Integrating diffusion tensor imaging and neurite orientation dispersion and density imaging to improve the predictive capabilities of CED models

This paper aims to develop a comprehensive and subject-specific model to predict the drug reach in Convection-Enhanced Delivery (CED) interventions. To this end, we make use of an advance diffusion imaging technique, namely the Neurite Orientation Dispersion and Density Imaging (NODDI), to incorporate a more precise description of the brain microstructure into predictive computational models. The NODDI dataset is used to obtain a voxel-based quantification of the extracellular space volume fraction that we relate to the white matter (WM) permeability. Since the WM can be considered as a transversally isotropic porous medium, two equations, respectively for permeability parallel and perpendicular to the axons, are derived from a numerical analysis on a simplified geometrical model that reproduces flow through fibre bundles. This is followed by the simulation of the injection of a drug in a WM area of the brain and direct comparison of the outcomes of our results with a state-of-the-art model, which uses conventional diffusion tensor imaging. We demonstrate the relevance of the work by showing the impact of our newly derived permeability tensor on the predicted drug distribution, which differs significantly from the alternative model in terms of distribution shape, concentration profile and infusion linear penetration length

Reconstruction of ovine axonal cytoarchitecture enables more accurate models of brain biomechanics

There is an increased need and focus to understand how local brain microstructure affects the transport of drug molecules directly administered to the brain tissue, for example in convection-enhanced delivery procedures. This study reports a systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fibres, namely the corpus callosum, the fornix and the corona radiata, with the specific aim to map different regions of the tissue and provide essential information for the development of accurate models of brain biomechanics. Ovine samples are imaged using scanning electron microscopy combined with focused ion beam milling to generate 3D volume reconstructions of the tissue at subcellular spatial resolution. Focus is placed on the characteristic cytological feature of the white matter: the axons and their alignment in the tissue. For each tract, a 3D reconstruction of relatively large volumes, including a significant number of axons, is performed and outer axonal ellipticity, outer axonal cross-sectional area and their relative perimeter are measured. The study of well-resolved microstructural features provides useful insight into the fibrous organization of the tissue, whose micromechanical behaviour is that of a composite material presenting elliptical tortuous tubular axonal structures embedded in the extra-cellular matrix. Drug flow can be captured through microstructurally-based models using 3D volumes, either reconstructed directly from images or generated in silico using parameters extracted from the database of images, leading to a workflow to enable physically-accurate simulations of drug delivery to the targeted tissue

Hybrid fibroin/polyurethane small-diameter vascular grafts: from fabrication to in vivo preliminary assessment

To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane (R)) was herein used to fabricate very small-calibre grafts (o(in) = 1.5 mm) via electrospinning. Bio-hybrid grafts were in vitro characterized in terms of morphology and mechanical behaviour, and compared to similar grafts of pure SF. Similarly, two native vessels from a rodent model (abdominal aorta and vena cava) were harvested and characterized. Preliminary implants were performed on Lewis rats to confirm the suitability of Silkothane (R) grafts for small-calibre applications, specifically as aortic insertion and femoral shunt. The manufacturing process generated pliable grafts consisting of a randomized fibrous mesh and exhibiting similar geometrical features to rat aortas. Both Silkothane (R) and pure SF grafts showed radial compliances in the range from 1.37 +/- 0.86 to 1.88 +/- 1.01% 10(-2) mmHg(-1), lower than that of native vessels. The Silkothane (R) small-calibre devices were also implanted in rats demonstrating to be adequate for vascular applications; all the treated rats survived the surgery for three months after implantation, and 16 rats out of 17 (94%) still showed blood flow inside the graft at sacrifice. The obtained results lay the basis for a deeper investigation of the interaction between the Silkothane (R) graft and the implant site, which may deal with further analysis on the potentialities in terms of degradability and tissue formation, on longer time-points

Subarctic climate for the earliest Homo sapiens in Europe

Acknowledgments The re-excavation of Bacho Kiro Cave was jointly conducted by the National Institute of Archaeology with Museum, Bulgarian Academy of Sciences, Sofia and the Department of Human Evolution at the MPI-EVA. We would like to thank the National Museum of Natural History (Sofia), the Archaeology Department at the New Bulgarian University (Sofia), the Regional Museum of History in Gabrovo, and the History Museum in Dryanovo for assistance on this project and the opportunity to study the Bacho Kiro Cave faunal material. We would like to thank M. Trost, S. Hesse, M. Kaniecki, and P. Dittmann (MPI-EVA) for technical assistance during stable isotope sample preparation. S. Steinbrenner is thanked for technical assistance with TC/EA-IRMS maintenance. Thanks are also due to H. Temming and U. Schwarz (MPI-EVA) for the production of microCT scans and replicas of the sample materials. We would also like to acknowledge the assistance of to D. Veres with taking OSL samples. Last but not least we would like to thank the handling editor, S. Ortman, as well as three anonymous reviewers for their thoughtful comments that greatly improved this manuscript. Funding: The field work was financed by the Max Planck Society. The stable isotope work was funded by the Max Planck Society as part of S.P.’s doctoral project. S.P. was supported by the Max Planck Society and the University of Aberdeen. K.B. was supported by a Philip Leverhulme Prize from The Leverhulme Trust (PLP-2019-284). N.B.’s work was supported as part of a grant by the German Research Foundation (“PALÄODIET” Project 378496604). V.A. was supported by a grant from the Foundation for Science and Technology, Portugal (IF/01157/2015/CP1308/CT0002). Author contributions: The study was devised by S.P., K.B., S.P.M., J.-J.H., and T.T. Archaeological excavation was undertaken by N.S. and T.T. in collaboration with Z.R. and S.P.M. who all contributed contextual information. V.A. collected sedimentological data at the site and untertook micromorphological investigations that provided information on site formation for this study. Zooarchaeological and paleontological analyses were performed by G.M.S. and R.S. OSL dating was carried out by T.L. Radiocarbon dating and recalibration of radiocarbon dates were conducted by H.F. MC-ICPMS analysis was conducted by N.B. and S.P. Sampling, sample processing for oxygen and strontium stable isotope analysis, and TC/EA-IRMS analysis were carried out by S.P. Code and data analyses were written and conducted by S.P. N.-H.T. consulted on statistical analysis and coding. S.P. wrote the paper with input from all authors. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.Peer reviewedPublisher PD

The unexplained success of stentplasty vasospasm treatment

Background Cerebral vasospasm (CVS) following subarachnoid hemorrhage occurs in up to 70% of patients. Recently, stents have been used to successfully treat CVS. This implies that the force required to expand spastic vessels and resolve vasospasm is lower than previously thought. Objective We develop a mechanistic model of the spastic arterial wall to provide insight into CVS and predict the forces required to treat it. Material and Methods The arterial wall is modelled as a cylindrical membrane using a constrained mixture theory that accounts for the mechanical roles of elastin, collagen and vascular smooth muscle cells (VSMC). We model the pressure diameter curve prior to CVS and predict how it changes following CVS. We propose a stretch-based damage criterion for VSMC and evaluate if several commercially available stents are able to resolve vasospasm. Results The model predicts that dilatation of VSMCs beyond a threshold of mechanical failure is sufficient to resolve CVS without damage to the underlying extracellular matrix. Consistent with recent clinical observations, our model predicts that existing stents have the potential to provide sufficient outward force to successfully treat CVS and that success will be dependent on an appropriate match between stent and vessel. Conclusion Mathematical models of CVS can provide insights into biological mechanisms and explore treatment approaches. Improved understanding of the underlying mechanistic processes governing CVS and its mechanical treatment may assist in the development of dedicated stents

A mechanobiological model of the urinary bladder : integrative modelling of outlet obstruction

We present the first model to simulate the adaptive growth and remodeling (G&R) response of the bladder wall to bladder outlet obstruction (BOO). The model is calibrated and validated with an experimental rodent model of BOO. The bladder is modeled as a multi-layered, nonlinear elastic spherical membrane using a constrained mixture model that includes both passive and active components. The mechanical model is integrated with a shorter time scale micturition model that accounts for the active mechanics of voiding and dependence of flowrate on urethral resistance. Over a second time scale, constituents are configured and subsequently remodel to achieve a homeostatic state at the onset of voiding. Simulations of remodeling in response to the tenfold increase in outlet resistance arising from BOO, predict an initial loss of voiding capacity. Subsequent smooth muscle cell (SMC) hypertrophy enables the bladder wall to generate sufficient active tension to restore voiding functionality. Consistent with the experimental observations, the model predicts: hypertrophy of SMC and enlargement of the bladder over realistic timescales; collagen remodeling to maintain its role as a protective sheath; and increased voiding duration with lower average flow rate. This integrative G&R modeling approach provides fundamental insight into the adaptation of the bladder’s structural-functional relationship in response to outlet obstruction

Virtual (computed) fractional flow reserve: future role in acute coronary syndromes

The current management of acute coronary syndromes (ACS) is with an invasive strategy to guide treatment. However, identifying the lesions which are physiologically significant can be challenging. Non-invasive imaging is generally not appropriate or timely in the acute setting, so the decision is generally based upon visual assessment of the angiogram, supplemented in a small minority by invasive pressure wire studies using fractional flow reserve (FFR) or related indices. Whilst pressure wire usage is slowly increasing, it is not feasible in many vessels, patients and situations. Limited evidence for the use of FFR in non-ST elevation (NSTE) ACS suggests a 25% change in management, compared with traditional assessment, with a shift from more to less extensive revascularisation. Virtual (computed) FFR (vFFR), which uses a 3D model of the coronary arteries constructed from the invasive angiogram, and application of the physical laws of fluid flow, has the potential to be used more widely in this situation. It is less invasive, fast and can be integrated into catheter laboratory software. For severe lesions, or mild disease, it is probably not required, but it could improve the management of moderate disease in 'real time' for patients with non-ST elevation acute coronary syndromes (NSTE-ACS), and in bystander disease in ST elevation myocardial infarction. Its practicability and impact in the acute setting need to be tested, but the underpinning science and potential benefits for rapid and streamlined decision-making are enticing

Advancing the understanding of treponemal disease in the past and present

Syphilis was perceived to be a new disease in Europe in the late 15th century, igniting a debate about its origin that continues today in anthropological, historical, and medical circles. We move beyond this age-old debate using an interdisciplinary approach that tackles broader questions to advance the understanding of treponemal infection (syphilis, yaws, bejel, and pinta). How did the causative organism(s) and humans co-evolve? How did the related diseases caused by Treponema pallidum emerge in different parts of the world and affect people across both time and space? How are T. pallidum subspecies related to the treponeme causing pinta? The current state of scholarship in specific areas is reviewed with recommendations made to stimulate future work. Understanding treponemal biology, genetic relationships, epidemiology, and clinical manifestations is crucial for vaccine development today and for investigating the distribution of infection in both modern and past populations. Paleopathologists must improve diagnostic criteria and use a standard approach for recording skeletal lesions on archaeological human remains. Adequate contextualization of cultural and environmental conditions is necessary, including site dating and justification for any corrections made for marine or freshwater reservoir effects. Biogeochemical analyses may assess aquatic contributions to diet, physiological changes arising from treponemal disease and its treatments (e.g., mercury), or residential mobility of those affected. Shifting the focus from point of origin to investigating who is affected (e.g., by age/sex or socioeconomic status) and disease distribution (e.g., coastal/ inland, rural/urban) will advance our understanding of the treponemal disease and its impact on people through time

The ecology, subsistence and diet of ~45,000-year-old Homo sapiens at Ilsenhöhle in Ranis, Germany

Recent excavations at Ranis (Germany) identified an early dispersal of Homo sapiens into the higher latitudes of Europe by 45,000 years ago. Here we integrate results from zooarchaeology, palaeoproteomics, sediment DNA and stable isotopes to characterize the ecology, subsistence and diet of these early H. sapiens. We assessed all bone remains (n = 1,754) from the 2016-2022 excavations through morphology (n = 1,218) or palaeoproteomics (zooarchaeology by mass spectrometry (n = 536) and species by proteome investigation (n = 212)). Dominant taxa include reindeer, cave bear, woolly rhinoceros and horse, indicating cold climatic conditions. Numerous carnivore modifications, alongside sparse cut-marked and burnt bones, illustrate a predominant use of the site by hibernating cave bears and denning hyaenas, coupled with a fluctuating human presence. Faunal diversity and high carnivore input were further supported by ancient mammalian DNA recovered from 26 sediment samples. Bulk collagen carbon and nitrogen stable isotope data from 52 animal and 10 human remains confirm a cold steppe/tundra setting and indicate a homogenous human diet based on large terrestrial mammals. This lower-density archaeological signature matches other Lincombian-Ranisian-Jerzmanowician sites and is best explained by expedient visits of short duration by small, mobile groups of pioneer H. sapiens. [Abstract copyright: © 2024. The Author(s).

Stable isotopes show Homo sapiens dispersed into cold steppes ~45,000 years ago at Ilsenhöhle in Ranis, Germany

The spread of Homo sapiens into new habitats across Eurasia ~45,000 years ago and the concurrent disappearance of Neanderthals represents a critical evolutionary turnover in our species' history. 'Transitional' technocomplexes, such as the Lincombian-Ranisian-Jerzmanowician (LRJ), characterize the European record during this period but their makers and evolutionary significance have long remained unclear. New evidence from Ilsenhöhle in Ranis, Germany, now provides a secure connection of the LRJ to H. sapiens remains dated to ~45,000 years ago, making it one of the earliest forays of our species to central Europe. Using many stable isotope records of climate produced from 16 serially sampled equid teeth spanning ~12,500 years of LRJ and Upper Palaeolithic human occupation at Ranis, we review the ability of early humans to adapt to different climate and habitat conditions. Results show that cold climates prevailed across LRJ occupations, with a temperature decrease culminating in a pronounced cold excursion at ~45,000-43,000 cal BP. Directly dated H. sapiens remains confirm that humans used the site even during this very cold phase. Together with recent evidence from the Initial Upper Palaeolithic, this demonstrates that humans operated in severe cold conditions during many distinct early dispersals into Europe and suggests pronounced adaptability. [Abstract copyright: © 2024. The Author(s).