Highly Sensitized Candidates Remain at Risk for Microvascular Inflammation Even When Donor-specific Antibody Is Avoided: A Matched Cohort Study.

BACKGROUND: Microvascular inflammation (MVI) is a key feature of antibody-mediated rejection (AMR) among patients with HLA donor-specific antibody (DSA), but MVI at AMR thresholds (Banff glomerulitis [g] + peritubular capillaritis [ptc] score ≥ 2) without DSA has been increasingly recognized. We aimed to determine the incidence of MVI among highly sensitized kidney transplant recipients without DSA. METHODS: We performed a single-center, retrospective, matched cohort study comparing outcomes of kidney transplant recipients with cPRA ≥90% with preexisting DSA (n = 49), cPRA ≥90% without preexisting DSA (n = 47), and matched controls with cPRA = 0 without preexisting DSA (n = 49). Controls were matched by age, donor type, and transplant date. Indication and surveillance biopsies combined with annual de novo DSA screening were obtained. RESULTS: Kidney transplant recipients with a cPRA ≥90% and no evidence of preexisting or de novo DSA had a higher incidence of MVI (glomerulitis + peritubular capillaritis ≥ 2) than patients with cPRA = 0 [35% (17/49) versus 12% (6/49), P = 0.0003] over a median (interquartile range) follow-up of 5 (4-6) y posttransplant. Among this cPRA ≥90% group without DSA, MVI persisted in 54% of cases on follow-up biopsy (7/13), and 24% (4/13) of cases developed transplant glomerulopathy (Banff cg score > 0). CONCLUSIONS: Highly sensitized transplant recipients have a high incidence of persistent and progressive MVI, even without DSA. The mechanisms underlying these histologic features needs to be elucidated, but this information is important to consider when making decisions about transplantation among highly sensitized individuals.

The Significance of Major Histocompatibility Complex Class I Chain-related Molecule A in Solid Organ and Hematopoietic Stem Cell Transplantation: A Comprehensive Overview.

Improving long-term allograft survival and minimizing recipient morbidity is of key importance in all of transplantation. Improved matching of classical HLA molecules and avoiding HLA donor-specific antibody has been a major focus; however, emerging data suggest the relevance of nonclassical HLA molecules, major histocompatibility complex class I chain-related gene A (MICA) and B, in transplant outcomes. The purpose of this review is to discuss the structure, function, polymorphisms, and genetics of the MICA molecule and relates this to clinical outcomes in solid organ and hematopoietic stem cell transplantation. The tools available for genotyping and antibody detection will be reviewed combined with a discussion of their shortcomings. Although data supporting the relevance of MICA molecules have accumulated, key knowledge gaps exist and should be addressed before widespread implementation of MICA testing for recipients pre- or posttransplantation.

Early post-transplant recurrence of ANCA vasculitis while on belatacept maintenance immunosuppression.

Post-transplant recurrence of ANCA-associated vasculitis (AAV) is infrequent, with recurrence within weeks of transplantation being even rarer. We describe an unusual case of AAV recurrence within 2 weeks post-transplant. Our patient received a deceased donor kidney transplant (KDPI 60%) after 6 years on hemodialysis for end-stage renal disease from AAV. She was induced with thymoglobulin and steroids, and maintained on belatacept, mycophenolate and prednisone. Time-zero biopsy showed acute tubular injury. Due to persistent delayed graft function by post-operative day 14, she underwent repeat biopsy, which showed focal segmental necrotizing and crescentic glomerulonephritis, with positive MPO, PR3 and negative anti-glomerular basement membrane antibodies. As her findings were in keeping with recurrent AAV, she underwent induction with rituximab, prednisone and intravenous immunoglobulin, with repeat rituximab 14 days later because of increasing B-lymphocyte counts. Belatacept was replaced with tacrolimus due to concerns with autoimmunity. Fortunately, renal function began to recover 4 days after treatment. In addition to highlighting potential immunologic mechanisms in AAV and the use of rituximab in post-transplant recurrence, our case suggests that for systemic autoimmune disease, patients maintained on belatacept must be monitored closely for recurrence, particularly in the setting of delayed graft function.

Multi-Level Neuromorphic Devices Built on Emerging Ferroic Materials: A Review.

Achieving multi-level devices is crucial to efficiently emulate key bio-plausible functionalities such as synaptic plasticity and neuronal activity, and has become an important aspect of neuromorphic hardware development. In this review article, we focus on various ferromagnetic (FM) and ferroelectric (FE) devices capable of representing multiple states, and discuss the usage of such multi-level devices for implementing neuromorphic functionalities. We will elaborate that the analog-like resistive states in ferromagnetic or ferroelectric thin films are due to the non-coherent multi-domain switching dynamics, which is fundamentally different from most memristive materials involving electroforming processes or significant ion motion. Both device fundamentals related to the mechanism of introducing multilevel states and exemplary implementations of neural functionalities built on various device structures are highlighted. In light of the non-destructive nature and the relatively simple physical process of multi-domain switching, we envision that ferroic-based multi-state devices provide an alternative pathway toward energy efficient implementation of neuro-inspired computing hardware with potential advantages of high endurance and controllability.

In situ unsupervised learning using stochastic switching in magneto-electric magnetic tunnel junctions.

Spiking neural networks (SNNs) offer a bio-plausible and potentially power-efficient alternative to conventional deep learning. Although there has been progress towards implementing SNN functionalities in custom CMOS-based hardware using beyond Von Neumann architectures, the power-efficiency of the human brain has remained elusive. This has necessitated investigations of novel material systems which can efficiently mimic the functional units of SNNs, such as neurons and synapses. In this paper, we present a magnetoelectric-magnetic tunnel junction (ME-MTJ) device as a synapse. We arrange these synapses in a crossbar fashion and perform in situ unsupervised learning. We leverage the capacitive nature of write-ports in ME-MTJs, wherein by applying appropriately shaped voltage pulses across the write-port, the ME-MTJ can be switched in a probabilistic manner. We further exploit the sigmoidal switching characteristics of ME-MTJ to tune the synapses to follow the well-known spike timing-dependent plasticity (STDP) rule in a stochastic fashion. Finally, we use the stochastic STDP rule in ME-MTJ synapses to simulate a two-layered SNN to perform image classification tasks on a handwritten digit dataset. Thus, the capacitive write-port and the decoupled-nature of read-write path of ME-MTJs allow us to construct a transistor-less crossbar, suitable for energy-efficient implementation of in situ learning in SNNs. This article is part of the theme issue 'Harmonizing energy-autonomous computing and intelligence'.

In-situ, In-Memory Stateful Vector Logic Operations based on Voltage Controlled Magnetic Anisotropy.

Recently, the exponential increase in compute requirements demanded by emerging applications like artificial intelligence, Internet of things, etc. have rendered the state-of-art von-Neumann machines inefficient in terms of energy and throughput owing to the well-known von-Neumann bottleneck. A promising approach to mitigate the bottleneck is to do computations as close to the memory units as possible. One extreme possibility is to do in-situ Boolean logic computations by using stateful devices. Stateful devices are those that can act both as a compute engine and storage device, simultaneously. We propose such stateful, vector, in-memory operations using voltage controlled magnetic anisotropy (VCMA) effect in magnetic tunnel junctions (MTJ). Our proposal is based on the well known manufacturable 1-transistor - 1-MTJ bit-cell and does not require any modifications in the bit-cell circuit or the magnetic device. Instead, we leverage the very physics of the VCMA effect to enable stateful computations. Specifically, we exploit the voltage asymmetry of the VCMA effect to construct stateful IMP (implication) gate and use the precessional switching dynamics of the VCMA devices to propose a massively parallel NOT operation. Further, we show that other gates like AND, OR, NAND, NOR, NIMP (complement of implication) can be implemented using multi-cycle operations.

Co-incubation with core proteins of HBV and HCV leads to modulation of human dendritic cells.

Hepatitis B and C (HBV and HCV) are hepatotropic viruses in humans with approximately 350 and 170 million chronic carriers respectively. Since both viruses have similar modes of transmission, many people are co-infected. Co-infection is common in intravenous drug users, HIV-positive individuals, and transplant recipients. Compared to mono-infected patients, co-infected patients exhibit exacerbated liver cirrhosis, hepatocellular carcinoma, and liver failure. Some of the pathogenic effects may be attributed in part to the structural core proteins of both viruses-ones that have displayed immunomodulatory properties. Yet, the effects of their combined interaction on the human immune system remain a mystery. We aimed to elucidate the combined effects of HBV and HCV core proteins on human dendritic cells' (DCs) ability to present antigens and stimulate antigen-specific T-cells. We observed that when DCs, differentiated from human peripheral blood monocytes, were co-incubated with both core proteins, IL-10 production was dramatically enhanced, IL-6, TNF-α, and IL-12 production was significantly reduced, and HLA-DR expression was downregulated. This instant functional and phenotypic modulation of DCs induced by a combination of HBV and HCV core proteins can allow them to behave like tolerizing DCs, inefficiently presenting antigens to CD4+ T-cells and even suppressing induction of the cellular immune response. These results reveal an important mechanism by which HBV and HCV synergistically induce immune tolerance early in infection that may be instrumental in establishing chronic, persistent infections.

Antimycobacterial activities of 5-alkyl (or halo)-3'-substituted pyrimidine nucleoside analogs.

Several 5-alkyl (or halo)-3'-azido (amino or halo) analogs of pyrimidine nucleosides have been synthesized and evaluated against Mycobacterium bovis, Mycobacterium tuberculosis and Mycobacterium avium. Among these compounds, 3'-azido-5-ethyl-2',3'-dideoxyuridine (3) was found to have significant antimycobacterial activities against M. bovis (MIC(50)=1µg/mL), M. tuberculosis (MIC(50)=10µg/mL) and M. avium (MIC(50)=10µg/mL).