Functional adaptive landscapes predict terrestrial capacity at the origin of limbs.

The acquisition of terrestrial, limb-based locomotion during tetrapod evolution has remained a subject of debate for more than a century1,2. Our current understanding of the locomotor transition from water to land is largely based on a few exemplar fossils such as Tiktaalik3, Acanthostega4, Ichthyostega5 and Pederpes6. However, isolated bony elements may reveal hidden functional diversity, providing a more comprehensive evolutionary perspective7. Here we analyse 40 three-dimensionally preserved humeri from extinct tetrapodomorphs that span the fin-to-limb transition and use functionally informed ecological adaptive landscapes8-10 to reconstruct the evolution of terrestrial locomotion. We show that evolutionary changes in the shape of the humerus are driven by ecology and phylogeny and are associated with functional trade-offs related to locomotor performance. Two divergent adaptive landscapes are recovered for aquatic fishes and terrestrial crown tetrapods, each of which is defined by a different combination of functional specializations. Humeri of stem tetrapods share a unique suite of functional adaptations, but do not conform to their own predicted adaptive peak. Instead, humeri of stem tetrapods fall at the base of the crown tetrapod landscape, indicating that the capacity for terrestrial locomotion occurred with the origin of limbs. Our results suggest that stem tetrapods may have used transitional gaits5,11 during the initial stages of land exploration, stabilized by the opposing selective pressures of their amphibious habits. Effective limb-based locomotion did not arise until loss of the ancestral 'L-shaped' humerus in the crown group, setting the stage for the diversification of terrestrial tetrapods and the establishment of modern ecological niches12,13.

Tail-propelled aquatic locomotion in a theropod dinosaur.

In recent decades, intensive research on non-avian dinosaurs has strongly suggested that these animals were restricted to terrestrial environments1. Historical proposals that some groups, such as sauropods and hadrosaurs, lived in aquatic environments2,3 were abandoned decades ago4-6. It has recently been argued that at least some of the spinosaurids-an unusual group of large-bodied theropods of the Cretaceous era-were semi-aquatic7,8, but this idea has been challenged on anatomical, biomechanical and taphonomic grounds, and remains controversial9-11. Here we present unambiguous evidence for an aquatic propulsive structure in a dinosaur, the giant theropod Spinosaurus aegyptiacus7,12. This dinosaur has a tail with an unexpected and unique shape that consists of extremely tall neural spines and elongate chevrons, which forms a large, flexible fin-like organ capable of extensive lateral excursion. Using a robotic flapping apparatus to measure undulatory forces in physical models of different tail shapes, we show that the tail shape of Spinosaurus produces greater thrust and efficiency in water than the tail shapes of terrestrial dinosaurs and that these measures of performance are more comparable to those of extant aquatic vertebrates that use vertically expanded tails to generate forward propulsion while swimming. These results are consistent with the suite of adaptations for an aquatic lifestyle and piscivorous diet that have previously been documented for Spinosaurus7,13,14. Although developed to a lesser degree, aquatic adaptations are also found in other members of the spinosaurid clade15,16, which had a near-global distribution and a stratigraphic range of more than 50 million years14, pointing to a substantial invasion of aquatic environments by dinosaurs.

Size and shape regional differentiation during the development of the spine in the nine-banded armadillo (Dasypus novemcinctus).

Xenarthrans (armadillos, anteaters, sloths, and their extinct relatives) are unique among mammals in displaying a distinctive specialization of the posterior trunk vertebrae-supernumerary vertebral xenarthrous articulations. This study seeks to understand how xenarthry develops through ontogeny and if it may be constrained to appear within pre-existing vertebral regions. Using three-dimensional geometric morphometrics on the neural arches of vertebrae, we explore phenotypic, allometric, and disparity patterns of the different axial morphotypes during the ontogeny of nine-banded armadillos. Shape-based regionalization analyses showed that the adult thoracolumbar column is divided into three regions according to the presence or absence of ribs and the presence or absence of xenarthrous articulations. A three-region division was retrieved in almost all specimens through development, although younger stages (e.g., fetuses, neonates) have more region boundary variability. In size-based regionalization analyses, thoracolumbar vertebrae are separated into two regions: a prediaphragmatic, prexenarthrous region, and a postdiaphragmatic xenarthrous region. We show that posterior thoracic vertebrae grow at a slower rate, while anterior thoracics and lumbars grow at a faster rate relatively, with rates decreasing anteroposteriorly in the former and increasing anteroposteriorly in the latter. We propose that different proportions between vertebrae and vertebral regions might result from differences in growth pattern and timing of ossification.

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.

Osteohistology of Greererpeton provides insight into the life history of an early Carboniferous tetrapod.

The vertebrate transition to land is one of the most consequential, yet poorly understood periods in tetrapod evolution. Despite the importance of the water-land transition in establishing modern ecosystems, we still know very little about the life histories of the earliest tetrapods. Bone histology provides an exceptional opportunity to study the biology of early tetrapods and has the potential to reveal new insights into their life histories. Here, we examine the femoral bone histology from an ontogenetic series of Greererpeton, an early tetrapod from the Middle-Late Mississippian (early Carboniferous) of North America. Thin-sections and micro-CT data show a moderately paced rate of bone deposition with significant cortical thickening through development. An interruption to regular bone deposition, as indicated by a zone of avascular tissue and growth marks, is notable at the same late juvenile stage of development throughout our sample. This suggests that an inherent aspect to the life history of juvenile Greererpeton resulted in a temporary reduction in bone deposition. We review several possible life history correlates for this bony signature including metamorphosis, an extended juvenile phase, environmental stress, and movement (migration/dispersal) between habitats. We argue that given the anatomy of Greererpeton, it is unlikely that events related to polymorphism (metamorphosis, extended juvenile phase) can explain the bony signature observed in our sample. Furthermore, the ubiquity of this signal in our sample indicates a taxon-level rather than a population-level trait, which is expected for an environmental stress. We conclude that movement via dispersal represents a likely correlate, as such events are a common life history strategy of aquatically bound vertebrates.

Clinical effectiveness of adding azithromycin to antimicrobial prophylaxis for cesarean delivery.

BACKGROUND: A recent large clinical trial demonstrated an approximately 50% decrease in the rate of postoperative infection in women who were laboring and/or had rupture of membranes for >4 hours and who received azithromycin in addition to standard preoperative antibiotic prophylaxis at the time of cesarean delivery. Given these results, our institution made a policy change in May 2017 to add azithromycin to standard preoperative prophylaxis for all cesarean deliveries. OBJECTIVE: This study aimed to evaluate the clinical effectiveness of adding azithromycin to preoperative antibiotic prophylaxis for cesarean delivery. STUDY DESIGN: We conducted a before-and-after cohort study of women delivered via cesarean delivery at our institution. The preimplementation group included women who delivered from March 1, 2016, to February 28, 2017, (before an institutional practice change of adding azithromycin to standard preoperative prophylaxis), and the postimplementation group included women who delivered from September 1, 2017, to August 31, 2018 (allowing a 6-month period for uptake of the practice change). The primary outcome was a composite of postoperative infections (endometritis, wound infection, other maternal infections). Unadjusted and adjusted risk ratios and 95% confidence intervals were estimated using a modified Poisson regression model. RESULTS: In the preimplementation (n=1171) and postimplementation (n=1168) groups, the incidence rates of the composite outcomes were 4.7% and 5.3%, respectively (P=.49). Both unadjusted (relative risk, 1.13; 95% confidence interval, 0.78-1.62) and adjusted (adjusted relative risk, 1.06; 95% confidence interval, 0.74-1.52) comparisons were not significantly different. In addition, results were statistically nonsignificant, but in the direction of lower rates of infection, in the after cohort for women in labor and/or with rupture of membranes for ≥4 hours (relative risk, 0.88 [95% confidence interval, 0.56-1.39]; adjusted relative risk, 0.82 [95% confidence interval, 0.52-1.30]) and for women with clinical chorioamnionitis (relative risk, 0.37 [95% confidence interval, 0.08-1.67]; data too sparse for adjusted analysis). In the subgroup of women who were not in labor, the after cohort had a statistically nonsignificant increased risk of the composite outcome in both unadjusted (relative risk, 1.53; 95% confidence interval, 0.86-2.72) and adjusted (adjusted relative risk, 1.48; 95% confidence interval, 0.83-2.65]) comparisons. CONCLUSION: In clinical practice, the addition of azithromycin to standard preoperative antibiotic prophylaxis for cesarean delivery may have an effect size smaller than seen in the large clinical trial prompting this practice change. Extrapolation of this regimen to women not in labor may be ineffective.

Insulin Dosing, Glycemic Control, and Perinatal Outcomes in Pregnancies Complicated by Type-2 Diabetes.

OBJECTIVE: This study aimed to evaluate the prevalence of severe insulin resistance (insulin requirements ≥2 units/kg) at delivery and the relationship between severe insulin resistance, glycemic control, and adverse perinatal outcomes in pregnant women with type-2 diabetes mellitus. STUDY DESIGN: This is a retrospective cohort study of women with type-2 diabetes mellitus who delivered between January 2015 and December 2017 at a tertiary academic medical center. Maternal demographic information, self-monitored blood sugars, and insulin doses were abstracted from the medical record. Multivariable logistic regression was used to identify maternal baseline characteristics associated with severe insulin resistance at delivery. RESULTS: Overall 72/160 (45%) of women had severe insulin resistance. Women in the severe insulin resistance group demonstrated evidence of suboptimal glycemic control as evidenced by higher mean hemoglobin A1c (HbA1c) values (7.2 [ ± 1.1] vs. 6.6 [ ± 1.3%], p = 0.003), higher mean fasting (104.0 [ ± 17.4] vs. 95.2 [ ± 11.7 mg/dL], p < 0.001) and postprandial glucose values (132.4 [ ± 17.2] vs. 121.9 [ ± 16.9 mg/dL]), p < 0.001), and a higher percentage of total glucose values that were elevated above targets (37.7 [95% confidence interval (CI): 26.8-50] vs. 25.6 [95% CI: 13.3-41.3%], p < 0.001). Maternal HbA1c ≥6.5% and insulin use prior to pregnancy were associated with a higher prevalence of severe insulin resistance, while Hispanic ethnicity and non-White race were associated with a lower prevalence of severe insulin resistance. The rates of adverse perinatal outcomes including large for gestational age (LGA) birth weight, cesarean delivery, and hypertensive disorders of pregnancy did not differ between groups. CONCLUSION: Severe insulin resistance is common among pregnant women with type-2 diabetes, and it is associated with suboptimal glycemic control. Future studies are necessary to develop strategies to identify women with severe insulin resistance early in pregnancy and facilitate adequate insulin dosing. KEY POINTS: · Severe insulin resistance is common.. · BMI does not predict severe insulin resistance.. · Suboptimal glycemic control is common..

Sphenodontian phylogeny and the impact of model choice in Bayesian morphological clock estimates of divergence times and evolutionary rates.

BACKGROUND: The vast majority of all life that ever existed on earth is now extinct and several aspects of their evolutionary history can only be assessed by using morphological data from the fossil record. Sphenodontian reptiles are a classic example, having an evolutionary history of at least 230 million years, but currently represented by a single living species (Sphenodon punctatus). Hence, it is imperative to improve the development and implementation of probabilistic models to estimate evolutionary trees from morphological data (e.g., morphological clocks), which has direct benefits to understanding relationships and evolutionary patterns for both fossil and living species. However, the impact of model choice on morphology-only datasets has been poorly explored. RESULTS: Here, we investigate the impact of a wide array of model choices on the inference of evolutionary trees and macroevolutionary parameters (divergence times and evolutionary rates) using a new data matrix on sphenodontian reptiles. Specifically, we tested different clock models, clock partitioning, taxon sampling strategies, sampling for ancestors, and variations on the fossilized birth-death (FBD) tree model parameters through time. We find a strong impact on divergence times and background evolutionary rates when applying widely utilized approaches, such as allowing for ancestors in the tree and the inappropriate assumption of diversification parameters being constant through time. We compare those results with previous studies on the impact of model choice to molecular data analysis and provide suggestions for improving the implementation of morphological clocks. Optimal model combinations find the radiation of most major lineages of sphenodontians to be in the Triassic and a gradual but continuous drop in morphological rates of evolution across distinct regions of the phenotype throughout the history of the group. CONCLUSIONS: We provide a new hypothesis of sphenodontian classification, along with detailed macroevolutionary patterns in the evolutionary history of the group. Importantly, we provide suggestions to avoid overestimated divergence times and biased parameter estimates using morphological clocks. Partitioning relaxed clocks offers methodological limitations, but those can be at least partially circumvented to reveal a detailed assessment of rates of evolution across the phenotype and tests of evolutionary mosaicism.

Prenatal diagnosis of middle interhemispheric variant of holoprosencephaly: Report of two cases.

Holoprosencephaly ranges in severity based on the degree of anatomic abnormality. Middle interhemispheric variant of holoprosencephaly is a less common and often milder variant that has the characteristic sonographic findings of an absent cavum septum pellucidum and a single fused ventricle. This subtype may be associated with genetic conditions that have not been well-described in the literature. We present two cases of middle interhemispheric variant of holoprosencephaly diagnosed on fetal ultrasound.

Wrong drug and wrong dose dispensing errors identified in pharmacist professional liability claims.

OBJECTIVE: This study aimed to identify pharmacist professional liability patterns and trends associated with 2 of the most common allegations in legal claims: wrong drug dispensing errors and wrong dose dispensing errors. METHODS: This study used pharmacist professional liability claim data from the Healthcare Providers Service Organization professional liability insurance program, underwritten by CNA. The final 2018 claims dataset consisted of pharmacist professional liability (i.e., malpractice) claims that closed between 2012 and 2016 and incurred a payment of at least $1 from the Healthcare Providers Service Organization program. Using malpractice claim data, the claims were classified by clinical license (pharmacist or pharmacy technician), primary allegation type, and total payment amount. These claims were then analyzed to determine the risk factors that most often led to wrong drug and wrong dose dispensing errors and the factors that led to claims with higher-than-average total payments. Then, the results were compared with the 2013 claims dataset to identify patterns and trends. RESULTS: Inclusion criteria, applied to 1264 reported adverse incidents and claims, created the 2018 claim dataset consisting of 184 closed claims over the 5 years available for review. The average total payment was $124,407 for closed claims with a payment of at least $1. Wrong drug dispensing errors represented 36.8% of claims in the 2018 dataset, and wrong dose dispensing errors represented 15.3% of claims. Comparisons with the 2013 dataset revealed that the percentage of claims associated with wrong drug dispensing errors decreased from 43.8% in the 2013 dataset to 36.8% in the 2018 dataset. The percentage of wrong dose claims also decreased since the 2013 dataset from 31.5% to 15.3%. CONCLUSION: Although technology and automation have contributed to improvements in the area of medication error prevention, wrong drug and wrong dose dispensing errors continue to occur because of system and human factor errors.

Heterochronic shifts and conserved embryonic shape underlie crocodylian craniofacial disparity and convergence.

The distinctive anatomy of the crocodylian skull is intimately linked with dietary ecology, resulting in repeated convergence on blunt- and slender-snouted ecomorphs. These evolutionary shifts depend upon modifications of the developmental processes which direct growth and morphogenesis. Here we examine the evolution of cranial ontogenetic trajectories to shed light on the mechanisms underlying convergent snout evolution. We use geometric morphometrics to quantify skeletogenesis in an evolutionary context and reconstruct ancestral patterns of ontogenetic allometry to understand the developmental drivers of craniofacial diversity within Crocodylia. Our analyses uncovered a conserved embryonic region of morphospace (CER) shared by all non-gavialid crocodylians regardless of their eventual adult ecomorph. This observation suggests the presence of conserved developmental processes during early development (before Ferguson stage 20) across most of Crocodylia. Ancestral state reconstruction of ontogenetic trajectories revealed heterochrony, developmental constraint, and developmental systems drift have all played essential roles in the evolution of ecomorphs. Based on these observations, we conclude that two separate, but interconnected, developmental programmes controlling craniofacial morphogenesis and growth enabled the evolutionary plasticity of skull shape in crocodylians.

Vertebral architecture in the earliest stem tetrapods.

The construction of the vertebral column has been used as a key anatomical character in defining and diagnosing early tetrapod groups. Rhachitomous vertebrae--in which there is a dorsally placed neural arch and spine, an anteroventrally placed intercentrum and paired, posterodorsally placed pleurocentra--have long been considered the ancestral morphology for tetrapods. Nonetheless, very little is known about vertebral anatomy in the earliest stem tetrapods, because most specimens remain trapped in surrounding matrix, obscuring important anatomical features. Here we describe the three-dimensional vertebral architecture of the Late Devonian stem tetrapod Ichthyostega using propagation phase-contrast X-ray synchrotron microtomography. Our scans reveal a diverse array of new morphological, and associated developmental and functional, characteristics, including a possible posterior-to-anterior vertebral ossification sequence and the first evolutionary appearance of ossified sternal elements. One of the most intriguing features relates to the positional relationships between the vertebral elements, with the pleurocentra being unexpectedly sutured or fused to the intercentra that directly succeed them, indicating a 'reverse' rhachitomous design. Comparison of Ichthyostega with two other stem tetrapods, Acanthostega and Pederpes, shows that reverse rhachitomous vertebrae may be the ancestral condition for limbed vertebrates. This study fundamentally revises our current understanding of vertebral column evolution in the earliest tetrapods and raises questions about the presumed vertebral architecture of tetrapodomorph fish and later, more crownward, tetrapods.

Adaptation and constraint in the evolution of the mammalian backbone.

BACKGROUND: The axial skeleton consists of repeating units (vertebrae) that are integrated through their development and evolution. Unlike most tetrapods, vertebrae in the mammalian trunk are subdivided into distinct thoracic and lumbar modules, resulting in a system that is constrained in terms of count but highly variable in morphology. This study asks how thoracolumbar regionalization has impacted adaptation and evolvability across mammals. Using geometric morphometrics, we examine evolutionary patterns in five vertebral positions from diverse mammal species encompassing a broad range of locomotor ecologies. We quantitatively compare the effects of phylogenetic and allometric constraints, and ecological adaptation between regions, and examine their impact on evolvability (disparity and evolutionary rate) of serially-homologous vertebrae. RESULTS: Although phylogenetic signal and allometry are evident throughout the trunk, the effect of locomotor ecology is partitioned between vertebral positions. Lumbar vertebral shape correlates most strongly with ecology, differentiating taxa based on their use of asymmetric gaits. Similarly, disparity and evolutionary rates are also elevated posteriorly, indicating a link between the lumbar region, locomotor adaptation, and evolvability. CONCLUSION: Vertebral regionalization in mammals has facilitated rapid evolution of the posterior trunk in response to selection for locomotion and static body support.

Three-dimensional mobility and muscle attachments in the pectoral limb of the Triassic cynodont Massetognathus pascuali (Romer, 1967).

The musculoskeletal configuration of the mammalian pectoral limb has been heralded as a key anatomical feature leading to the adaptive radiation of mammals, but limb function in the non-mammaliaform cynodont outgroup remains unresolved. Conflicting reconstructions of abducted and adducted posture are based on mutually incompatible interpretations of ambiguous osteology. We reconstruct the pectoral limb of the Triassic non-mammaliaform cynodont Massetognathus pascuali in three dimensions, by combining skeletal morphology from micro-computed tomography with muscle anatomy from an extended extant phylogenetic bracket. Conservative tests of maximum range of motion suggest a degree of girdle mobility, as well as substantial freedom at the shoulder and the elbow joints. The glenoid fossa supports a neutral pose in which the distal end of the humerus points 45° posterolaterally from the body wall, intermediate between classically 'sprawling' and 'parasagittal' limb postures. Massetognathus pascuali is reconstructed as having a near-mammalian complement of shoulder muscles, including an incipient rotator cuff (m. subscapularis, m. infraspinatus, m. supraspinatus, and m. teres minor). Based on close inspection of the morphology of the glenoid fossa, we hypothesize a posture-driven scenario for the evolution of the therian ball-and-socket shoulder joint. The musculoskeletal reconstruction presented here provides the anatomical scaffolding for more detailed examination of locomotor evolution in the precursors to mammals.

Three-dimensional limb joint mobility in the early tetrapod Ichthyostega.

The origin of tetrapods and the transition from swimming to walking was a pivotal step in the evolution and diversification of terrestrial vertebrates. During this time, modifications of the limbs­particularly the specialization of joints and the structures that guide their motions­fundamentally changed the ways in which early tetrapods could move. Nonetheless, little is known about the functional consequences of limb anatomy in early tetrapods and how that anatomy influenced locomotion capabilities at this very critical stage in vertebrate evolution. Here we present a three-dimensional reconstruction of the iconic Devonian tetrapod Ichthyostega and a quantitative and comparative analysis of limb mobility in this early tetrapod. We show that Ichthyostega could not have employed typical tetrapod locomotory behaviours, such as lateral sequence walking. In particular, it lacked the necessary rotary motions in its limbs to push the body off the ground and move the limbs in an alternating sequence. Given that long-axis rotation was present in the fins of tetrapodomorph fishes, it seems that either early tetrapods evolved through an initial stage of restricted shoulder and hip joint mobility or that Ichthyostega was unique in this respect. We conclude that early tetrapods with the skeletal morphology and limb mobility of Ichthyostega were unlikely to have made some of the recently described Middle Devonian trackways.

Mechanics of evolutionary digit reduction in fossil horses (Equidae).

Digit reduction is a major trend that characterizes horse evolution, but its causes and consequences have rarely been quantitatively tested. Using beam analysis on fossilized centre metapodials, we tested how locomotor bone stresses changed with digit reduction and increasing body size across the horse lineage. Internal bone geometry was captured from 13 fossil horse genera that covered the breadth of the equid phylogeny and the spectrum of digit reduction and body sizes, from Hyracotherium to Equus To account for the load-bearing role of side digits, a novel, continuous measure of digit reduction was also established-toe reduction index (TRI). Our results show that without accounting for side digits, three-toed horses as late as Parahippus would have experienced physiologically untenable bone stresses. Conversely, when side digits are modelled as load-bearing, species at the base of the horse radiation through Equus probably maintained a similar safety factor to fracture stress. We conclude that the centre metapodial compensated for evolutionary digit reduction and body mass increases by becoming more resistant to bending through substantial positive allometry in internal geometry. These results lend support to two historical hypotheses: that increasing body mass selected for a single, robust metapodial rather than several smaller ones; and that, as horse limbs became elongated, the cost of inertia from the side toes outweighed their utility for stabilization or load-bearing.

Adrenomedullin improves fertility and promotes pinopodes and cell junctions in the peri-implantation endometrium.

Implantation is a complex event demanding contributions from both embryo and endometrium. Despite advances in assisted reproduction, endometrial receptivity defects persist as a barrier to successful implantation in women with infertility. We previously demonstrated that maternal haploinsufficiency for the endocrine peptide adrenomedullin (AM) in mice confers a subfertility phenotype characterized by defective uterine receptivity and sparse epithelial pinopode coverage. The strong link between AM and implantation suggested the compelling hypothesis that administration of AM prior to implantation may improve fertility, protect against pregnancy complications, and ultimately lead to better maternal and fetal outcomes. Here, we demonstrate that intrauterine delivery of AM prior to blastocyst transfer improves the embryo implantation rate and spacing within the uterus. We then use genetic decrease-of-function and pharmacologic gain-of-function mouse models to identify potential mechanisms by which AM confers enhanced implantation success. In epithelium, we find that AM accelerates the kinetics of pinopode formation and water transport and that, in stroma, AM promotes connexin 43 expression, gap junction communication, and barrier integrity of the primary decidual zone. Ultimately, our findings advance our understanding of the contributions of AM to uterine receptivity and suggest potential broad use for AM as therapy to encourage healthy embryo implantation, for example, in combination with in vitro fertilization.

Experimental determination of three-dimensional cervical joint mobility in the avian neck.

BACKGROUND: Birds have highly mobile necks, but neither the details of how they realize complex poses nor the evolution of this complex musculoskeletal system is well-understood. Most previous work on avian neck function has focused on dorsoventral flexion, with few studies quantifying lateroflexion or axial rotation. Such data are critical for understanding joint function, as musculoskeletal movements incorporate motion around multiple degrees of freedom simultaneously. Here we use biplanar X-rays on wild turkeys to quantify three-dimensional cervical joint range of motion in an avian neck to determine patterns of mobility along the cranial-caudal axis. RESULTS: Range of motion can be generalized to a three-region model: cranial joints are ventroflexed with high axial and lateral mobility, caudal joints are dorsiflexed with little axial rotation but high lateroflexion, and middle joints show varying amounts axial rotation and a low degree of lateroflexion. Nonetheless, variation within and between regions is high. To attain complex poses, substantial axial rotation can occur at joints caudal to the atlas/axis complex and zygapophyseal joints can reduce their overlap almost to osteological disarticulation. Degrees of freedom interact at cervical joints; maximum lateroflexion occurs at different dorsoventral flexion angles at different joints, and axial rotation and lateroflexion are strongly coupled. Further, patterns of joint mobility are strongly predicted by cervical morphology. CONCLUSION: Birds attain complex neck poses through a combination of mobile intervertebral joints, coupled rotations, and highly flexible zygapophyseal joints. Cranial-caudal patterns of joint mobility are tightly linked to cervical morphology, such that function can be predicted by form. The technique employed here provides a repeatable protocol for studying neck function in a broad array of taxa that will be directly comparable. It also serves as a foundation for future work on the evolution of neck mobility along the line from non-avian theropod dinosaurs to birds.

The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach.

PURPOSE: Prostaglandins play a critical role in cervical ripening by increasing inflammatory mediators in the cervix and inducing cervical remodeling. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) exert different effects on these processes and on myometrial contractility. These mechanistic differences may affect outcomes in women treated with dinoprostone, a formulation identical to endogenous PGE2, compared with misoprostol, a PGE1 analog. The objective of this review is to evaluate existing evidence regarding mechanistic differences between PGE1 and PGE2, and consider the clinical implications of these differences in patients requiring cervical ripening for labor induction. METHODS: We conducted a critical narrative review of peer-reviewed articles identified using PubMed and other online databases. RESULTS: While both dinoprostone and misoprostol are effective in cervical ripening and labor induction, they differ in their clinical and pharmacological profiles. PGE2 has been shown to stimulate interleukin-8, an inflammatory cytokine that promotes the influx of neutrophils and induces remodeling of the cervical extracellular matrix, and to induce functional progesterone withdrawal. Misoprostol has been shown to elicit a dose-dependent effect on myometrial contractility, which may affect rates of uterine tachysystole in clinical practice. CONCLUSIONS: Differences in the mechanism of action between misoprostol and PGE2 may contribute to their variable effects in the cervix and myometrium, and should be considered to optimize outcomes.

The scaling of postcranial muscles in cats (Felidae) I: forelimb, cervical, and thoracic muscles.

The body masses of cats (Mammalia, Carnivora, Felidae) span a ~300-fold range from the smallest to largest species. Despite this range, felid musculoskeletal anatomy remains remarkably conservative, including the maintenance of a crouched limb posture at unusually large sizes. The forelimbs in felids are important for body support and other aspects of locomotion, as well as climbing and prey capture, with the assistance of the vertebral (and hindlimb) muscles. Here, we examine the scaling of the anterior postcranial musculature across felids to assess scaling patterns between different species spanning the range of felid body sizes. The muscle architecture (lengths and masses of the muscle-tendon unit components) for the forelimb, cervical and thoracic muscles was quantified to analyse how the muscles scale with body mass. Our results demonstrate that physiological cross-sectional areas of the forelimb muscles scale positively with increasing body mass (i.e. becoming relatively larger). Many significantly allometric variables pertain to shoulder support, whereas the rest of the limb muscles become relatively weaker in larger felid species. However, when phylogenetic relationships were corrected for, most of these significant relationships disappeared, leaving no significantly allometric muscle metrics. The majority of cervical and thoracic muscle metrics are not significantly allometric, despite there being many allometric skeletal elements in these regions. When forelimb muscle data were considered in isolation or in combination with those of the vertebral muscles in principal components analyses and MANOVAs, there was no significant discrimination among species by either size or locomotory mode. Our results support the inference that larger felid species have relatively weaker anterior postcranial musculature compared with smaller species, due to an absence of significant positive allometry of forelimb or vertebral muscle architecture. This difference in strength is consistent with behavioural changes in larger felids, such as a reduction of maximal speed and other aspects of locomotor abilities.