Zirconium as a Promising Synovial Biomarker for Loose Cemented Knee Prosthesis.

BACKGROUND: Aseptic loosening is the most common mode of failure after total knee arthroplasty. Despite this, the diagnosis often remains challenging and mainly relies on imaging modalities. Until today, no biomarker exists to aid in diagnosing loosening of the implants. As zirconium (Zr) is often found in bone cement, where it serves as radiopacifier, this study aimed to establish Zr as a synovial biomarker for loosened cemented knee prostheses. METHODS: A total of 31 patients scheduled for revision of a cemented knee prostheses were included. In all patients, the initial used cement contained Zr. After arthrotomy, specimens of synovial fluid were taken and levels of Zr were measured by inductively coupled plasma mass spectrometry. Depending on the necessary amount of force for explantation, the implants were graded "loose" or "well-fixed". Preoperative radiographs were evaluated by 2 independent physicians. RESULTS: The concentration of Zr in the synovial fluid differed significantly (P < .001) between the "loose" (mean 170.9 µg/L, range 0 to 1941 µg/L) and the "well-fixed" (mean 0.6 µg/L, range 0 to 6 µg/L) implants. The receiver operating characteristic analysis revealed 0.25 µg/l as an optimal cutoff value leading to a sensitivity of 0.84, a specificity of 0.92, a positive predictive value of 0.94, and a negative predictive value of 0.79. There was no significant difference in the diagnostic performance compared to radiographs (P = .66). CONCLUSIONS: Zirconium proved to be a reliable novel synovial biomarker for diagnosing aseptic loosening of knee prothesis fixed with cement containing Zr. This biomarker should not be interpreted in isolation, but in combination with existing diagnostic tools.

Epichloë fungal endophyte interactions in perennial ryegrass (Lolium perenne L.) modified to accumulate foliar lipids for increased energy density.

BACKGROUND: Commercial cultivars of perennial ryegrass infected with selected Epichloë fungal endophytes are highly desirable in certain pastures as the resulting mutualistic association has the capacity to confer agronomic benefits (such as invertebrate pest deterrence) largely due to fungal produced secondary metabolites (e.g., alkaloids). In this study, we investigated T2 segregating populations derived from two independent transformation events expressing diacylglycerol acyltransferase (DGAT) and cysteine oleosin (CO) genes designed to increase foliar lipid and biomass accumulation. These populations were either infected with Epichloë festucae var. lolii strain AR1 or Epichloë sp. LpTG-3 strain AR37 to examine relationships between the introduced trait and the endophytic association. Here we report on experiments designed to investigate if expression of the DGAT + CO trait in foliar tissues of perennial ryegrass could negatively impact the grass-endophyte association and vice versa. Both endophyte and plant characters were measured under controlled environment and field conditions. RESULTS: Expected relative increases in total fatty acids of 17-58% accrued as a result of DGAT + CO expression with no significant difference between the endophyte-infected and non-infected progeny. Hyphal growth in association with DGAT + CO expression appeared normal when compared to control plants in a growth chamber. There was no significant difference in mycelial biomass for both strains AR1 and AR37, however, Epichloë-derived alkaloid concentrations were significantly lower on some occasions in the DGAT + CO plants compared to the corresponding null-segregant progenies, although these remained within the reported range for bioactivity. CONCLUSIONS: These results suggest that the mutualistic association formed between perennial ryegrass and selected Epichloë strains does not influence expression of the host DGAT + CO technology, but that endophyte performance may be reduced under some circumstances. Further investigation will now be required to determine the preferred genetic backgrounds for introgression of the DGAT + CO trait in combination with selected endophyte strains, as grass host genetics is a major determinant to the success of the grass-endophyte association in this species.

How venom pore placement may influence puncture performance in snake fangs.

When designing experimental studies, it is important to understand the biological context of the question being asked. For example, many biological puncture experiments embed the puncture tool to a standardized depth based on a percentage of the total tool length, to compare the performance between tools. However, this may not always be biologically relevant to the question being asked. To understand how definitions of penetration depth may influence comparative results, we performed puncture experiments on a series of venomous snake fangs using the venom pore location as a functionally relevant depth standard. After exploring variation in pore placement across snake phylogeny, we compared the work expended during puncture experiments across a set of snake fangs using various depth standards: puncture initiation, penetration to a series of depths defined by the venom pore and penetration to 15% of fang length. Contrary to our hypothesis, we found almost no pattern in pore placement between clades, dietary groups or venom toxicity. Rank correlation statistics of our experimental energetics results showed no difference in the broad comparison of fangs when different puncture depth standards were used. However, pairwise comparisons between fangs showed major shifts in significance patterns between the different depth standards used. These results imply that the interpretation of experimental puncture data will heavily depend upon which depth standard is used during the experiments. Our results illustrate the importance of understanding the biological context of the question being addressed when designing comparative experiments.

Development and calibration of a high dynamic range and autonomous ocean-light instrument to measure sub-surface profiles in ice-covered waters.

The optical chain and logger (OptiCAL) is an autonomous ice-tethered observatory equipped with multiple light sensors for mapping the variation of light with depth. We describe the instrument and present an ensemble calibration for downwelling irradiance E P A R in [µm o l m -2 s -1]. Results from a long-term deployment in the Arctic Ocean demonstrate that the OptiCAL can cover the high dynamic range of under-ice light levels from July to November and produce realistic values in terms of magnitude when compared to modeled surface irradiance. Transient features of raised light levels at specific depths associated with nearby leads in the ice underline the importance of depth-resolved light measurements.

Efficacy of post-operative partial weight-bearing after total knee arthroplasty - a prospective observational trial.

PURPOSE: There is little evidence proving the concept of partial weight-bearing to be efficient and feasible. Using insole pressure measurement systems, this study aimed to explore the compliance to prescribed weight-bearing restrictions after total knee arthroplasty (TKA). METHODS: 50 patients after TKA were recruited in a prospective manner. They were advised to limit weight-bearing of the affected limb to 200 N. True load was measured via insole force-sensors on day one after surgery (M1) and before discharge (M2). Compliance to the rehabilitation protocol was the primary outcome parameter. RESULTS: At M1 and M2 compliance to the rehabilitation protocol was 0% und 2%, respectively. 84% (M1) and 90% (M2) of patients overloaded the affected limb during every step. The affected limb was loaded with 50% ± 14% (M1) and 57% ± 17% (M2) of body weight. Patients older than 65 loaded the affected limb on average 17% (M1) and 34% (M2) more than their younger counterparts did. This difference was even more pronounced when walking stairs up (49% increase on average) and down (53% increase on average). CONCLUSION: Surgeons must take into consideration that the ability to maintain partial weight-bearing after TKA is highly dependent on the age of the patient and the achievable load reduction is determined by the patient's body weight.

The AMADEUS score is not a sufficient predictor for functional outcome after autologous chondrocyte implantation (ACI) of the knee: data from the German Cartilage Registry (KnorpelRegister DGOU).

INTRODUCTION: The AMADEUS (Area Measurement And DEpth and Underlying Structures) score has advanced to a commonly used tool for MRI-based chondral defect severity grading prior to cartilage knee surgery. It was the intention of this study to assess the AMADEUS for a potential correlation with clinical data by patient-reported outcome measures (PROMs). METHODS: A total of 51 patients undergoing ACI (autologous chondrocyte implantation) between 2016 and 2022 were found eligible and retrospectively analyzed. All patients were registered in the German Cartilage Registry prior to surgery and follow-up data were collected using the Knee Osteoarthritis Outcome score (KOOS), the International Knee Documentation Committee (IKDC) Form and the numeric rating scale (NRS). Pre-operative MRI images were scored by three raters using the AMADEUS classification system, and an overall AMADEUS score was calculated which was subsequently correlated with pre- and post-operative PROMs. RESULTS: Mean patient age was 32.67 ± 8.37 years and mean defect size area 343.04 mm2 ± 139.45 mm2. No correlative capacity of the pre- and postoperative IKDC, KOOS or NRS scores was found with the AMADEUS final score or any of its subscores. From the pre- to postoperative visit, a significant improvement of the PROMs (IKDC: 45.53 ± 21.00 vs. 59.83 ± 17.93, p = 0.04; KOOS Pain: 58.00 ± 16.70 vs. 76.06 ± 19.20, p = 0.03; KOOS ADL: 64.17 ± 18.76 vs. 82.11 ± 16.68, p < 0.01; KOOS Sports: 26.11 ± 18.52 vs. 50.56 ± 23.94, p = 0.01; KOOS QOL: 25.50 ± 14.26 ± 45.28 ± 19.03, p = 0.00) was found. Intraclass correlation coefficients showed an overall good interrater agreement for the AMADEUS total score (ICC = 0.75). CONCLUSIONS: Study results suggest no correlative capacity of the AMADEUS with routinely used PROMs in patients undergoing ACI. Therefore, radiographically assessed cartilage defect characteristics poorly translate to pre- and postoperative patient-reported outcome data.

Infant drug exposure via breast milk.

More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.

Mental health, welfare or justice: An introductory global overview of differences between countries in the scale and approach to secure placements of children and young people.

BACKGROUND: Estimates suggest that over a million children per year are deprived of their liberty across the world. Little is known about the types, ethos or distribution of secure beds in which they are detained. AIM: This study aims to provide quantitative data with background information, to explore similarities and differences across jurisdictions, and to inform critical inquiry into key concepts and practices. METHODS: Data was obtained using an opportunistic sample of affluent countries, derived from an emerging academic/practice network of senior professionals. Depending on jurisdiction, data was already in the public domain or specifically requested. Data requests were related to the nature and size of health, welfare and criminal justice elements of secure beds and recent occupancy. Key professionals working in child secure settings, within jurisdictions, provided commentary on local approaches. RESULTS: Data was incomplete but allowed for comparisons between 10 jurisdictions. The proportions of the populations of children and young people detained varied by jurisdiction as did their distribution across variations of secure settings. Not all jurisdictions had all three kinds of secure settings. Definitions of secure beds varied depending on the use of relational, procedural or physical security. CONCLUSION: Findings are tentative but suggestion solely considering numerical descriptions of children's detention is misleading; our study highlights ways in which comparative studies may be improved. Within reported jurisdictions, the framework of health, welfare and justice was meaningful but this may not hold true with a wider international application of this method. Open interrogation of this data would be enhanced by the inclusion of children's perspectives.

Ecological opportunity and the rise and fall of crocodylomorph evolutionary innovation.

Understanding the origin, expansion and loss of biodiversity is fundamental to evolutionary biology. The approximately 26 living species of crocodylomorphs (crocodiles, caimans, alligators and gharials) represent just a snapshot of the group's rich 230-million-year history, whereas the fossil record reveals a hidden past of great diversity and innovation, including ocean and land-dwelling forms, herbivores, omnivores and apex predators. In this macroevolutionary study of skull and jaw shape disparity, we show that crocodylomorph ecomorphological variation peaked in the Cretaceous, before declining in the Cenozoic, and the rise and fall of disparity was associated with great heterogeneity in evolutionary rates. Taxonomically diverse and ecologically divergent Mesozoic crocodylomorphs, like marine thalattosuchians and terrestrial notosuchians, rapidly evolved novel skull and jaw morphologies to fill specialized adaptive zones. Disparity in semi-aquatic predatory crocodylians, the only living crocodylomorph representatives, accumulated steadily, and they evolved more slowly for most of the last 80 million years, but despite their conservatism there is no evidence for long-term evolutionary stagnation. These complex evolutionary dynamics reflect ecological opportunities, that were readily exploited by some Mesozoic crocodylomorphs but more limited in Cenozoic crocodylians.

Testing the influence of crushing surface variation on seed-cracking performance among beak morphs of the African seedcracker Pyrenestes ostrinus.

Extreme phenotypic polymorphism is an oft-cited example of evolutionary theory in practice. Although these morphological variations are assumed to be adaptive, few studies have biomechanically tested such hypotheses. Pyrenestes ostrinus (the African seedcracker finch) shows an intraspecific polymorphism in beak size and shape that is entirely diet driven and allelically determined. Three distinct morphs feed upon soft sedge seeds during times of abundance, but during lean times switch to specializing on three different species of sedge seeds that differ significantly in hardness. Here, we test the hypothesis that beak morphology is directly related to consuming seeds of different hardness. We used a novel experimental analysis to test how beak morphology affects the efficiency of cracking sedge seeds of variable hardness, observing that neither mandibular ramus width nor crushing surface morphology had significant effects on the ability to crack different seed types. It is likely that feeding performance is correlated with other aspects of beak size and shape, such as beak depth and strength, muscle force or gape. Our results highlight how even seemingly straightforward examples of adaptive selection in nature can be complex in practice.

Nest substrate and tool shape significantly affect the mechanics and energy requirements of avian eggshell puncture.

Some host species of avian obligate brood parasites reject parasitic eggs from their nest whereas others accept them, even though they recognize them as foreign. One hypothesis to explain this seemingly maladaptive behavior is that acceptors are unable to pierce and remove the parasitic eggshell. Previous studies reporting on the force and energy required to break brood parasites' eggshells were typically static tests performed against hard substrate surfaces. Here, we considered host nest as a substrate to simulate this potentially critical aspect of the natural context for egg puncture while testing the energy required to break avian eggshells. Specifically, as a proof of concept, we punctured domestic chicken eggs under a series of conditions: varying tool shape (sharp versus blunt), tool dynamics (static versus dynamic) and the presence of natural bird nests (of three host species). The results show a complex set of statistically significant interactions between tool shapes, puncture dynamics and nest substrates. Specifically, the energy required to break eggs was greater for the static tests than for the dynamic tests, but only when using a nest substrate and a blunt tool. In turn, in the static tests, the addition of a nest significantly increased energy requirements for both tool types, whereas during dynamic tests, the increase in energy associated with the nest presence was significant only when using the sharp tool. Characterizing the process of eggshell puncture in increasingly naturalistic contexts will help in understanding whether and how hosts of brood parasites evolve to reject foreign eggs.

Development of a Clinical Prediction Model for In-hospital Mortality from the South African Cohort of the African Surgical Outcomes Study.

BACKGROUND: Data on the factors that influence mortality after surgery in South Africa are scarce, and neither these data nor data on risk-adjusted in-hospital mortality after surgery are routinely collected. Predictors related to the context or setting of surgical care delivery may also provide insight into variation in practice. Variation must be addressed when planning for improvement of risk-adjusted outcomes. Our objective was to identify the factors predicting in-hospital mortality after surgery in South Africa from available data. METHODS: A multivariable logistic regression model was developed to identify predictors of 30-day in-hospital mortality in surgical patients in South Africa. Data from the South African contribution to the African Surgical Outcomes Study were used and included 3800 cases from 51 hospitals. A forward stepwise regression technique was then employed to select for possible predictors prior to model specification. Model performance was evaluated by assessing calibration and discrimination. The South African Surgical Outcomes Study cohort was used to validate the model. RESULTS: Variables found to predict 30-day in-hospital mortality were age, American Society of Anesthesiologists Physical Status category, urgent or emergent surgery, major surgery, and gastrointestinal-, head and neck-, thoracic- and neurosurgery. The area under the receiver operating curve or c-statistic was 0.859 (95% confidence interval: 0.827-0.892) for the full model. Calibration, as assessed using a calibration plot, was acceptable. Performance was similar in the validation cohort as compared to the derivation cohort. CONCLUSION: The prediction model did not include factors that can explain how the context of care influences post-operative mortality in South Africa. It does, however, provide a basis for reporting risk-adjusted perioperative mortality rate in the future, and identifies the types of surgery to be prioritised in quality improvement projects at a local or national level.

Clinical lactation studies and the role of pharmacokinetic modeling and simulation in predicting drug exposures in breastfed infants.

The relative lack of information on medication use during breastfeeding is an ongoing problem for health professionals and mothers alike. Most nursing mothers are prescribed some form of medication, yet some mothers either discontinue breastfeeding or avoid medications entirely. Although regulatory authorities have proposed a framework for clinical lactation studies, data on drug passage into breastmilk are often lacking. Model-based approaches can potentially be used to estimate the passage of drugs into milk, predict exposures in breastfed infants, and identify drugs that need clinical lactation studies. When a human study is called for, measurement of the drug concentration in milk are often adequate to characterize safety. Data from these studies can be leveraged to further refine pharmacokinetic models with subsequent Monte Carlo simulations to estimate the spread of exposure values. Both clinical lactation studies and model-based approaches have some limitations and pitfalls which are discussed.

The Effects of Selenomethionine on the Escape Behaviours of Fathead Minnows.

Selenium (Se) is an essential micronutrient for animals and yet becomes toxic with only a small increase in concentration. Toxicological studies have reported various effects of Se on fishes, including developmental impacts and deformities of the musculature and sensory systems. This paper investigates the impact of sublethal concentrations of Se on the ability of the Fathead Minnow (Pimephales promelas) to perform escape responses, a routine behaviour important to predator-prey dynamics. Predation is among the strongest evolutionary driving forces in nature. Changes to this dynamic can have effects that cascade through the ecosystem. We used responses to mechanical and visual stimuli to determine the impact of environmentally relevant concentrations of dietary selenomethionine on the behaviour of minnows. Latency to respond to the stimulus and kinematic performance were assessed. Our results indicated that there was no significant effect of selenomethionine on either the visual response to a threat or burst swimming behaviours of the fast-start response in minnows. Levels of Se in tissues approached that of tissue-specific guidelines set by regulatory bodies across North America. This suggests that current regulations are adequately protecting this key component of predator avoidance in Fathead Minnows.

Making a point: shared mechanics underlying the diversity of biological puncture.

A viper injecting venom into a target, a mantis shrimp harpooning a fish, a cactus dispersing itself via spines attaching to passing mammals; all these are examples of biological puncture. Although disparate in terms of materials, kinematics and phylogeny, all three examples must adhere to the same set of fundamental physical laws that govern puncture mechanics. The diversity of biological puncture systems is a good case study for how physical laws can be used as a baseline for comparing disparate biological systems. In this Review, I explore the diversity of biological puncture and identify key variables that influence these systems. First, I explore recent work on biological puncture in a diversity of organisms, based on their hypothesized objectives: gripping, injection, damage and defence. Variation within each category is discussed, such as the differences between gripping for prey capture, gripping for dispersal of materials or gripping during reproduction. The second half of the Review is focused on specific physical parameters that influence puncture mechanics, such as material properties, stress, energy, speed and the medium within which puncture occurs. I focus on how these parameters have been examined in biology, and how they influence the evolution of biological systems. The ultimate objective of this Review is to outline an initial framework for examining the mechanics and evolution of puncture systems across biology. This framework will not only allow for broad biological comparisons, but also create a baseline for bioinspired design of both tools that puncture efficiently and materials that can resist puncture.

Drugs in Lactation.

One impediment to breastfeeding is the lack of information on the use of many drugs during lactation, especially newer ones. The principles of drug passage into breastmilk are well established, but have often not been optimally applied prospectively. Commonly used preclinical rodent models for determining drug excretion into milk are very unreliable because of marked differences in milk composition and transporters compared to those of humans. Measurement of drug concentrations in humans remains the gold standard, but computer modeling is promising. New FDA labeling requirements present an opportunity to apply modeling to preclinical drug development in place of conventional animal testing for drug excretion into breastmilk, which should improve the use of medications in nursing mothers.

A new method for studying cryptococcosis in a murine model using 99mTc-Cryptococcus gattii.

Cryptococcus gattii is one of the etiologic agents of cryptococcosis, a systemic mycosis that occurs in healthy and immunosuppressed humans and animals worldwide. Primary pulmonary infection caused by C. gattii is usually followed by fungal dissemination to the central nervous system, resulting in high mortality rates. In this context, animal models of cryptococcosis are useful in the study of fungal pathogenesis and host response against the pathogen, and for testing novel therapeutic options. The most frequently applied method to study fungal dissemination from the lungs to other organs is by culturing tissues, which is not accurate for the detection and quantification of fungal load at early stages of the infection. To overcome this problem, the purpose of this study was to develop a new method for the quantification of Cryptococcus dissemination. One C. gattii strain was efficiently radiolabeled with technetium-99m (99mTc), without affecting viability of the cells. Further, the 99mTc-C. gattii (111 MBq) strain was used to infect mice by intratracheal and intravenous route for biodistribution studies. 99mTc-C. gattii was successfully used in detection of the yeast in the brain of mice 6 hours postinoculation, while the detection using colony forming units was possible only 24 hours postinfection. Our results provided an alternative method that could be applied in further investigations regarding the efficacy of antifungals, fungal virulence, and host-pathogen interactions.

Mechanical sensitivity and the dynamics of evolutionary rate shifts in biomechanical systems.

The influence of biophysical relationships on rates of morphological evolution is a cornerstone of evolutionary theory. Mechanical sensitivity-the correlation strength between mechanical output and the system's underlying morphological components-is thought to impact the evolutionary dynamics of form-function relationships, yet has rarely been examined. Here, we compare the evolutionary rates of the mechanical components of the four-bar linkage system in the raptorial appendage of mantis shrimp (Order Stomatopoda). This system's mechanical output (kinematic transmission (KT)) is highly sensitive to variation in its output link, and less sensitive to its input and coupler links. We found that differential mechanical sensitivity is associated with variation in evolutionary rate: KT and the output link exhibit faster rates of evolution than the input and coupler links to which KT is less sensitive. Furthermore, for KT and, to a lesser extent, the output link, rates of evolution were faster in 'spearing' stomatopods than 'smashers', indicating that mechanical sensitivity may influence trait-dependent diversification. Our results suggest that mechanical sensitivity can impact morphological evolution and guide the process of phenotypic diversification. The connection between mechanical sensitivity and evolutionary rates provides a window into the interaction between physical rules and the evolutionary dynamics of morphological diversification.

Herbivorous dinosaur jaw disparity and its relationship to extrinsic evolutionary drivers.

Morphological responses of nonmammalian herbivores to external ecological drivers have not been quantified over extended timescales. Herbivorous nonavian dinosaurs are an ideal group to test for such responses, because they dominated terrestrial ecosystems for more than 155 Myr and included the largest herbivores that ever existed. The radiation of dinosaurs was punctuated by several ecologically important events, including extinctions at the Triassic/Jurassic (Tr/J) and Jurassic/Cretaceous (J/K) boundaries, the decline of cycadophytes, and the origin of angiosperms, all of which may have had profound consequences for herbivore communities. Here we present the first analysis of morphological and biomechanical disparity for sauropodomorph and ornithischian dinosaurs in order to investigate patterns of jaw shape and function through time. We find that morphological and biomechanical mandibular disparity are decoupled: mandibular shape disparity follows taxonomic diversity, with a steady increase through the Mesozoic. By contrast, biomechanical disparity builds to a peak in the Late Jurassic that corresponds to increased functional variation among sauropods. The reduction in biomechanical disparity following this peak coincides with the J/K extinction, the associated loss of sauropod and stegosaur diversity, and the decline of cycadophytes. We find no specific correspondence between biomechanical disparity and the proliferation of angiosperms. Continual ecological and functional replacement of pre-existing taxa accounts for disparity patterns through much of the Cretaceous, with the exception of several unique groups, such as psittacosaurids that are never replaced in their biomechanical or morphological profiles.

Initial radiation of jaws demonstrated stability despite faunal and environmental change.

More than 99 per cent of the roughly 58,000 living vertebrate species have jaws. This major clade, whose members are collectively known as gnathostomes ('jawed mouths'), made its earliest definitive appearance in the Silurian period, 444-416 million years (Myr) ago, with both the origin of the modern (crown-group) radiation and the presumptive invasion of land occurring by the end of the Devonian period (359 Myr ago). These events coincided with a major faunal shift that remains apparent today: the transition from Silurian ecosystems dominated by jawless fishes (agnathans) to younger assemblages composed almost exclusively of gnathostomes. This pattern has inspired several qualitative descriptions of the trophic radiation and ecological ascendance of the earliest jawed vertebrates. Here we present a quantitative analysis of functional variation in early gnathostome mandibular elements, placing constraints on our understanding of evolutionary patterns during this critical interval. We document an initial increase in functional disparity in the Silurian that stabilized by the first stage of the Devonian, before the occurrence of an Emsian (∼400 Myr ago) oxygenation event implicated in the trophic radiation of vertebrates. Subsequent taxonomic diversification during the Devonian did not result in increased functional variation; instead, new taxa revisited and elaborated on established mandibular designs. Devonian functional space is dominated by lobe-finned fishes and 'placoderms'; high disparity within the latter implies considerable trophic innovation among jaw-bearing stem gnathostomes. By contrast, the major groups of living vertebrates--ray-finned fishes and tetrapods--show surprisingly conservative mandibular morphologies with little indication of functional diversification or innovation. Devonian gnathostomes reached a point where they ceased to accrue further mandibular functional disparity before becoming taxonomic dominants relative to 'ostracoderm'-grade jawless fishes, providing a new perspective on classic adaptive hypotheses concerning this fundamental shift in vertebrate biodiversity.