging findings and the medical history. However, as the presence of viral RNA does not ensure infectivity, it is still to be clarified which Ct values are associated with the viral viability. Anti-SARS-CoV-2 IgA antibodies may support the diagnosis and moreover, novel methods, such as quantifying SARS-CoV-2 nucleocapsid antigen in serum may provide important answers in organ transplantations and donor selections.

Profile of Blood Donor Deferrals in a Tertiary Care Centre-Our Institutional Experience

Background: It is the prime duty of transfusion services to provide safe, adequate and timely need of blood and the blood products. Understanding the reasons for donor deferral can help in planning more efficient recruitment strategies and educate and motivate temporarily deferred donors in order to maintain a safe and adequate supply of blood products. Aims of the Study: To evaluate and analyze the blood donor deferral pattern in a tertiary care hospital blood bank and to review its influence on blood safety. Methodology: This retrospective study was conducted in the blood bank, CHRI from the year January 2015 to December 2018. Data like demographic data, clinical history, physical examination, haematological examination, stored in the blood bank was retrived. The donors will be deferred based on standard WHO guidelines. The collected deferral data was analyzed using SPSS software 2011version 20. Results: During the study period there were 7010 registered blood donors. The deferral rate was 5.19%. Among the donor deferrals, females were more commonly deferred ie 31.66%. The deferral rate among voluntary and replacement donors are 4.71% and 11.62% respectively. The rate of permanent deferral (17.86%) was less compared to temporary deferral (82.14%). Among temporary deferral anaemia is the most common cause (27.75%). Seropositive for Hepatitis B is the most common cause for permenant deferral (52.30%). Conclusion: In our study temporary deferral is higher this necessities the need of education, motivation of these donors for future donation to maintain a healthy and safe donor pool.

A Funhouse Mirror: Muscular Co-Contractions as a Reflection of a Spontaneous Aberrant Regeneration of the Brachial Plexus Injury in the Adults: Anatomical Background, an Attempt to Classify and their Clinical Relevance within the Reconstruction Strategies

A certain number of spontaneously recovering birth injuries to the brachial (BPI) plexus are known to be accompanied by muscle co-contractions (Co-Cs). The process of aberrant spontaneous regeneration contributes to the appearance of this phenomenon. Treatment strategies are mostly narrowed down to temporarily “switching off” the antagonist, allowing the agonist to perform. Less is known about the incidence of BPI-associated Co-Cs in adults (a-BPI), the control of which mainly presumes the extrapolation of a treatment strategy that has been shown to be effective in infants. Nowadays, surgical reconstruction of independent elbow flexion at BPIs relies heavily on redirection (transfer) of nerves that produce their own Co-Cs. These induced Co-Cs could potentially be reduced. Selecting the appropriate nerve transfer strategy (when the donor pool is narrowing), with its potential impact on the already complex and intricate global and segmental biomechanics of the upper extremity, becomes challenging. The chapter presents the anatomical background for the occurrence of muscular Co-Cs, a work on clinical classification of both regeneration associated and induced Co-Cs, possible surgical strategies, their benefits and limitations, in the presence of regeneration-associated muscle Co-Cs at a-BPI and clinical examples.

Hemoglobin-Based Oxygen Carriers: Potential Applications in Solid Organ Preservation

Ameliorating graft injury induced by ischemia and hypoxia, expanding the donor pool, and improving graft quality and recipient prognosis are still goals pursued by the transplant community. The preservation of organs during this process from donor to recipient is critical to the prognosis of both the graft and the recipient. At present, static cold storage, which is most widely used in clinical practice, not only reduces cell metabolism and oxygen demand through low temperature but also prevents cell edema and resists apoptosis through the application of traditional preservation solutions, but these do not improve hypoxia and increase oxygenation of the donor organ. In recent years, improving the ischemia and hypoxia of grafts during preservation and repairing the quality of marginal donor organs have been of great concern. Hemoglobin-based oxygen carriers (HBOCs) are “made of” natural hemoglobins that were originally developed as blood substitutes but have been extended to a variety of hypoxic clinical situations due to their ability to release oxygen. Compared with traditional preservation protocols, the addition of HBOCs to traditional preservation protocols provides more oxygen to organs to meet their energy metabolic needs, prolong preservation time, reduce ischemia–reperfusion injury to grafts, improve graft quality, and even increase the number of transplantable donors. The focus of the present study was to review the potential applications of HBOCs in solid organ preservation and provide new approaches to understanding the mechanism of the promising strategies for organ preservation.

Australian Perspectives on Opt-In and Opt-Out Consent Systems for Deceased Organ Donation

Introduction: As many countries change to opt-out systems to address organ shortages, calls for similar reform in Australia persist. Community perspectives on consent systems for donation remain under-researched, therefore Australian perspectives on consent systems and their effectiveness in increasing donation rates were explored. Design: In this descriptive cross-sectional study, participants completed a survey presenting opt-in, soft opt-out, and hard opt-out systems, with corresponding descriptions. Participants chose the system they perceived as most effective and described their reasoning. Results: Participants (N = 509) designated soft opt-out as the most effective system (52.3%; hard opt-out 33.7%; opt-in 13.7%). Those who identified with an ethnic/cultural group or were not registered had greater odds of choosing opt-out. Six themes identified in thematic analysis reflected their reasoning: (1) who decides (individual, shared decision with family); (2) right to choose; (3) acceptability (ethics, fairness); and utility in overcoming barriers for (4) individuals (apathy, awareness, ease of donating, fear/avoidance of death); (5) family (easier family experience, family veto); (6) society (normalizing donation, donation as default, expanding donor pool). Choice and overcoming individual barriers were more frequently endorsed themes for opt-in and opt-out, respectively. Discussion: Results suggested the following insights regarding system effectiveness: uphold/prioritize individual's recorded donation decision above family wishes; involve family in decision making if no donation preference is recorded; retain a register enabling opt-in and opt-out for unequivocal decisions and promoting individual control; and maximize ease of registering. Future research should establish whether systems considered effective are also acceptable to the community to address organ shortages.

Non-Genetic Determinants of Clonotypic T Cell Expansion Following Allogeneic Stem Cell Transplant

Background: The immunologic basis of acute GVHD fundamentally involves alloreactive donor T cells that recognize foreign major histocompatibility complex (MHC)-peptide structures derived from both major and minor antigen mismatches with the host. Within this paradigm, the relationship between the donor and recipient genetics represents a closed system that dictates the potential ability of any given T cell receptor (TCR) to expand, raising the question of whether there are predictable aspects of TCR reconstitution at a clonal level. Take a hypothetical example - if genetically identical twins were to receive allogeneic grafts from the same donor and both recipients develop GVHD, would one expect similar TCRs to be clonally expanded? It has been challenging to rigorously explore this phenomenon, however, because of the vast combinatorial diversity of αβ TCRs, the high prevalence of low copy number TCRs, and sampling constraints - all of which render tracking and comparing TCR expansion between the donor and host difficult. Methods: We address these challenges in order to better understand the predictability TCR clonal dynamics through an analysis platform utilizing 1) a series of matched and mismatched murine transplant experiments where genetically identical littermates receive T cells from the same polyclonal donor pool, thus creating multiple transplant replicates simulating the twin transplant system describe above (Fig 1), and 2) probabilistic modeling of individual TCR frequencies to account for partitioning stochasticity (variation in how low copy number TCRs are distributed from donor to recipient). We conduct high-throughput DNA-based TCR amplicon sequencing for both donor and post-transplant recipient samples to generate over 20 million TCRs and model the expansion rates of all identifiable TCRs in each transplant system using a Bayesian approach. Results: While overall V and J gene usage were similar amongst identical recipients (Fig 2), we find that a small fraction of TCR clonotypes appears to have widely disparate clone counts amongst identical recipients receiving the same donor T cell pool. For example, we saw 9,739, 129 and 0 copies of a particular TCR in 3 different recipients in our B6->B6D2F1 system (Fig 3). In order to distinguish whether TCR count discrepancies seen across identical recipients is simply a reflection of donor partitioning stochasticity or true differential expansion (Fig 4), we apply a Bayesian algorithm to identify differential expanders, which represent TCRs that are asymmetrically expanded between recipients of a genetically identical pair (Fig 5). These TCRs can be generated from both memory and naïve T cell compartments. The presence of these differentially expanded clones amongst identical recipients suggests that non-genetic dependent mechanisms may influence which TCRs expand post-transplant. We next show that broad gut decontamination of microbiota with peri-transplant vancomycin, gentamicin, cefoxitin and metronidazole dramatically reduced the fraction of differential expanders (p<0.0001). However, the change in inflammation from microbiome depletion did not appear to drive this difference, as 1) MyD88/TRIF double knockout recipients (deficient TLR signaling) did not show a reduction in differential expanders, and 2) altering conditioning intensity (900cGy to 1300 cGy TBI) also did not change the fraction of differential expanders. Rather, the difference is likely antigenically driven, as differential expanders are enriched in antigen specificity compared to other TCR sequences (p<0.0001) based on published algorithm that identify TCRs with similar amino acid sequence overlap. Conclusions: These results refine our current understanding of clonal T cell selection and expansion after allogeneic BMT and suggests that for a given transplant system, individual TCR selection is not solely dictated by genetic donor and recipient major and/or minor histocompatibility disparities. Rather, microbiota-derived molecules appear to behave as minor antigens to direct systemic clonal TCR selection. These data suggest a novel mechanism by which the microbiome may modulate transplant outcome, challenging current paradigms suggesting the microbiota primarily drive inflammation via their PAMP activities. Figure 1 Figure 1. Disclosures Hill: Applied Molecular Transport: Research Funding; Syndax Pharmaceuticals: Research Funding; Compass Therapeutics: Research Funding; NapaJun Pharma: Consultancy; Generon corporation: Consultancy; iTeos Therapeutics: Consultancy, Research Funding; Neoleukin Therapeutics: Consultancy; Roche: Research Funding.

Do Trade Agreements Contribute to the Decline in Labor Share? Evidence from Latin American Countries

In this paper, we explore the role of trade in the evolution of labor share in Latin American countries. We use trade agreements with large economies (the United States, the European Union, and China) to capture the effect of sharp changes in trade. In the last two decades, labor share has displayed a negative trend among those countries that signed trade agreements, while in other countries labor share increased, widening the gap by 7 percentage points. We apply synthetic control methods to estimate the average causal impact of trade agreements on labor share. While effects are heterogeneous in our eight case studies, the average impact is negative between 2 to 4 percentage points of GDP four years after the entry into force of the trade agreements. This result is robust to the specification used and to the set of countries in the donor pool. We also find that, after trade agreements, exports of manufactured goods and the share of industry in GDP increase on average, most notably in the case studies where negative effects on labor share are significant. A decomposition shows that all the reduction in labor share is explained by a negative impact on real wages.

Sex Disparities in Organ Donation: Finding an Equitable Donor Pool

Background The majority of living organ donors are women, but few are deceased organ donors, which increases risks associated with sex mismatched organs. We sought to identify reasons for sex disparities in organ donation and strategies for equity. Methods and Results Using Amazon's Mechanical Turk, we examined US adults' perceptions regarding donation in a mixed‐methods survey study. Results were compared by sex with Fisher's exact test and T‐tests for quantitative results and qualitative descriptive analyses for write‐in responses. Among 667 participants (55% women), the majority of men (64.8%) and women (63.4%) self‐identified as registered donors. Women's willingness to donate their own organs to family members ( P =0.03) or strangers ( P =0.03) was significantly higher than men. Donors from both sexes were guided by: desire to help, personal experience, and believing organs would be useless to deceased donors. Non‐donors from both sexes were guided by: no reason, medical mistrust, contemplating donation. When considering whether to donate organs of a deceased family member, women were equally guided by a family member's wishes and believing the family member had no further use for organs. Men had similar themes but valued the family member's wishes more. Among non‐donors, both sexes would consider donation if more information was provided. Conclusions In a national survey, both sexes had similar reasons for becoming and not becoming an organ donor. However, compared with men, women were more willing to donate their organs to family members and strangers. Improving education and communicating wishes regarding organ donation with direct relatives may increase sex equity in deceased organ donation.

Ex vivo normothermic perfusion in heart transplantation: a review of the TransMedics® Organ Care System

Cardiac transplantation is the gold standard for treatment for select patients with end-stage heart failure, yet donor supply is limited. Ex vivo machine perfusion is an emerging technology capable of safely preserving organs and expanding the viable donor pool. The TransMedics® Organ Care System™ is an investigational device which mimics physiologic conditions while maintaining the heart in a warm, beating state rather than cold storage. The use of Organ Care System allows increased opportunities for using organs from marginal donors, distant procurement sites, donation after cardiac death, and in recipients with complex anatomy. In the future, bioengineering technologies including use of mesenchymal stem cells, viral vector delivery of gene therapy, and alternate devices may further broaden the field of ex vivo machine perfusion.