ASXL1/TET2 genotype-based risk stratification outperforms ASXL1 mutational impact and is independent of mutant variant allele fractions in chronic myelomonocytic leukemia.

Not available.

Identifying physical therapists' attitudes, beliefs, and barriers toward diagnostic imaging referral: a mixed-methods study.

OBJECTIVE: Ten states, including the District of Columbia, have laws that currently permit physical therapists (PTs) to directly order diagnostic imaging (DI) in the United States. Military and civilian PTs order DI judiciously and appropriately demonstrating optimal patient outcomes and satisfaction when compared to other medical professionals. However, no studies have explored perceived attitudes, beliefs, and barriers to PT DI referral specific to North Dakota (ND). Therefore, the purpose of this mixed-methods study was to identify ND PTs' attitudes, beliefs, and barriers toward DI referral. METHODS: A total of 147 participants completed an online survey with a subset of 17 participants agreeing to an interview. Frequency counts of demographic data and perceived barriers were completed. A binary logistic regression was run on demographic data. One-on-one interviews were conducted with a thematic coding process completed within a qualitative analysis. RESULTS: Seventy-four percent of PTs reported not currently referring for DI, although 71% felt that it would improve their patient outcomes. PTs with post-professional training (OR = 4.59), a doctorate degree (OR = 3.84), practicing in an orthopaedic or sports setting (OR = 3.55), and practicing within an urban setting of ND (OR = 3.01) were more likely to refer for DI. The main barriers identified in the survey included: (1) the logistics of performing a DI referral, (2) DI referrals only privileged to other medical providers, (3) provider/work relationship dynamics, (4) the cost of continuing education (CE), (5) and the inability to identify CE. One-on-one interviews further identified five main themes related to DI referral. DISCUSSION/CONCLUSION: Several barriers identified resulted in 74.1% of PTs not directly referring for DI, although certain characteristics (post-professional training, doctorate degree, orthopaedic/sports setting, practicing in an urban area in ND) were more likely to refer for DI. This study may help improve future adoption and implementation of DI referral in current and future states.

Highly Responsive Plasmon Modulation in Dopant-Segregated Nanocrystals.

Electron transfer to and from metal oxide nanocrystals (NCs) modulates their infrared localized surface plasmon resonance (LSPR), revealing fundamental aspects of their photophysics and enabling dynamic optical applications. We synthesized and chemically reduced dopant-segregated Sn-doped In2O3 NCs, investigating the influence of radial dopant segregation on LSPR modulation and near-field enhancement (NFE). We found that core-doped NCs show large LSPR shifts and NFE change during chemical titration, enabling broadband modulation in LSPR energy of over 1000 cm-1 and of peak extinction over 300%. Simulations reveal that the evolution of the LSPR spectra during chemical reduction results from raising the surface Fermi level and increasing the donor defect density in the shell region. These results establish dopant segregation as a useful strategy to engineer the dynamic optical modulation in plasmonic semiconductor NC heterostructures going beyond what is possible with conventional plasmonic metals.

Impact of claudin-10 deficiency on amelogenesis: Lesson from a HELIX tooth.

In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin-10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron-based X-ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations.

The microbiome of common bedding materials before and after use on commercial dairy farms.

BACKGROUND: Bovine mastitis is one of the most economically important diseases affecting dairy cows. The choice of bedding material has been identified as an important risk factor contributing to the development of mastitis. However, few reports examine both the culturable and nonculturable microbial composition of commonly used bedding materials, i.e., the microbiome. Given the prevalence of nonculturable microbes in most environments, this information could be an important step to understanding whether and how the bedding microbiome acts as a risk factor for mastitis. Therefore, our objective was to characterize the microbiome composition and diversity of bedding material microbiomes, before and after use. METHODS: We collected 88 bedding samples from 44 dairy farms in the U.S. Unused (from storage pile) and used (out of stalls) bedding materials were collected from four bedding types: new sand (NSA), recycled manure solids (RMS), organic non-manure (ON) and recycled sand (RSA). Samples were analyzed using 16S rRNA sequencing of the V3-V4 region. RESULTS: The overall composition as well as the counts of several microbial taxa differed between bedding types, with Proteobacteria, Actinobacteria, Bacteroidetes and Firmicutes dominating across all types. Used bedding contained a significantly different microbial composition than unused bedding, but the magnitude of this difference varied by bedding type, with RMS bedding exhibiting the smallest difference. In addition, positive correlations were observed between 16S rRNA sequence counts of potential mastitis pathogens (bacterial genera) and corresponding bedding bacterial culture data. CONCLUSION: Our results strengthen the role of bedding as a potential source of mastitis pathogens. The consistent shift in the microbiome of all bedding types that occurred during use by dairy cows deserves further investigation to understand whether this shift promotes pathogen colonization and/or persistence, or whether it can differentially impact udder health outcomes. Future studies of bedding and udder health may be strengthened by including a microbiome component to the study design.

Bayesian spatial modelling of geostatistical data using INLA and SPDE methods: A case study predicting malaria risk in Mozambique.

Bayesian spatial models are widely used to analyse data that arise in scientific disciplines such as health, ecology, and the environment. Traditionally, Markov chain Monte Carlo (MCMC) methods have been used to fit these type of models. However, these are highly computationally intensive methods that present a wide range of issues in terms of convergence and can become infeasible in big data problems. The integrated nested Laplace approximation (INLA) method is a computational less-intensive alternative to MCMC that allows us to perform approximate Bayesian inference in latent Gaussian models such as generalised linear mixed models and spatial and spatio-temporal models. This approach can be used in combination with the stochastic partial differential equation (SPDE) approach to analyse geostatistical data that have been collected at particular sites to predict the spatial process underlying the data as well as to assess the effect of covariates and model other sources of variability. Here we demonstrate how to fit a Bayesian spatial model using the INLA and SPDE approaches applied to freely available data of malaria prevalence and risk factors in Mozambique. We show how to fit and interpret the model to predict malaria risk and assess the effect of covariates using the R-INLA package, and provide the R code necessary to reproduce the results or to use it in other spatial applications.

IKKß-NF-κB signaling in adult chondrocytes promotes the onset of age-related osteoarthritis in mice.

Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in articular chondrocytes increased with age, concomitant with the onset of spontaneous OA in wild-type mice. Chondrocyte-specific expression of a constitutively active form of inhibitor of κB kinase ß (IKKß) in young adult mice accelerated the onset of the OA-like phenotype observed in aging wild-type mice, including degenerative changes in the articular cartilage, synovium, and menisci. Both in vitro and in vivo, chondrocytes expressing activated IKKß had a proinflammatory secretory phenotype characterized by markers typically associated with the senescence-associated secretory phenotype (SASP). Expression of these factors was differentially regulated by p65, which contains a transactivation domain, and p50, which does not. Whereas the loss of p65 blocked the induction of genes encoding SASP factors in chondrogenic cells treated with interleukin-1ß (IL-1ß) in vitro, the loss of p50 enhanced the IL-1ß­induced expression of some SASP factors. The loss of p50 further exacerbated cartilage degeneration in mice with chondrocyte-specific IKKß activation. Overall, our data reveal that IKKß-mediated activation of p65 can promote OA onset and that p50 may limit cartilage degeneration in settings of joint inflammation including advanced age.

Deep-time biodiversity patterns and the dinosaurian fossil record of the Late Cretaceous Western Interior, North America.

In order for palaeontological data to be informative to ecologists seeking to understand the causes of today's diversity patterns, palaeontologists must demonstrate that actual biodiversity patterns are preserved in our reconstructions of past ecosystems. During the Late Cretaceous, North America was divided into two landmasses, Laramidia and Appalachia. Previous work has suggested strong faunal provinciality on Laramidia at this time, but these arguments are almost entirely qualitative. We quantitatively investigated faunal provinciality in ceratopsid and hadrosaurid dinosaurs using a biogeographic network approach and investigated sampling biases by examining correlations between dinosaur occurrences and collections. We carried out a model-fitting approach using generalized least-squares regression to investigate the sources of sampling bias we identified. We find that while the raw data strongly support faunal provinciality, this result is driven by sampling bias. The data quality of ceratopsids and hadrosaurids is currently too poor to enable fair tests of provincialism, even in this intensively sampled region, which probably represents the best-known Late Cretaceous terrestrial ecosystem on Earth. To accurately reconstruct biodiversity patterns in deep time, future work should focus on smaller scale, higher resolution case studies in which the effects of sampling bias can be better controlled.

Spatial sampling heterogeneity limits the detectability of deep time latitudinal biodiversity gradients.

The latitudinal biodiversity gradient (LBG), in which species richness decreases from tropical to polar regions, is a pervasive pattern of the modern biosphere. Although the distribution of fossil occurrences suggests this pattern has varied through deep time, the recognition of palaeobiogeographic patterns is hampered by geological and anthropogenic biases. In particular, spatial sampling heterogeneity has the capacity to impact upon the reconstruction of deep time LBGs. Here we use a simulation framework to test the detectability of three different types of LBG (flat, unimodal and bimodal) over the last 300 Myr. We show that heterogeneity in spatial sampling significantly impacts upon the detectability of genuine LBGs, with known biodiversity patterns regularly obscured after applying the spatial sampling window of fossil collections. Sampling-standardization aids the reconstruction of relative biodiversity gradients, but cannot account for artefactual absences introduced by geological and anthropogenic biases. Therefore, we argue that some previous studies might have failed to recover the 'true' LBG type owing to incomplete and heterogeneous sampling, particularly between 200 and 20 Ma. Furthermore, these issues also have the potential to bias global estimates of past biodiversity, as well as inhibit the recognition of extinction and radiation events.

Early life of Neanderthals.

The early onset of weaning in modern humans has been linked to the high nutritional demand of brain development that is intimately connected with infant physiology and growth rate. In Neanderthals, ontogenetic patterns in early life are still debated, with some studies suggesting an accelerated development and others indicating only subtle differences vs. modern humans. Here we report the onset of weaning and rates of enamel growth using an unprecedented sample set of three late (∼70 to 50 ka) Neanderthals and one Upper Paleolithic modern human from northeastern Italy via spatially resolved chemical/isotopic analyses and histomorphometry of deciduous teeth. Our results reveal that the modern human nursing strategy, with onset of weaning at 5 to 6 mo, was present among these Neanderthals. This evidence, combined with dental development akin to modern humans, highlights their similar metabolic constraints during early life and excludes late weaning as a factor contributing to Neanderthals' demise.

Growth and development of the third permanent molar in Paranthropus robustus from Swartkrans, South Africa.

Third permanent molars (M3s) are the last tooth to form but have not been used to estimate age at dental maturation in early fossil hominins because direct histological evidence for the timing of their growth has been lacking. We investigated an isolated maxillary M3 (SK 835) from the 1.5 to 1.8-million-year-old (Mya) site of Swartkrans, South Africa, attributed to Paranthropus robustus. Tissue proportions of this specimen were assessed using 3D X-ray micro-tomography. Thin ground sections were used to image daily growth increments in enamel and dentine. Transmitted light microscopy and synchrotron X-ray fluorescence imaging revealed fluctuations in Ca concentration that coincide with daily growth increments. We used regional daily secretion rates and Sr marker-lines to reconstruct tooth growth along the enamel/dentine and then cementum/dentine boundaries. Cumulative growth curves for increasing enamel thickness and tooth height and age-of-attainment estimates for fractional stages of tooth formation differed from those in modern humans. These now provide additional means for assessing late maturation in early hominins. M3 formation took ≥ 7 years in SK 835 and completion of the roots would have occurred between 11 and 14 years of age. Estimated age at dental maturation in this fossil hominin compares well with what is known for living great apes.

Dual-Mode Infrared Absorption by Segregating Dopants within Plasmonic Semiconductor Nanocrystals.

When aliovalent dopants are sufficiently segregated to the core or near the surface of semiconductor nanocrystals, charge carriers donated by the dopants are also segregated to the core or near the surface, respectively. In Sn-doped indium oxide nanocrystals, we find that this contrast in free charge carrier concentration creates a core and shell with differing dielectric properties and results in two distinctly observable plasmonic extinction peaks. The trends in this dual-mode optical response with shell growth differ from core/shell nanoparticles composed of traditional plasmonic metals such as Au and Ag. We developed a model employing a core/shell effective medium approximation that can fit the dual-mode spectra and explain the trends in the extinction response. Lastly, we show that dopant segregation can improve sensitivity of plasmon spectra to changes in refractive index of the surrounding environment.

Mobilization of Antibiotic Resistance: Are Current Approaches for Colocalizing Resistomes and Mobilomes Useful?

Antimicrobial resistance (AMR) poses a global human and animal health threat, and predicting AMR persistence and transmission remains an intractable challenge. Shotgun metagenomic sequencing can help overcome this by enabling characterization of AMR genes within all bacterial taxa, most of which are uncultivatable in laboratory settings. Shotgun sequencing, therefore, provides a more comprehensive glance at AMR "potential" within samples, i.e., the "resistome." However, the risk inherent within a given resistome is predicated on the genomic context of various AMR genes, including their presence within mobile genetic elements (MGEs). Therefore, resistome risk stratification can be advanced if AMR profiles are considered in light of the flanking mobilizable genomic milieu (e.g., plasmids, integrative conjugative elements (ICEs), phages, and other MGEs). Because such mediators of horizontal gene transfer (HGT) are involved in uptake by pathogens, investigators are increasingly interested in characterizing that resistome fraction in genomic proximity to HGT mediators, i.e., the "mobilome"; we term this "colocalization." We explored the utility of common colocalization approaches using alignment- and assembly-based techniques, on clinical (human) and agricultural (cattle) fecal metagenomes, obtained from antimicrobial use trials. Ordination revealed that tulathromycin-treated cattle experienced a shift in ICE and plasmid composition versus untreated animals, though the resistome was unaffected during the monitoring period. Contrarily, the human resistome and mobilome composition both shifted shortly after antimicrobial administration, though this rebounded to pre-treatment status. Bayesian networks revealed statistical AMR-MGE co-occurrence in 19 and 2% of edges from the cattle and human networks, respectively, suggesting a putatively greater mobility potential of AMR in cattle feces. Conversely, using Mobility Index (MI) and overlap analysis, abundance of de novo-assembled contigs supporting resistomes flanked by MGE increased shortly post-exposure within human metagenomes, though > 40 days after peak dose such contigs were rare (∼2%). MI was not substantially altered by antimicrobial exposure across all cattle metagenomes, ranging 0.5-4.0%. We highlight that current alignment- and assembly-based methods estimating resistome mobility yield contradictory and incomplete results, likely constrained by approach-specific data inputs, and bioinformatic limitations. We discuss recent laboratory and computational advancements that may enhance resistome risk analysis in clinical, regulatory, and commercial applications.

Reassessment of the TM 1517 odonto-postcranial assemblage from Kromdraai B, South Africa, and the maturational pattern of Paranthropus robustus.

OBJECTIVES: The Pleistocene taxon Paranthropus robustus was established in 1938 following the discovery at Kromdraai B, South Africa, of the partial cranium TM 1517a and associated mandible TM 1517b. Shortly thereafter, a distal humerus (TM 1517g), a proximal ulna (TM 1517e), and a distal hallucial phalanx (TM 1517k) were collected nearby at the site, and were considered to be associated with the holotype. TM 1517a-b represents an immature individual; however, no analysis of the potentially associated postcranial elements has investigated the presence of any endostructural remnant of recent epiphyseal closure. This study aims at tentatively detecting such traces in the three postcranial specimens from Kromdraai B. MATERIALS AND METHODS: By using µXCT techniques, we assessed the developmental stage of the TM 1517b's C-M3 roots and investigated the inner structure of TM 1517g, TM 1517e, and TM 1517k. RESULTS: The M2 shows incompletely closed root apices and the M3 a half-completed root formation stage. The distal humerus was likely completely fused, while the proximal ulna and the distal hallucial phalanx preserve endosteal traces of the diaphyseo-epiphyseal fusion process. DISCUSSION: In the hominin fossil record, there are few unambiguously associated craniodental and postcranial remains sampling immature individuals, an essential condition for assessing the taxon-specific maturational patterns. Our findings corroborate the original association of the craniodental and postcranial remains representing the P. robustus type specimen. As with other Plio-Pleistocene hominins, the odonto-postcranial maturational pattern of TM 1517 more closely fits an African great ape rather than the extant human pattern.

MEGARes 2.0: a database for classification of antimicrobial drug, biocide and metal resistance determinants in metagenomic sequence data.

Antimicrobial resistance (AMR) is a threat to global public health and the identification of genetic determinants of AMR is a critical component to epidemiological investigations. High-throughput sequencing (HTS) provides opportunities for investigation of AMR across all microbial genomes in a sample (i.e. the metagenome). Previously, we presented MEGARes, a hand-curated AMR database and annotation structure developed to facilitate the analysis of AMR within metagenomic samples (i.e. the resistome). Along with MEGARes, we released AmrPlusPlus, a bioinformatics pipeline that interfaces with MEGARes to identify and quantify AMR gene accessions contained within a metagenomic sequence dataset. Here, we present MEGARes 2.0 (https://megares.meglab.org), which incorporates previously published resistance sequences for antimicrobial drugs, while also expanding to include published sequences for metal and biocide resistance determinants. In MEGARes 2.0, the nodes of the acyclic hierarchical ontology include four antimicrobial compound types, 57 classes, 220 mechanisms of resistance, and 1,345 gene groups that classify the 7,868 accessions. In addition, we present an updated version of AmrPlusPlus (AMR ++ version 2.0), which improves accuracy of classifications, as well as expanding scalability and usability.

Rare Orbital Metastasis Originating From a Neuroendocrine Tumor.

BACKGROUND: This case study details a rare orbital metastasis originating from the gastrointestinal tract. A patient presented with proptosis of the right eye precipitated by a slow-growing orbital tumor. A biopsy confirmed a low-grade neuroendocrine tumor. Imaging studies were completed, with magnetic resonance (MR) imaging of the orbits providing the most detailed images of the mass. Fusion software images were created from the MR images and indium In 111 pentetreotide (octreoscan) studies, which confirmed the presence of the neuroendocrine carcinoid tumor. DISCUSSION: Orbital metastases are a rare condition associated with various symptoms, most commonly proptosis and diplopia. Imaging modalities, such as MR, computed tomography, and nuclear medicine technology, are instrumental in detecting and assessing these masses. Fusion imaging software can provide additional opportunities for facilities without hybrid scanners. The treatment of choice for orbital metastases is octreotide therapy; however, radiation therapy, partial or complete surgical removal of the tumor, and chemotherapy also are used. CONCLUSION: Traditional imaging techniques and fusion imaging techniques are essential for diagnosing and treating orbital metastases.

Multi-center evaluation of dose conformity in stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) is an emerging technique for treating oligometastases, but limited data is available on what plan quality is achievable for a range of modalities and clinical sites. METHODS: SBRT plans for lung, spine, bone, adrenal, liver and node sites from 17 participating centers were reviewed. Centers used various delivery techniques including static and rotational intensity-modulation and multiple non-coplanar beams. Plans were split into lung and other body sites and evaluated with different plan quality metrics, including two which are independent of target coverage; "prescription dose spillage" (PDS) and "modified gradient index" (MGI). These were compared to constraints from the ROSEL and RTOG 0813 clinical trials. RESULTS: Planning target volume (PTV) coverage was compromised (PTV V100% < 90%) in 29% of patient plans in order to meet organ-at-risk (OAR) tolerances, supporting the use of plan quality metrics which are independent of target coverage. Both lung (n = 48) and other body (n = 99) site PDS values agreed well with ROSEL constraints on dose spillage, but RTOG 0813 values were too high to detect sub-optimal plans. MGI values for lung plans were mis-matched to both sets of previous constraints, with ROSEL values too high and RTOG 0813 values too low. MGI values were lower for other body plans as expected, though this was only statistically significant for PTV volumes <20 cm3. CONCLUSIONS: Updated guidance for lung and other body site SBRT plan quality using the PDS and MGI metrics is presented.

Investigating Effects of Tulathromycin Metaphylaxis on the Fecal Resistome and Microbiome of Commercial Feedlot Cattle Early in the Feeding Period.

The objective was to examine effects of treating commercial beef feedlot cattle with therapeutic doses of tulathromycin, a macrolide antimicrobial drug, on changes in the fecal resistome and microbiome using shotgun metagenomic sequencing. Two pens of cattle were used, with all cattle in one pen receiving metaphylaxis treatment (800 mg subcutaneous tulathromycin) at arrival to the feedlot, and all cattle in the other pen remaining unexposed to parenteral antibiotics throughout the study period. Fecal samples were collected from 15 selected cattle in each group just prior to treatment (Day 1), and again 11 days later (Day 11). Shotgun sequencing was performed on isolated metagenomic DNA, and reads were aligned to a resistance and a taxonomic database to identify alignments to antimicrobial resistance (AMR) gene accessions and microbiome content. Overall, we identified AMR genes accessions encompassing 9 classes of AMR drugs and encoding 24 unique AMR mechanisms. Statistical analysis was used to identify differences in the resistome and microbiome between the untreated and treated groups at both timepoints, as well as over time. Based on composition and ordination analyses, the resistome and microbiome were not significantly different between the two groups on Day 1 or on Day 11. However, both the resistome and microbiome changed significantly between these two sampling dates. These results indicate that the transition into the feedlot-and associated changes in diet, geography, conspecific exposure, and environment-may exert a greater influence over the fecal resistome and microbiome of feedlot cattle than common metaphylactic antimicrobial drug treatment.

Novel 3D geometry and models of the lower regions of large trees for use in carbon accounting of primary forests.

There is high uncertainty in the contribution of land-use change to anthropogenic climate change, especially pertaining to below-ground carbon loss resulting from conversion of primary-to-secondary forest. Soil organic carbon (SOC) and coarse roots are concentrated close to tree trunks, a region usually unmeasured during soil carbon sampling. Soil carbon estimates and their variation with land-use change have not been correspondingly adjusted. Our aim was to deduce allometric equations that will allow improvement of SOC estimates and tree trunk carbon estimates, for primary forest stands that include large trees in rugged terrain. Terrestrial digital photography, photogrammetry and GIS software were used to produce 3D models of the buttresses, roots and humus mounds of large trees in primary forests dominated by Eucalyptus regnans in Tasmania. Models of 29, in situ eucalypts were made and analysed. 3D models of example eucalypt roots, logging debris, rainforest tree species, fallen trees, branches, root and trunk slices, and soil profiles were also derived. Measurements in 2D, from earlier work, of three buttress 'logs' were added to the data set. The 3D models had high spatial resolution. The modelling allowed checking and correction of field measurements. Tree anatomical detail was formulated, such as buttress shape, humus volume, root volume in the under-sampled zone and trunk hollow area. The allometric relationships developed link diameter at breast height and ground slope, to SOC and tree trunk carbon, the latter including a correction for senescence. These formulae can be applied to stand-level carbon accounting. The formulae allow the typically measured, inter-tree SOC to be corrected for not sampling near large trees. The 3D models developed are irreplaceable, being for increasingly rare, large trees, and they could be useful to other scientific endeavours.

Response to Comment on "The growth pattern of Neandertals, reconstructed from a juvenile skeleton from El Sidrón (Spain)".

The comment by DeSilva challenges our suggestion that brain growth of the El Sidrón J1 Neandertal was still incomplete at 7.7 years of age. Evidence suggests that endocranial volume is likely to represent less than 90% adult size at El Sidrón as well as Neandertal male plus Krapina samples, in line with further evidence from endocranial surface histology and dural sinus groove size.