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Purpose: CBCT‐guided online‐adaptive radiotherapy (oART) systems have been made possible by using artificial intelligence and automation to substantially reduce treatment planning time during on‐couch adaptive sessions. Evaluating plans generated during an adaptive session presents significant challenges to the clinical team as the planning process gets compressed into a shorter window than offline planning. We identified MU variations up to 30% difference between the adaptive plan and the reference plan in several oART sessions that caused the clinical team to question the accuracy of the oART dose calculation. We investigated the cause of MU variation and the overall accuracy of the dose delivered when MU variations appear unnecessarily large. Methods: Dosimetric and adaptive plan data from 604 adaptive sessions of 19 patients undergoing CBCT‐guided oART were collected. The analysis included total MU per fraction, planning target volume (PTV) and organs at risk (OAR) volumes, changes in PTV‐OAR overlap, and DVH curves. Sessions with MU greater than two standard deviations from the mean were reoptimized offline, verified by an independent calculation system, and measured using a detector array. Results: MU variations relative to the reference plan were normally distributed with a mean of −1.0% and a standard deviation of 11.0%. No significant correlation was found between MU variation and anatomic changes. Offline reoptimization did not reliably reproduce either reference or on‐couch total MUs, suggesting that stochastic effects within the oART optimizer are likely causing the variations. Independent dose calculation and detector array measurements resulted in acceptable agreement with the planned dose. Conclusions: MU variations observed between oART plans were not caused by any errors within the oART workflow. Providers should refrain from using MU variability as a way to express their confidence in the treatment planning accuracy. Clinical decisions during on‐couch adaptive sessions should rely on validated secondary dose calculations to ensure optimal plan selection. [ABSTRACT FROM AUTHOR]

Key Clinical Message: A patient presented with cardiogenic shock, requiring the implantation of a left ventricular assist device (LVAD), and acute myeloblastic leukemia. This necessitated total body irradiation (TBI) while balancing dose reduction to the LVAD components to avoid potential radiation damage. Here we outline our treatment approach and dose estimates to the LVAD. This case report discusses the delivery of TBI to a patient with an LVAD. This treatment required radiation‐dose determinations and consequential reductions for the heart, LVAD, and an external controller connected to the LVAD. The patient was treated using a traditional 16MV anterior posterior (AP)/posterior anterior (PA) technique at a source‐to‐surface‐distance of 515 cm for 400 cGy in two fractions. A 3 cm thick Cerrobend block was placed on the beam spoiler to reduce dose to the heart and LVAD to 150 cGy. The external controller was placed in a 1 cm thick acrylic box to reduce neutron dose and positioned as far from the treatment fields as achievable. In vivo measurements were made using optically stimulated luminescence dosimeters (OSLDs) placed inside the box at distances of 2 cm, 8.5 cm, and 14 cm from the field edge, and on the patient along the central axis and centered behind the LVAD block. Further ion chamber measurements were made using a solid water phantom to more accurately estimate the dose delivered to the LVAD. Neutron dose measurements were also conducted. The total estimated dose to the controller ranged from 135.3 cGy to 91.5 cGy. The LVAD block reduced the surface dose to the patient to 271.6 cGy (68.1%). The block transmission factors of the 3 cm Cerrobend block measured in the phantom were 45% at 1 cm depth and decreased asymptotically to around 30% at 3 cm depth. Applying these transmission factors to the in vivo measurements yielded a dose of 120 cGy to the implanted device. The neutron dose the LVAD region is estimated around 0.46 cGy. Physical limitations of the controller made it impossible to completely avoid dose. Shielding is recommended. The block had limited dose reduction to the surface, due to secondary particles, but appropriately reduced the dose at 3 cm and beyond. More research on LVADs dose limits would be beneficial. [ABSTRACT FROM AUTHOR]

Abstract Background A classical example of repeated speciation coupled with ecological diversification is the evolution of 14 closely related species of Darwin’s (Galápagos) finches (Thraupidae, Passeriformes). Their adaptive radiation in the Galápagos archipelago took place in the last 2–3 million years and some of the molecular mechanisms that led to their diversification are now being elucidated. Here we report evolutionary analyses of genome of the large ground finch, Geospiza magnirostris. Results 13,291 protein-coding genes were predicted from a 991.0 Mb G. magnirostris genome assembly. We then defined gene orthology relationships and constructed whole genome alignments between the G. magnirostris and other vertebrate genomes. We estimate that 15% of genomic sequence is functionally constrained between G. magnirostris and zebra finch. Genic evolutionary rate comparisons indicate that similar selective pressures acted along the G. magnirostris and zebra finch lineages suggesting that historical effective population size values have been similar in both lineages. 21 otherwise highly conserved genes were identified that each show evidence for positive selection on amino acid changes in the Darwin's finch lineage. Two of these genes (Igf2r and Pou1f1) have been implicated in beak morphology changes in Darwin’s finches. Five of 47 genes showing evidence of positive selection in early passerine evolution have cilia related functions, and may be examples of adaptively evolving reproductive proteins. Conclusions These results provide insights into past evolutionary processes that have shaped G. magnirostris genes and its genome, and provide the necessary foundation upon which to build population genomics resources that will shed light on more contemporaneous adaptive and non-adaptive processes that have contributed to the evolution of the Darwin’s finches.

The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10-30) and control (20-60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.

Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.