3-Year Left Ventricular Assist Device Outcomes and Strategy After Heart Transplant Allocation Score Change.

BACKGROUND: The United Network for Organ Sharing (UNOS) adopted new criteria for the heart allocation score on 10/18/2018 to reflect changing trends of candidates' mortality while awaiting transplant. We examined the impact of these policy changes on rates of left ventricular assist device (LVAD) implantation and outcomes posttransplant from a relatively newer UNOS database. METHODS: The UNOS registry was used to identify first-time adult heart recipients with LVAD at listing or transplant who underwent transplantation between 1/1/2016 and 3/10/2020. Survival data was collected through 3/30/2023. Those listed prior to 10/18/2018 but transplanted after were excluded. Patients were divided into before or after change groups. Demographics and clinical parameters were compared. Survival was analyzed with Kaplan-Meier curves and log-rank tests. A p<0.05 was considered significant. RESULTS: We identified 4387 heart recipients with LVAD in the before (n=3606) and after (n=781) score change eras. The after group had a lower rate of LVAD implantation while listed compared to the before group (20.4% vs 34.9%, p<0.0001), and were more likely to be female (25.1% vs 20.2%, p=0.002); in both groups, most recipients (62.8%) were white. There was significantly farther distance from the donor hospital to transplant center in the after group (264.4 NM vs 144.2NM, p<0.0001) and decreased waitlist days (84.9 ± 105.1 vs 369.2 ± 459.5, p<0.0001). Recipients in the after group were more likely to utilize ECMO (3.7% vs 0.5%, p<0.0001) and IV inotropes (19.1% vs 7.5%, p<0.0001), and receive a CDC increased-risk donor organ (37.9% vs 30.5%, p<0.0001). Survival at 3-years was comparable between the two groups. CONCLUSIONS: The allocation score change in 2018 yielded considerable changes in mechanical circulatory support device implantation strategy and outcomes. The rate of LVAD implantation decreased with increased utilization of temporary mechanical circulatory support devices.

Guardian of the Genome: An Alternative RAG/Transib Co-Evolution Hypothesis for the Origin of V(D)J Recombination.

The appearance of adaptive immunity in jawed vertebrates is termed the immunological 'Big Bang' because of the short evolutionary time over which it developed. Underlying it is the recombination activating gene (RAG)-based V(D)J recombination system, which initiates the sequence diversification of the immunoglobulins and lymphocyte antigen receptors. It was convincingly argued that the RAG1 and RAG2 genes originated from a single transposon. The current dogma postulates that the V(D)J recombination system was established by the split of a primordial vertebrate immune receptor gene into V and J segments by a RAG1/2 transposon, in parallel with the domestication of the same transposable element in a separate genomic locus as the RAG recombinase. Here, based on a new interpretation of previously published data, we propose an alternative evolutionary hypothesis suggesting that two different elements, a RAG1/2 transposase and a Transib transposon invader with RSS-like terminal inverted repeats, co-evolved to work together, resulting in a functional recombination process. This hypothesis offers an alternative understanding of the acquisition of recombinase function by RAGs and the origin of the V(D)J system.

Individual Sea Urchin Coelomocytes Undergo Somatic Immune Gene Diversification.

The adaptive immune response in jawed vertebrates is marked by the ability to diversify somatically specific immune receptor genes. Somatic recombination and hypermutation of gene segments are used to generate extensive repertoires of T and B cell receptors. In contrast, jawless vertebrates utilize a distinct diversification system based on copy choice to assemble their variable lymphocyte receptors. To date, very little evidence for somatic immune gene diversification has been reported in invertebrate species. Here we show that the SpTransformer (SpTrf ; formerly Sp185/333) immune effector gene family members from individual coelomocytes from purple sea urchins undergo somatic diversification by means of gene deletions, duplications, and acquisitions of single nucleotide polymorphisms. While sperm cells from an individual sea urchin have identical SpTrf gene repertoires, single cells from two distinct coelomocyte subpopulations from the same sea urchin exhibit significant variation in the SpTrf gene repertoires. Moreover, the highly diverse gene sequences derived from single coelomocytes are all in-frame, suggesting that an unknown mechanism(s) driving these somatic changes involve stringent selection or correction processes for expression of productive SpTrf transcripts. Together, our findings infer somatic immune gene diversification strategy in an invertebrate.

Short tandem repeats, segmental duplications, gene deletion, and genomic instability in a rapidly diversified immune gene family.

BACKGROUND: Genomic regions with repetitive sequences are considered unstable and prone to swift DNA diversification processes. A highly diverse immune gene family of the sea urchin (Strongylocentrotus purpuratus), called Sp185/333, is composed of clustered genes with similar sequence as well as several types of repeats ranging in size from short tandem repeats (STRs) to large segmental duplications. This repetitive structure may have been the basis for the incorrect assembly of this gene family in the sea urchin genome sequence. Consequently, we have resolved the structure of the family and profiled the members by sequencing selected BAC clones using Illumina and PacBio approaches. RESULTS: BAC insert assemblies identified 15 predicted genes that are organized into three clusters. Two of the gene clusters have almost identical flanking regions, suggesting that they may be non-matching allelic clusters residing at the same genomic locus. GA STRs surround all genes and appear in large stretches at locations of putatively deleted genes. GAT STRs are positioned at the edges of segmental duplications that include a subset of the genes. The unique locations of the STRs suggest their involvement in gene deletions and segmental duplications. Genomic profiling of the Sp185/333 gene diversity in 10 sea urchins shows that no gene repertoires are shared among individuals indicating a very high gene diversification rate for this family. CONCLUSIONS: The repetitive genomic structure of the Sp185/333 family that includes STRs in strategic locations may serve as platform for a controlled mechanism which regulates the processes of gene recombination, gene conversion, duplication and deletion. The outcome is genomic instability and allelic mismatches, which may further drive the swift diversification of the Sp185/333 gene family that may improve the immune fitness of the species.