Hagfish genome elucidates vertebrate whole-genome duplication events and their evolutionary consequences.

Polyploidy or whole-genome duplication (WGD) is a major event that drastically reshapes genome architecture and is often assumed to be causally associated with organismal innovations and radiations. The 2R hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution. However, the timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved and whether these WGD events underlie vertebrate phenotypic diversification remains elusive. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and 2R occurred in the gnathostome stem-lineage, maximally in the late Cambrian-earliest Ordovician, after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced an additional independent genome triplication. Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only in the gnathostome but not in the cyclostome lineage, calling into question the general expectation that WGDs lead to leaps of bodyplan complexity.

A timescale for placental mammal diversification based on Bayesian modeling of the fossil record.

The timing of the placental mammal radiation has been the focus of debate over the efficacy of competing methods for establishing evolutionary timescales. Molecular clock analyses estimate that placental mammals originated before the Cretaceous-Paleogene (K-Pg) mass extinction, anywhere from the Late Cretaceous to the Jurassic. However, the absence of definitive fossils of placentals before the K-Pg boundary is compatible with a post-Cretaceous origin. Nevertheless, lineage divergence must occur before it can be manifest phenotypically in descendent lineages. This, combined with the non-uniformity of the rock and fossil records, requires the fossil record to be interpreted rather than read literally. To achieve this, we introduce an extended Bayesian Brownian bridge model that estimates the age of origination and, where applicable, extinction through a probabilistic interpretation of the fossil record. The model estimates the origination of placentals in the Late Cretaceous, with ordinal crown groups originating at or after the K-Pg boundary. The results reduce the plausible interval for placental mammal origination to the younger range of molecular clock estimates. Our findings support both the Long Fuse and Soft Explosive models of placental mammal diversification, indicating that the placentals originated shortly prior to the K-Pg mass extinction. The origination of many modern mammal lineages overlapped with and followed the K-Pg mass extinction.

Saccorhytus is an early ecdysozoan and not the earliest deuterostome.

The early history of deuterostomes, the group composed of the chordates, echinoderms and hemichordates1, is still controversial, not least because of a paucity of stem representatives of these clades2-5. The early Cambrian microscopic animal Saccorhytus coronarius was interpreted as an early deuterostome on the basis of purported pharyngeal openings, providing evidence for a meiofaunal ancestry6 and an explanation for the temporal mismatch between palaeontological and molecular clock timescales of animal evolution6-8. Here we report new material of S. coronarius, which is reconstructed as a millimetric and ellipsoidal meiobenthic animal with spinose armour and a terminal mouth but no anus. Purported pharyngeal openings in support of the deuterostome hypothesis6 are shown to be taphonomic artefacts. Phylogenetic analyses indicate that S. coronarius belongs to total-group Ecdysozoa, expanding the morphological disparity and ecological diversity of early Cambrian ecdysozoans.

A species-level timeline of mammal evolution integrating phylogenomic data.

High-throughput sequencing projects generate genome-scale sequence data for species-level phylogenies1-3. However, state-of-the-art Bayesian methods for inferring timetrees are computationally limited to small datasets and cannot exploit the growing number of available genomes4. In the case of mammals, molecular-clock analyses of limited datasets have produced conflicting estimates of clade ages with large uncertainties5,6, and thus the timescale of placental mammal evolution remains contentious7-10. Here we develop a Bayesian molecular-clock dating approach to estimate a timetree of 4,705 mammal species integrating information from 72 mammal genomes. We show that increasingly larger phylogenomic datasets produce diversification time estimates with progressively smaller uncertainties, facilitating precise tests of macroevolutionary hypotheses. For example, we confidently reject an explosive model of placental mammal origination in the Palaeogene8 and show that crown Placentalia originated in the Late Cretaceous with unambiguous ordinal diversification in the Palaeocene/Eocene. Our Bayesian methodology facilitates analysis of complete genomes and thousands of species within an integrated framework, making it possible to address hitherto intractable research questions on species diversifications. This approach can be used to address other contentious cases of animal and plant diversifications that require analysis of species-level phylogenomic datasets.

Experimental taphonomy of organelles and the fossil record of early eukaryote evolution.

The timing of origin of eukaryotes and the sequence of eukaryogenesis are poorly constrained because their fossil record is difficult to interpret. Claims of fossilized organelles have been discounted on the unsubstantiated perception that they decay too quickly for fossilization. We experimentally characterized the pattern and time scale of decay of nuclei, chloroplasts, and pyrenoids in red and green algae, demonstrating that they persist for many weeks postmortem as physical substrates available for preservation, a time scale consistent with known mechanisms of fossilization. Chloroplasts exhibit greater decay resistance than nuclei; pyrenoids are unlikely to be preserved, but their presence could be inferred from spaces within fossil chloroplasts. Our results are compatible with differential organelle preservation in seed plants. Claims of fossilized organelles in Proterozoic fossils can no longer be dismissed on grounds of plausibility, prompting reinterpretation of the early eukaryotic fossil record and the prospect of a fossil record of eukaryogenesis.

Laminectomy in patients with achondroplasia: the impact of time to surgery on long-term function.

STUDY DESIGN: Retrospective analysis, survey. OBJECTIVE: To describe a cohort of individuals with achondroplasia undergoing thoracolumbar laminectomy and to examine if shorter time to surgery was related to improvement in long-term functional outcome. SUMMARY OF BACKGROUND DATA: Data on the long-term benefits of laminectomy are mixed for such patients. Earlier intervention may be associated with greater likelihood of long-term benefit, but quantified data are lacking. METHODS: We retrospectively studied 49 patients with achondroplasia who underwent primary laminectomy for spinal stenosis. Patients completed a questionnaire to assess symptoms, walking distance, and independence (per Modified Rankin Scale), before surgery and currently. Responses were analyzed for the likelihood of improved walking distance or Rankin level. RESULTS: Our patients had the following mean values: age, 37.7 ± 10.6 years; body mass index, 31.8 ± 5.5; symptom duration, 74.0 ± 100.1 months; preoperative symptom severity score, 2.7 ± 1.0 points; mean changes in blocks walked, +0.39 ± 2.0; and Rankin level, +0.08 ± 1.47. Patients with a time-to-surgery interval of <6 months were 7.13 times (95% confidence interval [CI], 1.39-36.66) more likely to experience improvement in walking distance and 4.00 times (95% CI, 1.05-15.21) more likely to experience Rankin level improvement than patients whose interval was >6 months. Intervals of up to 12 and 24 months were associated with increased likelihoods of 4.95 (95% CI, 1.41-17.41) and 3.43 (95% CI, 1.05-11.22), respectively, of improved walking distance compared with those with longer time-to surgery intervals, but those Rankin level improvements were not statistically significant. CONCLUSION: Time from symptom onset to surgery in patients with achondroplasia is an important predictor of long-term functional outcome. For sustained long-term postsurgical improvement, the window of opportunity might be relatively narrow. Patients with achondroplasia should seek medical advice for spinal stenotic symptoms as soon as possible.

Progression of low back and lower extremity pain in a cohort of patients with achondroplasia.

OBJECT: The aim of this study was to assess the natural history of pain associated with spinal stenosis in individuals with achondroplasia and to characterize pain patterns and associated functional and psychological effects. METHODS: The authors measured pain severity, spatial distribution of pain, functional disability, psychological distress, physical symptoms other than pain, and healthcare utilization in 181 individuals with achondroplasia. They also assessed low back and/or lower extremity pain at the initial visit and 1-year follow-up via self-rated patient questionnaires, calculated composite scores from responses via component analyses, and used repeated measures linear regression analyses for score changes (significance, p < or = 0.05). RESULTS: At the follow-up, back pain severity was unchanged. Patients reported significant progression of pain toward involvement of the lower extremities and significant increases in lower extremity pain severity overall. There were also significant increases in healthcare utilization overall. Compared with patients with back pain only, those with back pain and proximal or distal leg pain had higher self-rated pain severity; higher functional disability; and more bowel and bladder dysfunction symptoms, sleep disturbances, extremity numbness, and psychological distress. CONCLUSIONS: Individuals with achondroplasia and symptomatic spinal stenosis often experience back pain, which may progress to lower extremity pain and debilitating consequences. A more thorough understanding of the progression of spatial pain characteristics and pain severity may aid clinical decision making regarding the optimal timing for intervention.

Rates of perioperative complications associated with laminectomies in patients with achondroplasia.

BACKGROUND: Lumbar decompressive surgery can be complicated by dural tears, infection, nerve root injury, deep venous thrombosis, and epidural hematoma. However, perioperative complications of multilevel laminectomies in patients with achondroplasia rarely are reported. Our objective was to determine the perioperative complication rates associated with laminectomies in patients with achondroplasia. METHODS: We reviewed the medical records of the initial laminectomies for all ninety-eight patients with achondroplasia at our institution, which included twenty-eight patients who had had previous spine surgeries at other institutions, and determined the rates of complications in the following categories: neurologic, pulmonary, cardiovascular, and gastrointestinal complications; intraoperative dural tears; infections at the incision site; and mortality. RESULTS: Sixty (61%) of ninety-eight patients had at least one perioperative complication. By category, these included intraoperative dural tears, which occurred in 37% (thirty-six patients); neurologic complications, in 23% (twenty-three patients); infections at the incision site, in 9% (nine patients); deep venous thrombosis, in 3% (three patients); pulmonary complications, in 3% (three patients); and gastrointestinal complications, in 3% (three patients). The only death was caused by a pulmonary embolism. CONCLUSIONS: Perioperative complications are common in patients with achondroplasia undergoing multilevel laminectomies, and the perioperative care team should be aware of these complications when caring for these patients.

Determinants of states' allocations of the master settlement agreement payments.

To determine which factors influence states' allocation decisions for the tobacco Master Settlement Agreement and the four individual settlements' annual payments, including the decision to securitize, we analyzed the effects of voter characteristics, political parties, interest groups, prior spending on public tobacco control programs, and state fiscal health on per capita settlement funds allocated to tobacco-control, health, and other programs. Tobacco-producing states and those with high proportions of conservative Democrats or elderly, black, Hispanic, or wealthy people tended to spend less on tobacco control. Education and medical lobbies had strong positive influences on per capita allocations for tobacco-control and health-related programs. State fiscal crises affected amounts spent by states from settlement funds as well as the probability of securitizing future cash flows from the settlements.

Monitoring visual status: why patients do or do not comply with practice guidelines.

OBJECTIVE: To determine factors affecting compliance with guidelines for annual eye examinations for persons diagnosed with diabetes mellitus (DM) or age-related macular degeneration (ARMD). DATA SOURCES/STUDY SETTING: Nationally representative, longitudinal sample of individuals 65+ drawn from the National Long-Term Care Survey (NLTCS) with linked Medicare claims records from 1991 to 1999. STUDY DESIGN: Medicare beneficiaries were followed from 1991 to 1999, unless mortality intervened. All claims data were analyzed for presence of ICD-9 codes indicating diagnosis of DM or ARMD and the performance of eye exams. The dependent variable was a binary indicator for whether a person had an eye exam or not during a 15-month period. Independent variables for demographics, living conditions, supplemental insurance, income, and other factors affecting the marginal cost and benefit of an eye exam were assessed to determine reasons for noncompliance. DATA COLLECTION/EXTRACTION METHODS: Panel data were created from claims files, 1991-1999, merged with data from the NLTCS. PRINCIPAL FINDINGS: The probability of having an exam reflected perceived benefits, which vary by patient characteristics (e.g., education, no dementia), and factors associated with the ease of visit. African Americans were much less likely to be examined than were whites. CONCLUSIONS: Having an exam reflects multiple factors. However, much of the variation in the probability of an exam remained unexplained as were reasons for the racial differences in use.

Estimates of incidence rates with longitudinal claims data.

OBJECTIVE: To estimate incidence rates of the 3 major chronic eye diseases--diabetic retinopathy (DR), glaucoma, and age-related macular degeneration (ARMD)--by using longitudinal claims data from Medicare. METHODS: Longitudinal cases were ascertained by using a national probability sample of Medicare beneficiaries aged 65 years and older in 1991 who initially had none of the eye diseases documented. After adjusting for death and enrollment in a health maintenance organization, claims filed by optometrists or ophthalmologists with an International Classification of Diseases, Ninth Revision, Clinical Modification code for all forms of DR, glaucoma, and ARMD were used to indicate diagnosis. RESULTS: Annual incidence rates for the 3 conditions after the first year of observation ranged from 14.3% to 17.7% (higher earlier) across an 8-year longitudinal follow-up. Incidence rates among those with diabetes mellitus for any form of DR varied between 3.8% and 6.5%, while those for glaucoma varied between 4.6% and 7.8% and those for ARMD varied between 7.5% and 9.3%. CONCLUSIONS: Longitudinal claims data after the first year provide relatively stable estimates of incidence rates on an annual basis. These estimates are comparable with those of the few population-based studies available.