Background. Few studies have addressed immunosuppression management after allograft failure (AF). Immunosuppression withdrawal to minimize complications must be balanced with the risk of sensitization and potentially reduced retransplantation. We aimed to determine relationships between immunosuppression, death, sensitization, and retransplantation among patients with AF. Methods. We performed a single-center retrospective study of patients transplanted from October 2007 to May 2017 with AF. We collected data on demographics, immunosuppression, calculated panel reactive antibody (cPRA) levels, death, retransplantation, and dialysis. Cox regression models were used to evaluate factors associated with death and retransplantation. Results. From October 2007 to May 2017, 1354 solitary ABO-compatible transplants were performed, of which 97 failed. Ten percent of patients received a preemptive retransplant. Among those who returned to dialysis (n = 87), 35% died, 25% received another transplant, and 30% remained on dialysis. After AF, 46% of patients discontinued immunosuppression. The cPRA was unchanged if immunosuppression was maintained, but immunosuppression discontinuation was associated with increased cPRA from a median (interquartile range) of 18 (0–99) to 96 (88.5–100.0; P = 0.003). Age at failure (hazard ratio, 1.1; confidence interval, 1.0-1.1) and cardiovascular disease were associated with death (hazard ratio, 2.9; confidence interval, 1.2-7.0) in multivariate analysis. Importantly, immunosuppression maintenance was not associated with increased death or retransplantation despite the increase in cPRA that occurred when immunosuppression was discontinued. Conclusions. Kidney transplant recipients with AF have a high mortality rate after dialysis initiation. Although immunosuppression withdrawal was associated with increased cPRA, it was not associated with reduced retransplantation. Therefore, it is reasonable to discontinue immunosuppression after AF despite sensitization if retransplantation is delayed.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder presented with social and communication deficits, restricted, repetitive behaviours and interest. Several recurrently mutated genetic risk-factors have been implicated in ASD manifestation. Chromodomain helicase remodeller (CHD8) is one such gene that is a master regulator mediating the expression of genes controlling neuron functions. We collected 8,124 exonic SNPs in CHD8 from 4 databases representing the general and ASD populations; subjected them to multi-layered analyses on >20 computational tools. We observed that nsSNPs were common in the general population. Distinct hotspots for truncating and nsSNPs were identified within exons encoding the N and C terminals, respectively. Evolutionarily conserved regions involving CHD8 core domains: Helicase-C-terminal, Helicase-ATPbinding and SNF2 N domains, recorded the lowest density but severely pathogenic SNPs. Conversely, evolutionarily variable regions-CHD7-binding and BRK domains-hosted the highest SNPs, but were benign. Post-Translational-Modifications (PTMS) occurred on residues outside domains (P<0.01) i.e., non-conserved regions of CHD8 including the N and C terminals that were determined to be Intrinsically-Disordered-Protein-Regions (IDPRs) with 9 Molecular-Recognition-Features sites. Contrastingly, ASD population recorded significantly higher incidences of truncating SNPs than general population (P<0.0001). ASD-SNPs frequently occurring within core domains were severely damaging and accounted for >30% of all ASD variations. The CHD7-DNA-binding motif, with most PTMs, recorded the highest recurring truncating ASD-SNPs. The CHD8 PPIs effortlessly recapitulated the phenotypes presented by children with CHD8 mutations. 11/13 (84.6%) interacting molecules were IDPs. We identified 9 CHD8 nsSNPs that produced the strongest long-range disturbances, altering the modelled protein's global conformational dynamics.
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