From Patterning Genes to Process: Unraveling the Gene Regulatory Networks That Pattern Heliconius Wings

Butterfly wing patterns have emerged as exceptional model systems with which to link the developmental and genetic processes that generate morphological variation with the ecological and evolutionary processes that shape this variation in natural populations. Among butterflies, research on species within the genus Heliconius has provided remarkable opportunities to explore how phenotypic diversity is generated within the context of an extraordinary adaptive radiation. Wing pattern diversity among the 48 species and hundreds of intraspecific variants arose within the last 12–14 million years and includes striking pattern convergence between distantly related species, as well as marked pattern divergence between closely related populations and species. Here, we synthesize recent research aimed at gaining a mechanistic understanding of how this variation is generated. This research integrates decades of controlled crossing experiments, and the discovery of major wing patterning genes (optix, aristaless1, WntA and cortex) with recent functional genetic manipulation using CRISPR/Cas9 targeted mutagenesis. The emerging data provides a rich framework with which to explore the repeatability of evolution, particularly within the context of how natural selection acts on divergent gene regulatory networks to generate both highly convergent, as well as highly divergent phenotypes. Overall, the functional data show that the gene regulatory networks underlying pattern variation diverge rapidly in Heliconius; yet these networks retain enough flexibility so that natural selection can drive the evolution of nearly identical patterns from different developmental genetic starting points. Moreover, for the first time this research is starting to illuminate the links between the genetic changes modulating pattern variation and how they influence the larger gene networks that are ultimately responsible for patterning a butterfly wing. There are still large gaps in our understanding, but current research priorities are well laid out and experimental methodologies are in place to address them. The challenge is to synthesize diverse research strategies into a cohesive picture of morphological evolution

Direct costs of radiotherapy for rectal cancer: A microcosting study

Background: Radiotherapy provides significant benefits in terms of reducing risk of local recurrence and death from rectal cancer. Despite this, up-to-date cost estimates for radiotherapy are lacking, potentially inhibiting policy and decision-making. Our objective was to generate an up-to-date estimate of the cost of traditional radiotherapy for rectal cancer and model the impact of a range of potential efficiency improvements. Methods: Microcosting methods were used to estimate total direct radiotherapy costs for long- (assumed at 45-50 Gy in 25 daily fractions over a 5 week period) and short-courses (assumed at 25 Gy in 5 daily fractions over a one week period). Following interviews and on-site visits to radiotherapy departments in two designated cancer centers, a radiotherapy care pathway for a typical rectal cancer patient was developed. Total direct costs were derived by applying fixed and variable unit costs to resource use within each care phase. Costs included labor, capital, consumables and overheads. Sensitivity analyses were performed. Results: Radiotherapy treatment was estimated to cost between €2,080 (5-fraction course) and €3,609 (25-fraction course) for an average patient in 2012. Costs were highest in the treatment planning phase for the short-course (€1,217; 58% of total costs), but highest in the radiation treatment phase for the long-course (€1,974: 60% of total costs). By simultaneously varying treatment time, capacity utilization rates and linear accelerator staff numbers, the base cost fell by 20% for 5-fractions: (€1,660) and 35% for 25-fractions: (€2,354). Conclusions: Traditional radiotherapy for rectal cancer is relatively inexpensive. Moreover, significant savings may be achievable through service organization and provision changes. These results suggest that a strong economic argument can be made for expanding the use of radiotherapy in rectal cancer treatment

Projecting productivity losses for cancer-related mortality 2011 - 2030

© 2016 The Author(s). Background: When individuals stop working due to cancer this represents a loss to society - the loss of productivity. The aim of this analysis was to estimate productivity losses associated with premature mortality from all adult cancers and from the 20 highest mortality adult cancers in Ireland in 2011, and project these losses until 2030. Methods: An incidence-based method was used to estimate the cost of cancer deaths between 2011 and 2030 using the Human Capital Approach. National data were used for cancer, population and economic inputs. Both paid work and unpaid household activities were included. Sensitivity analyses estimated the impact of assumptions around future cancer mortality rates, retirement ages, value of unpaid work, wage growth and discounting. Results: The 233,000 projected deaths from all invasive cancers in Ireland between 2011 and 2030 will result in lost productivity valued at €73 billion; €13 billion in paid work and €60 billion in household activities. These losses represent approximately 1.4 % of Ireland's GDP annually. The most costly cancers are lung (€14.4 billion), colorectal and breast cancer (€8.3 billion each). However, when viewed as productivity losses per cancer death, testis (€364,000 per death), cervix (€155,000 per death) and brain cancer (€136,000 per death) are most costly because they affect working age individuals. An annual 1 % reduction in mortality reduces productivity losses due to all invasive cancers by €8.5 billion over 20 years. Conclusions: Society incurs substantial losses in productivity as a result of cancer-related mortality, particularly when household production is included. These estimates provide valuable evidence to inform resource allocation decisions in cancer prevention and control

Deep Convergence, Shared Ancestry, and Evolutionary Novelty in the Genetic Architecture of Heliconius Mimicry

Convergent evolution can occur through different genetic mechanisms in different species. It is now clear that convergence at the genetic level is also widespread, and can be caused by either (i) parallel genetic evolution, where independently evolved convergent mutations arise in different populations or species, or (ii) collateral evolution in which shared ancestry results from either ancestral polymorphism or introgression among taxa. The adaptive radiation of Heliconius butterflies shows color pattern variation within species, as well as mimetic convergence between species. Using comparisons from across multiple hybrid zones, we use signals of shared ancestry to identify and refine multiple putative regulatory elements in Heliconius melpomene and its comimics, Heliconius elevatus and Heliconius besckei, around three known major color patterning genes: optix, WntA, and cortex. While we find that convergence between H. melpomene and H. elevatus is caused by a complex history of collateral evolution via introgression in the Amazon, convergence between these species in the Guianas appears to have evolved independently. Thus, we find adaptive convergent genetic evolution to be a key driver of regulatory changes that lead to rapid phenotypic changes. Furthermore, we uncover evidence of parallel genetic evolution at some loci around optix and WntA in H. melpomene and its distant comimic Heliconius erato. Ultimately, we show that all three of convergence, conservation, and novelty underlie the modular architecture of Heliconius color pattern mimicry

Children's Relative Age and Medicine Treatment for Attention-Deficit/Hyperactivity Disorder Across Australian Jurisdictions with Different School Enrolment Policies

Background: Children who are relatively young for their school grade are more likely to receive treatment for attention-deficit/hyperactivity disorder (ADHD). It is unclear whether the phenomenon also exists across Australia or is impacted by the school enrolment policy in place. Objective: We evaluated the association between children's relative age and initiation of ADHD medicines across Australian jurisdictions with different school enrolment policies and rates of delayed school entry. Methods: We used Australia-wide dispensing data for a 15% random sample of children 4-9 years of age in 2013-2017 to create a nationwide cohort. Due to high rates of delayed school entry in New South Wales (NSW), we used linked prescribing and education data for a cohort of NSW residents starting school in 2009 and 2012. We estimated incidence rate ratios (IRRs) for ADHD medicine across children's birth month, sex, and jurisdiction. We used asthma medicines as a negative control. Results: For girls, we observed a relative age effect in three out of five jurisdictions, with an IRR ranging from 1.3 to 2.8, comparing the youngest versus oldest birth month thirds. We observed more modest effects among boys, ranging from null to 1.5-fold. In NSW, the relatively youngest boys were less likely to initiate stimulant medicines than the oldest (IRR = 0.5, 95% confidence interval 0.29-0.78). We did not observe a relative age effect for initiation of asthma medicines. Conclusions: In jurisdictions with low rates of delayed entry, relatively young children were more likely to initiate ADHD medicines than their older classmates. We observed the inverse association in NSW where delayed entry was highest, likely reflecting the characteristics and needs of children who delay school entry for 1 year and become the oldest children in the grade. Increased awareness around children's maturity differences and school readiness may enhance appropriate diagnosis and treatment of ADHD

Policy challenges for the pediatric rheumatology workforce: Part III. the international situation

Survival dominates current pediatric global health priorities. Diseases of poverty largely contribute to overall mortality in children under 5 years of age. Infectious diseases and injuries account for 75% of cause-specific mortality among children ages 5-14 years. Twenty percent of the world's population lives in extreme poverty (income below US $1.25/day). Within this population, essential services and basic needs are not met, including clean water, sanitation, adequate nutrition, shelter, access to health care, medicines and education. In this context, musculoskeletal disease comprises 0.1% of all-cause mortality in children ages 5-14 years. Worldwide morbidity from musculoskeletal disease remains generally unknown in the pediatric age group. This epidemiologic data is not routinely surveyed by international agencies, including the World Health Organization. The prevalence of pediatric rheumatic diseases based on data from developed nations is in the range of 2,500 - 3,000 cases per million children. Developing countries' needs for musculoskeletal morbidity are undergoing an epidemiologic shift to chronic conditions, as leading causes of pediatric mortality are slowly quelled