Efficacy and safety of antazoline vs propafenone for conversion of paroxysmal atrial fibrillation to sinus rhythm: a randomized, double-blind study (AnProAF).

INTRODUCTION: Antazoline is a frequently used antiarrhythmic drug (AAD); however, to date, no randomized controlled trial has evaluated its efficacy and safety for cardioversion of recent­onset atrial fibrillation (AF) in comparison with other approved AADs. OBJECTIVES: This study aimed to compare clinical efficacy and safety of antazoline and propafenone for a rapid conversion of nonvalvular paroxysmal AF to sinus rhythm in patients without heart failure. PATIENTS AND METHODS: This was a single­center, randomized, double­blind study. It included patients with AF (lasting <48 hours) who were in a stable cardiopulmonary condition and eligible for cardioversion. The individuals who fulfilled the inclusion criteria were randomly assigned to receive either antazoline (up to 300 mg) or propafenone (up to 140 mg) intravenously. The primary end point was conversion of AF to sinus rhythm confirmed on electrocardiography. RESULTS: Overall, 94 participants (46 [48.9%] in the antazoline group and 48 [51.1%] in the propafenone group) were included. The mean (SD) age was 67.5 (14) years, and 40 participants (42.5%) were men. Successful AF conversion was observed in 29 patients (63%) from the antazoline group and 25 individuals (52.1%) from the propafenone group (P = 0.39). The median time to conversion was 10 minutes in the antazoline group and 30 minutes in the propafenone group (P = 0.03). Severe adverse events were observed in 5 patients (10.8%) treated with antazoline and 5 individuals (10.4%) who received propafenone. CONCLUSIONS: Intravenous antazoline demonstrated efficacy and safety comparable to those of intravenous propafenone for acute conversion of nonvalvular paroxysmal AF to sinus rhythm in patients without heart failure.

Differences in Responses of Immunosuppressed Kidney Transplant Patients to Moderna mRNA-1273 versus Pfizer-BioNTech.

Immunosuppressed kidney transplant (KT) recipients produce a weaker response to COVID-19 vaccination than immunocompetent individuals. We tested antiviral IgG response in 99 KT recipients and 66 healthy volunteers who were vaccinated with mRNA-1273 Moderna or BNT162b2 Pfizer-BioNTech vaccines. A subgroup of participants had their peripheral blood leukocytes (PBLs) evaluated for the frequency of T helper 1 (Th1) cells producing IL-2, IFN-γ and/or TNF-α, and IL-10-producing T-regulatory 1 (Tr) cells. Among KT recipients, 45.8% had anti-SARS-CoV-2 IgG compared to 74.1% of healthy volunteers (p = 0.009); also, anti-viral IgG levels were lower in recipients than in volunteers (p = 0.001). In terms of non-responders (≤2000 U/mL IgG), Moderna's group had 10.8% and Pfizer-BioNTech's group had 34.3% of non-responders at 6 months (p = 0.023); similarly, 15.7% and 31.3% were non-responders in Moderna and Pfizer-BioNTech groups at 12 months, respectively (p = 0.067). There were no non-responders among controls. Healthy volunteers had higher Th1 levels than KT recipients, while Moderna produced a higher Th1 response than Pfizer-BioNTech. In contrast, the Pfizer-BioNTech vaccine induced a higher Tr1 response than the Moderna vaccine (p < 0.05); overall, IgG levels correlated with Th1(fTTNF-α)/Tr1(fTIL-10) ratios. We propose that the higher number of non-responders in the Pfizer-BioNTech group than the Moderna group was caused by a more potent activity of regulatory Tr1 cells in KT recipients vaccinated with the Pfizer-BioNTech vaccine.

Improving Access to HLA-Matched Kidney Transplants for African American Patients.

Introduction: Kidney transplants fail more often in Black than in non-Black (White, non-Black Hispanic, and Asian) recipients. We used the estimated physicochemical immunogenicity for polymorphic amino acids of donor/recipient HLAs to select weakly immunogenic kidney transplants for Black vs. White or non-Black patients. Methods: OPTN data for 65,040 donor/recipient pairs over a 20-year period were used to calculate the individual physicochemical immunogenicity by hydrophobic, electrostatic and amino acid mismatch scores (HMS, EMS, AMS) and graft-survival outcomes for Black vs. White or vs. non-Black recipients, using Kaplan-Meier survival and Cox regression analyses. Simulations for re-matching recipients with donors were based on race-adjusted HMS thresholds with clinically achievable allocations. Results: The retrospective median kidney graft survival was 12.0 years in Black vs. 18.6 years in White (6.6-year difference; p>0.001) and 18.4 years in non-Black (6.4-year difference; p>0.01) recipients. Only 0.7% of Blacks received transplants matched at HLA-A/B/DR/DQ (HMS=0) vs. 8.1% in Whites (p<0.001). Among fully matched Blacks (HMS=0), graft survival was 16.1-years and in well-matched Blacks (HMS ≤ 3.0) it was 14.0-years. Whites had 21.6-years survival at HMS ≤ 3.0 and 18.7-years at HMS ≤ 7.0 whereas non-Blacks had 22.0-year at HMS ≤ 3.0 and 18.7-year at HMS ≤ 7.0, confirming that higher HMS thresholds produced excellent survival. Simulation of ABO-compatible donor-recipient pairs using race-adjusted HMS thresholds identified weakly immunogenic matches at HMS=0 for 6.1% Blacks and 18.0% at HMS ≤ 3.0. Despite prioritizing Black patients, non-Black patients could be matched at the same level as in current allocation (47.0% vs 56.5%, at HMS ≤ 7.0). Conclusions: Race-adjusted HMS (EMS, AMS)-based allocation increased the number of weakly immunogenic donors for Black patients, while still providing excellent options for non-Black recipients.

Low Hydrophobic Mismatch Scores Calculated for HLA-A/B/DR/DQ Loci Improve Kidney Allograft Survival.

We evaluated the impact of human leukocyte antigen (HLA) disparity (immunogenicity; IM) on long-term kidney allograft survival. The IM was quantified based on physicochemical properties of the polymorphic linear donor/recipient HLA amino acids (the Cambridge algorithm) as a hydrophobic, electrostatic, amino acid mismatch scores (HMS\AMS\EMS) or eplet mismatch (EpMM) load. High-resolution HLA-A/B/DRB1/DQB1 types were imputed to calculate HMS for primary/re-transplant recipients of deceased donor transplants. The multiple Cox regression showed the association of HMS with graft survival and other confounders. The HMS integer 0-10 scale showed the most survival benefit between HMS 0 and 3. The Kaplan-Meier analysis showed that: the HMS=0 group had 18.1-year median graft survival, a 5-year benefit over HMS>0 group; HMS ≤ 3.0 had 16.7-year graft survival, a 3.8-year better than HMS>3.0 group; and, HMS ≤ 7.8 had 14.3-year grafts survival, a 1.8-year improvement over HMS>7.8 group. Stratification based on EMS, AMS or EpMM produced similar results. Additionally, the importance of HLA-DR with/without -DQ IM for graft survival was shown. In our simulation of 1,000 random donor/recipient pairs, 75% with HMS>3.0 were re-matched into HMS ≤ 3.0 and the remaining 25% into HMS≥7.8: after re-matching, the 13.5 years graft survival would increase to 16.3 years. This approach matches donors to recipients with low/medium IM donors thus preventing transplants with high IM donors.

The 6-year clinical outcomes for patients registered in a multiregional United States Kidney Paired Donation program - a retrospective study.

We examined what happened during a 6-year period to 1121 end-stage renal disease patients who registered with their willing/incompatible living donors for kidney exchanges with the Alliance for Paired Donation (APD). Of all patients, 65% were transplanted: 37% in kidney paired donation (APD-KPD, APD-other-KPD); 10% with compatible live donors (APD-LD); and 18% with deceased donors (APD-DD). The remaining patients were withdrawn (sick/died/others; 15%), or were still waiting (20%). For those patients with a cPRA 0-94%, 72% received a transplant. In contrast, only 49% of very highly sensitized (VHS; cPRA 95-100%) were transplanted. Of the VHS patients, 50% were transplanted by KPD/APD-LD while 50% benefited through prioritization of deceased donors in the modified kidney allocation system (KAS introduced in 2014). All APD transplanted groups had similar death-censored 4-year graft survivals as their relevant Organ Procurement and Transplantation Network (OPTN) groups. It is noteworthy that VHS graft and patient survival results were comparable to less sensitized and nonsensitized patients. All patients should be encouraged to search for compatible donors through different options. Expanding the donor pool through KPD and the new KAS of the OPTN increases the likelihood of transplantation for VHS patients.

Standard 12-lead electrocardiogram tele-transmission: Support in diagnosing cardiovascular diseases in operations undertaken by Warsaw-area basic medical rescue teams between 2009 and 2013.

BACKGROUND: Basic medical rescue teams (BMRTs) administer aid in the pre-hospital phase to people in a life-threatening condition. A tele-transmission and teleconsultation system (TTaTC) supports the team without a physician. The aim of the presented study was to evaluate the application and spectrum of use of a 12-lead ECG TTaTC in BMRT operations. METHODS: Medical records of BMRTs in Warsaw from September 2009 to August 2013 regarding TTaTC were checked. Successful TTaTC, electrocardiography (ECG) results, sex, age, consultant advice, and decisions of BMRT leaders were analyzed. RESULTS: BMRTs performed 28,557 12-lead ECG transmissions within the analyzed period. The teams recorded 26,208 (91.8%) successful tele-transmissions, while 2,349 tests (8.2%) failed to reach the TC. The average TTaTC time was 6 min 12 s. The most common reason for using the ECG TTaTC was chest pain. ST-segment elevation myocardial infarction (STEMI) was diagnosed in 2.1% of the cases, and non-ST segment elevation myocardial infarction - NSTEMI - in 3.8%. Cardiac arrhythmia was recorded in 20.5% of the events. TTaTC proved to be useful when making decisions on transporting patients to appropriate hospitals. One hundred percent of STEMI cases - all confirmed by TC - were transported directly to cardiac centers. CONCLUSIONS: 1. TTaTC constitutes an increasing support in BMRT everyday operations and is widely used. 2. Standard ECG TTaTC with a physician improved BMRT diagnostic capaci-ties and exerted a beneficial impact on cardiovascular patient segregation and target hospital selection. 3. It seems possible to expand the scope of operations performed by BMRT members based on TTaTC.

PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRß mAb therapy.

AIMS/HYPOTHESIS: T cells play a major role in the pathogenesis of type 1 diabetes, and there is great interest in developing curative immunotherapies targeting these cells. In this study, a monoclonal antibody (mAb) targeting the T cell receptor ß-chain (TCRß) was investigated for its ability to prevent and reverse disease in mouse models of diabetes. METHODS: RIP-OVA(hi) (C57BL/6-Tg(Ins2-OVA)59Wehi/WehiJ) mice adoptively transferred with ovalbumin-specific T cells (an induced model of diabetes) and NOD mice (a spontaneous model of diabetes) were used to test anti-TCRß mAb therapy as a means of preventing and reversing type 1 diabetes. RESULTS: A single dose of anti-TCRß completely prevented disease in RIP-OVA(hi) mice without inducing the release of inflammatory cytokines. Transient anti-TCRß therapy prevented diabetes in 90% of NOD mice and reversed the disease after its onset in 73% of NOD mice. Long after the remission of type 1 diabetes, the anti-TCRß treated mice were able to reject BALB/c skin allografts with normal kinetics while maintaining normoglycaemia. Treatment did not cause significant reductions in lymphocyte numbers in the spleen or pancreatic lymph nodes, but did result in a decreased percentage of chemokine receptor 9 (CCR9) positive, CD8(+) T cells. Notably, anti-TCRß therapy increased the expression of programmed death 1 (PD-1) on the surface of the T cells; PD-1 expression is important for maintaining anti-TCRß-induced self-tolerance, as type 1 diabetes recurs in mice following a blockade of PD-1 signalling. CONCLUSIONS/INTERPRETATION: Anti-TCRß mAb is a safe and effective immunotherapy that results in reduced numbers of CCR9(+) T cells, an increased expression of PD-1 on T cells and the restoration of self-tolerance in NOD mice.

Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP.

Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA.

Optimizing the use of regulatory T cells in allotransplantation: recent advances and future perspectives.

Apart from clonal deletion of self-reactive T cells in the thymus, Tregs are the major regulators of immune responses in the periphery and maintain a state of self-tolerance free from autoimmune diseases. Due to their inherent suppressive function, Tregs are being explored for their therapeutic potential in preventing autoimmunity and improving survival of allografts. This review provides recent updates on Treg biology and their use in animal as well as clinical models of transplantation. We discuss potential problems that limit the widespread clinical application of Tregs and provide future perspectives on how to optimize their medical use. Special consideration is given to methods by which Tregs should be isolated and expanded in order to facilitate clinical therapies. We also focus on recent discussions of Treg stability and plasticity, with specific insights into preventing the loss of Treg suppression by allotransplant-mediated inflammation.

Current approaches in national kidney paired donation programs.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. While living donors provide anywhere from a small to a large fraction of kidneys for transplantation in different countries, at least one-third of these donors are incompatible with their potential recipients. To overcome these challenges, kidney paired donation (KPD) programs have been established that organize donor exchanges to find matches among the pool of incompatible pairs. Each program has developed its own features to accommodate local needs. Reasons for participating in KPD include blood group incompatibility, sensitization of the recipient against the donor, and the potential for improvement in transplant quality (e.g., age difference or graft size), and tissue compatibility. KPD programs use sophisticated algorithms to find matches among the pool of donor-recipient pairs to create simultaneous 2-way, 3-way, or 4-way exchanges or more complex non-simultaneous chains of transplants. These KPD allocation systems should be medically sound and ethically acceptable according to the principles of equity, utility, and justice. The variety of possible exchanges provided by these algorithms allows for maximizing the number of transplants, increasing the quality of transplants, and accommodating patients who are difficult to match. In this review, we describe several examples of successful KPD programs with diverse organizational approaches. By highlighting the strategies used by these programs to meet the needs of their patient populations, we aim to inspire improvements in existing programs and to provide a framework for expanding KPD to better serve international transplant communities.