Tracking the immune response profiles elicited by the BNT162b2 vaccine in COVID-19 unexperienced and experienced individuals.

Multiple vaccines have been approved to control COVID-19 pandemic, with Pfizer/BioNTech (BNT162b2) being widely used. We conducted a longitudinal analysis of the immune response elicited after three doses of the BNT162b2 vaccine in individuals who have previously experienced SARS-CoV-2 infection and in unexperienced ones. We conducted immunological analyses and single-cell transcriptomics of circulating T and B lymphocytes, combined to CITE-seq or LIBRA-seq, and VDJ-seq. We found that antibody levels against SARS-CoV-2 Spike, NTD and RBD from wild-type, delta and omicron VoCs show comparable dynamics in both vaccination groups, with a peak after the second dose, a decline after six months and a restoration after the booster dose. The antibody neutralization activity was maintained, with lower titers against the omicron variant. Spike-specific memory B cell response was sustained over the vaccination schedule. Clonal analysis revealed that Spike-specific B cells were polyclonal, with a partial clone conservation from natural infection to vaccination. Spike-specific T cell responses were oriented towards effector and effector memory phenotypes, with similar trends in unexperienced and experienced individuals. The CD8 T cell compartment showed a higher clonal expansion and persistence than CD4 T cells. The first two vaccinations doses tended to induce new clones rather than promoting expansion of pre-existing clones. However, we identified a fraction of Spike-specific CD8 T cell clones persisting from natural infection that were boosted by vaccination and clones specifically induced by vaccination. Collectively, our observations revealed a moderate effect of the second dose in enhancing the immune responses elicited after the first vaccination. Differently, we found that a third dose was necessary to restore comparable levels of neutralizing antibodies and Spike-specific T and B cell responses in individuals who experienced a natural SARS-CoV-2 infection.

Allografts use in orthopedic surgery: trend change over the past 11 years from a regional tissue bank.

Allografts are the second most transplanted tissue in medicine after blood and are now increasingly used for both primary and revision surgery. Allografts have the advantages of lower donor site morbidity, availability of multiple grafts, and shorter operative time. The Banks represents the bridge between Donor and Recipient and guarantees the quality and safety of the distributed allografts Given the increasing interest in these tissues, a retrospective analysis of data collected from the Regional Musculoskeletal Tissue Bank registry over an 11-year period (2009-2019) was conducted. The statistical analyses used were the Shapiro-Wilk normality test and a Poisson regression model. From January 2009 to December 2019, a total of 14,199 musculoskeletal tissues stored in the Regional Musculoskeletal Tissue Bank were provided for surgical allograft procedures. In 2009, the number of allografts performed was 925; this figure has steadily increased to 1599 in 2019. Epiphyses were taken as the reference tissue with an almost constant trend over the period, while a significant increase was denoted for extensor mechanism allograft, ligaments, tendons and long bone corticals (p < 0.001), processed bone tissues had no change in trend (p = 0.841). There was also a gradual decrease in the rate of microbiological positivity, as determined by bacteriological and serological tests performed on the collected tissues. This phenomenon is due to improved sampling techniques and the training of a dedicated team. Thus, we have seen how the use of allografts in orthopedic surgery has increased over the past 11 years, uniformly in terms of tissue type, except for the noticeable increase in ligamentous tissue.

Improving outcomes of in situ split liver transplantation in Italy over the last 25 years.

BACKGROUND & AIMS: Split liver transplant(ation) (SLT) is still considered a challenging procedure that is by no means widely accepted. We aimed to present data on 25-year trends in SLT in Italy, and to investigate if, and to what extent, outcomes have improved nationwide during this time. METHODS: The study included all consecutive SLTs performed from May 1993 to December 2019, divided into three consecutive periods: 1993-2005, 2006-2014, and 2015-2019, which match changes in national allocation policies. Primary outcomes were patient and graft survival, and the relative impact of each study period. RESULTS: SLT accounted for 8.9% of all liver transplants performed in Italy. A total of 1,715 in situ split liver grafts were included in the analysis: 868 left lateral segments (LLSs) and 847 extended right grafts (ERGs). A significant improvement in patient and graft survival (p <0.001) was observed with ERGs over the three periods. Predictors of graft survival were cold ischaemia time (CIT) <6 h (p = 0.009), UNOS status 2b (p <0.001), UNOS status 3 (p = 0.009), and transplant centre volumes: 25-50 cases vs. <25 cases (p = 0.003). Patient survival was significantly higher with LLS grafts in period 2 vs. period 1 (p = 0.008). No significant improvement in graft survival was seen over the three periods, where predictors of graft survival were CIT <6 h (p = 0.007), CIT <6 h vs. ≥10 h (p = 0.019), UNOS status 2b (p = 0.038), and UNOS status 3 (p = 0.009). Retransplantation was a risk factor in split liver graft recipients, with significantly worse graft and patient survival for both types of graft (p <0.001). CONCLUSIONS: Our analysis showed Italian SLT outcomes to have improved over the last 25 years. These results could help to dispel reservations regarding the use of this procedure. IMPACT AND IMPLICATIONS: Split liver transplant(ation) (SLT) is still considered a challenging procedure and is by no means widely accepted. This study included all consecutive in situ SLTs performed in Italy from May 1993 to December 2019. With more than 1,700 cases, it is one of the largest series, examining long-term national trends in in situ SLT since its introduction. The data presented indicate that the outcomes of SLT improved during this 25-year period. Improvements are probably due to better recipient selection, refinements in surgical technique, conservative graft-to-recipient matching, and the continuous, yet carefully managed, expansion of donor selection criteria under a strict mandatory split liver allocation policy. These results could help to dispel reservations regarding the use of this procedure.

SARS-COV-2 specific t-cells in patients with thyroid disorders related to COVID-19 are enriched in the thyroid and acquire a tissue-resident memory phenotype.

BACKGROUND: SARS-CoV-2 infections have been associated with the onset of thyroid disorders like classic subacute thyroiditis (SAT) or atypical SAT upon severe COVID disease (COV-A-SAT). Little is known about thyroid anti-viral immune responses. OBJECTIVES: To define the role of T-cells in COV-A-SAT. METHODS: T-cells from COV-A-SAT patients were analyzed by multi-dimensional flow cytometry, UMAP and DiffusionMap dimensionality reduction and FlowSOM clustering. T-cells from COVID-naïve healthy donors, patients with autoimmune thyroiditis (ATD) and with SAT following COVID vaccination were analyzed as controls. T-cells were analyzed four and eight months post-infection in peripheral blood and in thyroid specimen obtained by ultrasound-guided fine needle aspiration. SARS-COV2-specific T-cells were identified by cytokine production induced by SARS-COV2-derived peptides and with COVID peptide-loaded HLA multimers after HLA haplotyping. RESULTS: COV-A-SAT was associated with HLA-DRB1*13 and HLA-B*57. COV-A-SAT patients contained activated Th1- and cytotoxic CD4+ and CD8+ effector cells four months post-infection, which acquired a quiescent memory phenotype after eight months. Anti-SARS-CoV-2-specific T-cell responses were readily detectable in peripheral blood four months post-infection, but were reduced after eight months. CD4+ and CD8+ tissue-resident memory cells (TRM) were present in the thyroid, and circulating CXCR3+T-cells identified as their putative precursors. SARS-CoV-2-specific T-cells were enriched in the thyroid, and acquired a TRM phenotype eight months post-infection. CONCLUSIONS: The association of COV-A-SAT with specific HLA haplotypes suggests a genetic predisposition and a key role for T-cells. COV-A-SAT is characterized by a prolonged systemic anti-viral effector T-cell response and the late generation of COVID-specific TRM in the thyroid target tissue.

Histological evaluation of ischemic alterations in donors after cardiac death: A useful tool to predict post-transplant renal function.

Kidneys retrieved from donors after cardiac death (DCD) pose significant challenges from a clinical and technical point of view, undergoing a variable degree of ischemia-reperfusion injury. At present, the utilization of kidneys is assessed according to the Karpinski score, which does not take into account the ischemic insult and does not predict the functional recovery of the organ once transplanted. Therefore, the correlation between biopsy results and post-transplant graft function is still debated. In this study we examined kidney biopsies from DCD donors; we calculated the Karpinski score and subsequently identified and quantified the ischemic lesions in the glomerular, interstitial, and tubular compartments. These same lesions were quantified in kidney biopsies from donors after brain death (DBD) in a case-control analysis. The collected data were correlated with the clinical data of the donors and the post-transplant follow-up. Proximal tubule alterations are crucial in ischemia-reperfusion damage, showing precise histological alterations, which are more frequent in DCD than in DBD donors and are statistically correlated with functional recovery of the organ. Quantification of ischemic tubular lesions in biopsies of kidneys from DCD donors is a useful tool for predicting post-transplant renal function and a valid parameter for assessing the quality of the graft.

Donation after circulatory death and liver transplantation: a cohort study.

Donations after circulatory death (DCD) are still challenging in Italy because of prolonged ischemia time (tWIT) due to the law and logistical issues. This cohort study was primarily aimed at assessing the association between successful transplantation and DCD types in the North Italy Transplant program. Adjusted risk ratios (RR) and 95% confidence intervals (CIs) for type III versus type II DCD were estimated using a Poisson regression model with a robust error variance. All consecutive DCD between 2008 and 2020 were included. Among 142 DCD, 102 were eligible for liver donation, and 96 were proposed: 68/69 (99%) and 28/33 (85%) type III and II DCD, respectively. Sixty-nine livers were recovered, 51/68 (75%) from type III and 18/28 (64%) from type II DCD, respectively (RR: 1.18; 95% CI: 0.87-1.60). After ex-vivo perfusion, 50/68 (74%) and 14/28 (50%) livers from type III and type II DCD were transplanted (RR: 1.49; 95% CI: 1.01-2.19). The estimate decreased after further controlling for tWIT (RR: 1.11; 95% CI: 0.55-2.24). Five patients (7.8%) experienced a PNF, 3/50 and 2/14 from type III and type II DCD, respectively. Type III DCD livers were more likely to be transplanted than type II. Warm ischemia time might explain this difference.

Fifteen years and 382 extended right grafts from in situ split livers in a multicenter study: Are these still extended criteria liver grafts?

In situ split liver extended right grafts (SL-ERGs) are still considered marginal grafts. Our aim was to verify this statement at the present time. From 1997 to 2011, a multicenter, retrospective study based on a prospective database was performed at 9 liver transplantation (LT) centers in northern Italy; it included 382 in situ SL-ERG transplants in adults. There were 358 primary LTs and 24 retransplantations (RETXs). The 1-, 3-, and 5-year overall graft survival rate for LT with in situ SL-ERGs were 73.5%, 63.3%, and 60.7%, respectively, from 1997 to 2004 and 83.5%, 80.3%, and 80.3%, respectively, thereafter (P=0.0001). A shorter total ischemia time and fewer RETX grafts were the main differences between the characteristics of the 2 periods. From 1997 to 2011, the 1-, 3-, and 5-year graft survival rates showed a significant difference between the 358 primary LT in situ SL-ERGs and the 24 RETX in situ SL-ERGs (P<0.001). In a multivariate analysis, the main prognostic factor for 60-day graft survival was a total ischemia time<8 hours for the 358 primary in situ SL-ERGs. From 2005 to 2011, in 2473 LTs, the 5-year graft survival for 184 in situ SL-ERGs and 2289 whole grafts was 75% and 80% (P=0.3), respectively. Univariate and multivariate studies alike failed to indicate that the type of graft was a prognostic factor for graft survival. A donor age>60 years, RETX grafts, and urgency were the main prognostic factors for failure for all of the grafts. Although caution should be taken regarding the choice of appropriate donors, in situ SL-ERGs should no longer be considered marginal grafts for experienced LT centers. SL-ERGs should not be used in RETX settings, and when SL-ERGs are used as primary grafts, the total ischemia time should be less than 8 hours.

Cost-effectiveness of pretransplant sofosbuvir for preventing recurrent hepatitis C virus infection after liver transplantation.

There are reports of pretransplant sofosbuvir (SOF) plus ribavirin being effective in preventing recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). The aim of this study was to assess the cost-effectiveness of this strategy in the area served by the North Italy Transplant program. We retrospectively assessed the impact of HCV infection on post-LT survival in 2376 consecutive adult patients (MELD ≤ 25, unknown genotype, period 2004-2009) and the prevalence costs of conventional standard of care (SOC) antiviral therapy (pegylated interferon plus ribavirin) after LT. A Markov model was developed to compare two strategies: 12-24 weeks of SOF+ ribavirin for pre-LT anti-HCV treatment versus on-demand post-LT SOC antiviral therapy. Among the 1794 patients undergoing LT, 860 (48%) were HCV+ and 50% of them were given SOC therapy after LT (mean cost of drugs and adverse effect management = 14,421€ per patient). HCV etiology had a strong impact on post-LT survival (hazard ratio = 1.59, 95% CI = 1.22-2.09, P = 0.0007). After Monte Carlo simulation, pre-LT SOF therapy showed a median survival benefit of 1.5 quality-adjusted life years and an Incremental cost-effectiveness ratio (ICER) of 30,663€/QALY, proving cost-effective in our particular Italian scenario. The costs of SOF therapy, sustained viral response rate 12 weeks after LT, and recipient's age were the main ICER predictors at multivariate analysis. This study proposes a dynamic model based on real-life data from northern Italy for adjusting the costs of pre-LT direct-acting antiviral therapies to the actual sustained virological response reached after LT.

A method for establishing allocation equity among patients with and without hepatocellular carcinoma on a common liver transplant waiting list.

BACKGROUND & AIMS: The current organ allocation system for liver transplantation (LT) creates an imbalance between patients with and without hepatocellular carcinoma (HCC). We describe a model designed to re-establish allocation equity among patient groups using transplant benefit as the common endpoint. METHODS: We enrolled consecutive adult patients entering the waiting list (WL group, n=2697) and undergoing LT (LT group, n=1702) during the period 2004-2009 in the North Italy Transplant program area. Independent multivariable regressions (WL and LT models) were created for patients without HCC and for those with stage T2 HCC. Monte Carlo simulation was used to create distributions of transplant benefit, and covariates such as Model for End-stage Liver Disease (MELD) and alpha-fetoprotein (AFP) were combined in regression equations. These equations were then calibrated to create an "MELD equivalent" which matches HCC patients to non-HCC patients having the same numerical MELD score. RESULTS: Median 5 year transplant benefit was 15.12 months (8.75-25.35) for the non-HCC patients, and 28.18 months (15.11-36.38) for the T2-HCC patients (p<0.001). Independent predictors of transplant benefit were MELD score (estimate=0.89, p<0.001) among non-HCC patients, and MELD (estimate=1.14, p<0.001) and logAFP (estimate=-0.46, p<0.001) among HCC patients. The equation "HCC-MELD"=1.27∗MELD - 0.51∗logAFP+4.59 calculates a numerical score for HCC patients, whereby their transplant benefit is equal to that of non-HCC patients with the same numerical value for MELD. CONCLUSIONS: We describe a method for calibrating HCC and non-HCC patients according to survival benefit, and propose that this method has the potential, if externally validated, to restore equity to the organ allocation system.

A prospective policy development to increase split-liver transplantation for 2 adult recipients: results of a 12-year multicenter collaborative study.

OBJECTIVE: To analyze in a multicenter study the potential benefit of a new prospective policy development to increase split-liver procedures for 2 adult recipients. BACKGROUND: Split-liver transplantation is an important means of overcoming organ shortages. Division of the donor liver for 1 adult and 1 pediatric recipient has reduced the mortality of children waiting for liver transplantation but the benefits or disadvantages to survival when the liver is divided for 2 adults (adult-to-adult split-liver transplant, AASLT) compared with recipients of a whole graft have not been fully investigated. METHODS: We developed a computerized algorithm in selected donors for 2 adult recipients and applied it prospectively over a 12-year period among 7 collaborative centers. Patient and graft outcomes of this cohort receiving AASLT either as full right grafts or full left grafts were analyzed and retrospectively compared with a matched cohort of adults who received a conventional whole-liver transplant (WLT). Univariate and multivariate analysis was done for selected clinical variables in the AASLT group to assess the impact on the patient outcome. RESULTS: Sixty-four patients who received the AASLT had a high postoperative complication rate (64.1% grade III and IV) and a lower 5-year survival rate than recipients of a WLT (63.3% and 83.1%) CONCLUSIONS: AASLT should be considered a surgical option for selected smaller-sized adults only in experimental clinical studies in experienced centers.

Assessing the reliability of rapid frozen tissue sections from pre-transplant kidney biopsies in DCD donors and correlations with clinico-pathological data: a pilot study.

Compared to donations after brain death, donations after circulatory death present a series of difficulties: the acquisition of the family's consent, the need for qualified personnel and specific resources, death assessment, assessment of the organ, and graft care (pre- and post-transplant). These are all time-related factors that negatively impact the organ, resulting in increased tubular, glomerular, and vascular damage. The evaluation of the organ, as per today's standards, requires three hours for the preparation and processing of formalin-fixed paraffin-embedded (FFPE) samples. An alternative to this is the use of the extemporaneous frozen biopsy. However, frozen samples are considered a second choice in the decision-making process. This retrospective study investigates the reliability of the frozen samples in identifying a series of morphological alterations compared to the more accepted results from FFPE samples. Additionally, two important clinical data, terminal serum creatinine levels and warm ischemia time, were correlated to the presence of some morphological alterations in an attempt to find effective and fast strategies to predict the kidney transplant outcome.

Fairness and pitfalls of the Italian waiting list for elective liver transplantation: The ECALITA registry study.

BACKGROUND: The challenge of transplant waiting-lists is to provide organs for all candidates while maintaining efficiency and equity. AIMS: We investigated the probability of being transplanted or of waiting-list dropout in Italy. METHODS: Data from 12,749 adult patients waitlisted for primary liver-transplantation from January 2012 to December 2022 were collected from the National Transplant-Registry.The cohort was divided into Eras:1 (2012-2014);2 (2015-2018);and 3 (2019-2022). RESULTS: The one-year probability of undergoing transplant increased (67.6 % in Era 1vs73.8 % in Era 3,p < 0001) with a complementary 46 % decrease in waiting-list failures. Patients with hepatocellular-carcinoma were transplanted more often than cirrhotics[at model for end-stage liver-disease (MELD)-15:HR = 1.28,95 %CI:1.21-1.35;at MELD-25:HR = 1.04,95 %CI:0.92-1.19) and those with other indications (at MELD-15:HR = 1.27,95 %CI:1.11-1.46) across all eras. Candidates with Hepatitis-B-virus (HBV)related disease had a greater probability of transplant than those with Hepatitis-C virus-related (HR = 1.13,95 %CI:1.07-1.20), alcohol-related (HR = 1.13,95 %CI:1.05-1.21), and metabolic-related (HR = 1.18,95 %CI:1.09-1.28)disease. Waiting-list failures increased by 27 % every 5 MELD-points and by 14 % for every 5-year increase in recipient-age and decreased by 10 % with each 10-cm increase in stature. Blood-group O patients showed the highest probability of waiting-list failure (HR = 1.28,95 %CI:1.15-1.43). CONCLUSIONS: Liver-transplantation waiting-list success-rates have significantly improved in Italy, with patients with hepatocellular-carcinoma and/or HBV-related diseases being favored. High MELD-score, old-age, short-stature, and blood-group O were significant risk-factors for waiting-list failure. Efforts to improve organ-allocation and prioritization-policies are underway.

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study.

BACKGROUND AND RATIONALE: Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear. MATERIAL AND METHODS: We carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009-December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30-59mL/min/1.73m2), severe CKD (eGFR, 15-29mL/min/1.73m2), and end-stage renal disease (ESRD). RESULTS: We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD - 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis. CONCLUSION: The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.

Temporal trends of waitlistings for liver transplantation in Italy: The ECALITA (Evolution of IndiCAtion in LIver transplantation in ITAly) registry study.

BACKGROUND: Over the last decades relevant epidemiological changes of liver diseases have occurred, together with greatly improved treatment opportunities. AIM: To investigate how the indications for elective adult liver transplantation and the underlying disease etiologies have evolved in Italy. METHODS: We recruited from the National Transplant Registry a cohort comprising 17,317 adults patients waitlisted for primary liver transplantation from January-2004 to December-2020. Patients were divided into three Eras:1(2004-2011),2(2012-2014) and 3(2015-2020). RESULTS: Waitlistings for cirrhosis decreased from 65.9% in Era 1 to 46.1% in Era 3, while those for HCC increased from 28.7% to 48.7%. Comparing Eras 1 and 3, waitlistings for HCV-related cirrhosis decreased from 35.9% to 12.1%, yet those for HCV-related HCC increased from 8.5% to 26.7%. Waitlistings for HBV-related cirrhosis remained almost unchanged (13.2% and 12.4%), while those for HBV-related HCC increased from 4.0% to 11.6%. ALD-related cirrhosis decreased from 16.9% to 12.9% while ALD-related HCC increased from 1.9% to 3.9%. CONCLUSIONS: A sharp increase in liver transplant waitlisting for HCC and a concomitant decrease of waitlisting for cirrhosis have occurred In Italy. Despite HCV infection has noticeably decreased, still remains the primary etiology of waitlisting for HCC, while ALD and HBV represent the main causes for cirrhosis.

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study.

BACKGROUND AND RATIONALE: Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear. MATERIAL AND METHODS: We carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009-December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30-59mL/min/1.73m2), severe CKD (eGFR, 15-29mL/min/1.73m2), and end-stage renal disease (ESRD). RESULTS: We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD - 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis. CONCLUSION: The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.

Discovered cancers at postmortem donor examination: A starting point for quality improvement of donor assessment.

BACKGROUND: clinical and imaging investigations allow a detailed assessment of an organ donor, but a quota of cancer still elude detection. Complete autopsy of donors is even less frequently performed, due to economic issues and increasing availability of high-quality imaging. The aim of this study is to gather evidence from the literature on donor malignancy discovered at autopsy following organ donation and to discuss the utility and limitations of autopsy practice in the field of transplantation. METHODS: A systematic search according to PRISMA guidelines was carried out in Pubmed and Embase databases until September 2020 to select articles with reporting of cancer discovered in a donor at postmortem examination. Cancer discover in not-transplant setting were excluded. A descriptive synthesis was provided. RESULTS: Of 7388 articles after duplicates removal, 56 were included. Fifty-one studies reported on complete autopsy, while 5 dealt only with limited autopsy (prostate and central nervous system). The number of autopsies ranged between 1 and 246 with a total of 823 autopsies performed. The most frequent cancer discovered at autopsy was lymphoma (n = 13, 15%), followed by renal cell carcinoma (RCC) (n = 11, 13%), non-small cell lung cancer (NSCLC) (n = 10, 11%), melanoma (n = 10, 11%), choriocarcinoma (n = 6, 7%) and glioblastoma (GBM) (n = 6, 7%). CONCLUSIONS: Lymphoma and melanoma are still difficult-to-detect cancers both during donor investigation and at procurement, whilst prostate cancer and choriocarcinoma are almost always easily detected nowadays thank to blood markers and clinical examination. There have been improvements with time in pre-donation detection procedures which are now working well, particularly when complete imaging investigations are performed, given that detection rate of CT/MRI is high and accurate. Autopsy can play a role to help to establish the correct donor management pathways in case of cancer discover. Furthermore, it helps to better understand which cancers are still eluding detection and consequently to refine guidelines' assessment procedures.

The 3-T Model of Informed Consent for Nonstandard Risk Donors: A Proposal for Transplant Clinical Practice.

BACKGROUND: The risk of disease transmission from nonstandard risk donors (NSRDs) is low, and outcomes are similar or better relative to transplants performed with standard criteria donors. However, NSRDs have posed new ethical challenges to the informed consent (IC) process. Based on the shared decision-making model, coinciding with the 3 main timings of the IC process ([1] pretransplant assessments and waiting list registration, [2] time on the waiting list, and [3] time of the organ offer), we put forward a model (3-T Model) to summarize the knowledge on IC for NSRDs and to deliver conceptual and practical support to transplant providers on this emergent issue. METHODS: We searched PubMed and analyzed data from our area to provide evidence and ethical arguments to promote standardization of the timing of patient information, degree of patient participation, and disclosure of donor risk factors throughout the 3 stages of the time continuum leading to the potential acceptance of NSRDs. RESULTS: Each of the 3 timings carries special ethical significance and entails well-defined duties for transplant providers relative to patient involvement and information of the benefits and risks associated with NSRDs. Based on our framework, experience, and interpretation of the literature, we put forward a list of recommendations to combine standardization (ie, timing, content, and degree of patient participation) and individualization of IC. CONCLUSIONS: The 3-T Model may enable the prevention of physicians' arbitrariness and the promotion of patient-centered care. Future studies will assess the effectiveness of the 3-T Model in transplant clinical practice.

Integrated longitudinal immunophenotypic, transcriptional and repertoire analyses delineate immune responses in COVID-19 patients.

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5+ T-BET+ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8+ T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8+ T lymphocytes, while CD4+ T cells were less expanded and skewed toward TCM and TH2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8+ GZMB+ effector cells were clonally expanded both during the infection and post-infection, while CD8+ GZMK+ lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8+ GZMB+ and GZMK+ subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8+ T cell population with memory precursor-like features.

Human leukocyte antigen crossmatch testing is important for liver retransplantation.

Although human leukocyte antigen (HLA) crossmatching is often thought to be unnecessary for liver transplants (LTs), we provide evidence that for retransplants, it is essential. Sera from 139 retransplant patients who had received livers from deceased donors were retrospectively analyzed with single antigen beads on a Luminex platform for HLA antibodies. Each patient received at least 2 transplants and was followed up for at least 6 months from the second LT, which was deemed to have failed if the patient had a third LT or died. Second LT survival was calculated from the date of the second LT to the date of the third LT or death. Our study cohort consisted of 118 adult patients (> or = 18 years old) as well as 21 pediatric patients (<18 years old). Class I HLA antibodies were associated with significantly poorer regraft survival in adults [survival differences of 21.3% (P = 0.046), 22.1% (P = 0.042), and 23.7% (P = 0.033) at 1, 3, and 5 years, respectively]; however, the presence of these antibodies was not associated with significant survival differences in the pediatric population. A univariate analysis of the effect of class I antibodies on second LT survival in adults showed a hazard ratio of 2.0 (95% confidence interval = 1.0-3.8, P = 0.028). Graft survival in patients with and without HLA antibodies or class II antibodies was similar. Because class I antibodies have a deleterious effect on liver regraft survival, crossmatch testing should be performed before liver retransplantation.