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Abstract Background Cisplatin- based chemoradiotherapy is a crucial pillar in the treatment of HNSCC. The use of cisplatin comes with high toxicity rates as 35% of patients cannot sustain the planned dose while response is unpredictable. Unfortunately, there are no clinically applicable biomarkers to predict response. Based on the association of response with the number of DNA adducts and the involved molecular pathway to resolve cisplatin-induced DNA crosslinks in HNSCC, [195mPt]cisplatin (CISSPECT®) might have potential to monitor drug uptake and retention before treatment, and predict cisplatin response. The aim of this study is to investigate this concept by analyzing uptake, retention and biodistribution of [195mPt]cisplatin between known cisplatin-sensitive (VU-SCC-1131) and –resistant (VU-SCC-OE) HNSCC cell lines in vitro and xenografted in mice in vivo. Results By a variety of experiments in vitro, including cell cycle analyses, and in vivo, the sensitivity of cell line VU-SCC-1131 and resistance of cell line VU-SCC-OE for cisplatin was demonstrated. VU-SCC-OE was able to accumulate more [195mPt]cisplatin in the DNA, and showed an increased capability to repair [195mPt]cisplatin crosslinks compared to VU-SCC-1131. Notably, DNA binding of cisplatin increased even when cisplatin was removed from the medium, likely from intracellular sources. In vivo, [195mPt]cisplatin showed a rapid biodistribution to the large organs such as the liver, with no differences between intravenous and intraperitoneal administration. Most circulating [195mPt]cisplatin was cleared by renal filtration, and accumulation in kidney and liver remained high. Uptake in xenografts was rapid (blood:tumor ratio; 1:1) and highest after 1 h, while decreasing after 6 h in line with the concentration in the blood. Remarkably, there was no significant difference in uptake or retention between xenografts of the cisplatin-sensitive and -resistant cell line. Conclusion VU-SCC-1131 with a known FA deficiency and VU-SCC-OE displayed a significant difference in sensitivity to and recovery from cisplatin treatment, due to S-phase problems in VU-SCC-1131 at low doses, in line with the genetic defect. Using Pt-195m radioactivity analysis, we demonstrated the limited capability of cisplatin crosslink repair in VU-SCC-1131. Unexpectedly, we were not able to translate these findings to a mouse model for sensitivity prediction based on the biodistribution in the tumor, most likely as other factors such as influx counterbalanced repair. These data do not support response prediction by [195mPt]cisplatin, and applications to predict the toxic side-effects of cisplatin and to tailor dosing schemes seem more feasible.

IntroductionImaging biomarkers, such as the collateral score as determined from Computed Tomography Angiography (CTA) images, play a role in treatment decision making for acute stroke patients. In this manuscript, we present an end-to-end learning approach for automatic determination of a collateral score from a CTA image. Our aim was to investigate whether such end-to-end learning approaches can be used for this classification task, and whether the resulting classification can be used in existing outcome prediction models.MethodsThe method consists of a preprocessing step, where the CTA image is aligned to an atlas and divided in the two hemispheres: the affected side and the healthy side. Subsequently, a VoxResNet based convolutional neural network is used to extract features at various resolutions from the input images. This is done by using a Siamese model, such that the classification is driven by the comparison between the affected and healthy using a unique set of features for both hemispheres. After masking the resulting features for both sides with the vascular region and global average pooling (per hemisphere) and concatenation of the resulting features, a fully connected layer is used to determine the categorized collateral score.ExperimentsSeveral experiments have been performed to optimize the model hyperparameters and training procedure, and to validate the final model performance. The hyperparameter optimization and subsequent model training was done using CTA images from the MR CLEAN Registry, a Dutch multi-center multi-vendor registry of acute stroke patients that underwent endovascular treatment. A separate set of images, from the MR CLEAN Trial, served as an external validation set, where collateral scoring was assessed and compared with both human observers and a recent more traditional model. In addition, the automated collateral scores have been used in an existing functional outcome prediction model that uses both imaging and non-imaging clinical parameters.ConclusionThe results show that end-to-end learning of collateral scoring in CTA images is feasible, and does perform similar to more traditional methods, and the performance also is within the inter-observer variation. Furthermore, the results demonstrate that the end-to-end classification results also can be used in an existing functional outcome prediction model.

The use of augmented reality (AR) in teaching and studying neuroanatomy has been well researched. Previous research showed that AR-based learning of neuroanatomy has both alleviated cognitive load and was attractive to young learners. However, how the attractiveness of AR effects student motivation has not been discovered. Therefore, the motivational effects of AR were investigated in this research by the use of quantitative and qualitative methods. Motivation elicited by the GreyMapp-AR, an AR application, was investigated in medical and biomedical sciences students (n = 222; mean age: 19.7 ± 1.4 years) using the instructional measure of motivation survey (IMMS). Additional components (i.e., attention, relevance, confidence, and satisfaction) were also evaluated with motivation as measured by IMMS. Additionally, 19 students underwent audio-recorded individual interviews which were transcribed for qualitative analysis. Males regarded the relevance of AR significantly higher than females (P < 0.024). Appreciation of the GreyMapp-AR program was found to be significantly higher in students studying biomedical sciences as compared to students studying medicine (P < 0.011). Other components and scores did not show significant differences between student groups. Students expressed that AR was beneficial in increasing their motivation to study subcortical structures, and that AR could be helpful and motivating for preparing an anatomy examination. This study suggests that students are motivated to study neuroanatomy by the use of AR, although the components that make up their individual motivation can differ significantly between groups of students.

Polarized light imaging (PLI) is a new method which quantifies and visualizes nerve fiber direction. In this study, the educational value of PLI sections of the human brainstem were compared to histological sections stained with Luxol fast blue (LFB) using e-learning modules. Mental Rotations Test (MRT) was used to assess the spatial ability. Pre-intervention, post-intervention, and long-term (1 week) anatomical tests were provided to assess the baseline knowledge and retention. One-on-one electronic interviews after the last test were carried out to understand the students' perceptions of the intervention. Thirty-eight medical students, (19 female and 19 males, mean age 21.5 ± SD 2.4; median age: 21.0 years) participated with a mean MRT score of 13.2 ± 5.2 points and a mean pre-intervention knowledge test score of 49.9 ± 11.8%. A significant improvement in both, post-intervention and long-term test scores occurred after learning with either PLI or LFB e-learning module on brainstem anatomy (both P < 0.001). No difference was observed between groups in post-intervention test scores and long-term test scores (P = 0.913 and P = 0.403, respectively). A higher MRT-score was significantly correlated with a higher post-intervention test score (r[subscript k] = 0.321; P < 0.05, respectively), but there was not a significant association between the MRT- and the long-term scores (r[subscript k] = -0.078; P = 0.509). Interviews (n = 10) revealed three major topics: Learning (brainstem) anatomy by use of e-learning modules; The "need" of technological background information when studying brainstem sections; and Mnemonics when studying brainstem anatomy. Future studies should assess the cognitive burden of cross-sectional learning methods with PLI and/or LFB sections and their effects on knowledge retention.

Precancerous cells in the oral cavity may appear as oral potentially malignant disorders, but they may also present as dysplasia without visual manifestation in tumor-adjacent tissue. As it is currently not possible to prevent the malignant transformation of these oral precancers, new treatments are urgently awaited. Here, we generated precancer culture models using a previously established method for the generation of oral keratinocyte cultures and incorporated CRISPR/Cas9 editing. The generated cell lines were used to investigate the efficacy of a set of small molecule inhibitors. Tumor-adjacent mucosa and oral leukoplakia biopsies were cultured and genetically characterized. Mutations were introduced in CDKN2A and TP53 using CRISPR/Cas9 and combined with the ectopic activation of telomerase to generate cell lines with prolonged proliferation. The method was tested in normal oral keratinocytes and tumor-adjacent biopsies and subsequently applied to a large set of oral leukoplakia biopsies. Finally, a subset of the immortalized cell lines was used to assess the efficacy of a set of small molecule inhibitors. Culturing and genomic engineering was highly efficient for normal and tumor-adjacent oral keratinocytes, but success rates in oral leukoplakia were remarkably low. Knock-out of CDKN2A in combination with either the activation of telomerase or knock-out of TP53 seemed a prerequisite for immortalization. Prolonged culturing was accompanied by additional genetic aberrations in these cultures. The generated cell lines were more sensitive than normal keratinocytes to small molecule inhibitors of previously identified targets. In conclusion, while very effective for normal keratinocytes and tumor-adjacent biopsies, the success rate of oral leukoplakia cell culturing methods was very low. Genomic engineering enabled the prolonged culturing of OL-derived keratinocytes but was associated with acquired genetic changes. Further studies are required to assess to what extent the immortalized cultures faithfully represent characteristics of the cells in vivo.

Abstract We present a compact multi-modal and multi-scale retinal imaging instrument with an angiographic functional extension for clinical use. The system integrates scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT) and OCT angiography (OCTA) imaging modalities and provides multi-scale fields of view. For high resolution, and high lateral resolution in particular, cellular imaging correction of aberrations by adaptive optics (AO) is employed. The entire instrument has a compact design and the scanning head is mounted on motorized translation stages that enable 3D self-alignment with respect to the subject’s eye by tracking the pupil position. Retinal tracking, based on the information provided by SLO, is incorporated in the instrument to compensate for retinal motion during OCT imaging. The imaging capabilities of the multi-modal and multi-scale instrument were tested by imaging healthy volunteers and patients.

Neuroanatomy education is a challenging field which could benefit from modern innovations, such as augmented reality (AR) applications. This study investigates the differences on test scores, cognitive load, and motivation after neuroanatomy learning using AR applications or using cross-sections of the brain. Prior to two practical assignments, a pretest (extended matching questions, double-choice questions and a test on cross-sectional anatomy) and a mental rotation test (MRT) were completed. Sex and MRT scores were used to stratify students over the two groups. The two practical assignments were designed to study (1) general brain anatomy and (2) subcortical structures. Subsequently, participants completed a posttest similar to the pretest and a motivational questionnaire. Finally, a focus group interview was conducted to appraise participants' perceptions. Medical and biomedical students (n = 31); 19 males (61.3%) and 12 females (38.7%), mean age 19.2 [plus or minus] 1.7 years participated in this experiment. Students who worked with cross-sections (n = 16) showed significantly more improvement on test scores than students who worked with GreyMapp-AR (P = 0.035) (n = 15). Further analysis showed that this difference was primarily caused by significant improvement on the cross-sectional questions. Students in the cross-section group, moreover, experienced a significantly higher germane (P = 0.009) and extraneous cognitive load (P = 0.016) than students in the GreyMapp-AR group. No significant differences were found in motivational scores. To conclude, this study suggests that AR applications can play a role in future anatomy education as an add-on educational tool, especially in learning three-dimensional relations of anatomical structures.

Diffusion MRI (dMRI) is a unique tool for the study of brain circuitry, as it allows us to image both the macroscopic trajectories and the microstructural properties of axon bundles in vivo. The Human Connectome Project ushered in an era of impressive advances in dMRI acquisition and analysis. As a result of these efforts, the quality of dMRI data that could be acquired in vivo improved substantially, and large collections of such data became widely available. Despite this progress, the main limitation of dMRI remains: it does not image axons directly, but only provides indirect measurements based on the diffusion of water molecules. Thus, it must be validated by methods that allow direct visualization of axons but that can only be performed in post mortem brain tissue. In this review, we discuss methods for validating the various features of connectional anatomy that are extracted from dMRI, both at the macro-scale (trajectories of axon bundles), and at micro-scale (axonal orientations and other microstructural properties). We present a range of validation tools, including anatomic tracer studies, Klingler's dissection, myelin stains, label-free optical imaging techniques, and others. We provide an overview of the basic principles of each technique, its limitations, and what it has taught us so far about the accuracy of different dMRI acquisition and analysis approaches.

This report investigates the current state of physical (mechanical) robotics, automated warehousing approaches and assistive technologies in relation to the storage, handling and processing (particularly digitisation) of natural history collections.Robotics can sound futuristic, however we provide case studies that show many and growing examples of physical automation in the natural history and cultural heritage sectors, including barcodes and conveyor belts for digitisation; robots that handle multiple vials for molecular and genetic work; robots for use in in display or exhibition contexts; and automated warehousing of library collections. We provide a non-exhaustive example of an end to end workflow of storage, retrieval and processing and discuss aspects of the tools and challenges relevant to these stages. The Distributed System of Scientific Collections (DiSSCo), a new Research Infrastructure for natural science collections, should build on this, leading a future programme of pilots that develop understanding of independent stages, and can be connected to make progress towards end-to-end solutions.Robots, or automated systems, excel at repetitive tasks, and are developing rapidly to be able to handle more complex object types, at lower cost. High volume, high variety of objects, and considerations such as fragility are not unique to the natural history sector - they apply for example to major retail operations - however natural history collections do offer some of the more extreme examples of these challenges, and in particular are not replaceable. Increased consistency of storage units is likely to be a critical factor in enabling automated handling in future, as well as looking at automation possibilities when new collections storage spaces are developed and built. Engagement with industry and subject matter experts has been patchy and again we recommend that DiSSCo help to ensure a joined up engagement with the right incentives in place, and with clear communication of requirements and challenges for shared R&D.When examining return on investment for particular automation, collections-holding institutions need to consider not only time and cost of automation compared to human labour, but wider factors including: health and safety such as physical environment and repetitve strain injury; security; quality and consistency of outputs; degree of criticality in response times (e.g. if digitising on demand); effective use of spaces; and freeing up staff to conduct other tasks.Purely software-based automation is outside the scope of this report, but is also in increasing use and has enormous potential, for example to transform the extraction of label and specimen data at scale from images. The challenges of managing and digitising collections at scale under DiSSCo are likely to require a combination of hardware and software automation approaches.

We describe an effective approach to automated text digitisation with respect to natural history specimen labels. These labels contain much useful data about the specimen including its collector, country of origin, and collection date. Our approach to automatically extracting these data takes the form of a pipeline. Recommendations are made for the pipeline's component parts based on state-of-the-art technologies.Optical Character Recognition (OCR) can be used to digitise text on images of specimens. However, recognising text quickly and accurately from these images can be a challenge for OCR. We show that OCR performance can be improved by prior segmentation of specimen images into their component parts. This ensures that only text-bearing labels are submitted for OCR processing as opposed to whole specimen images, which inevitably contain non-textual information that may lead to false positive readings. In our testing Tesseract OCR version 4.0.0 offers promising text recognition accuracy with segmented images.Not all the text on specimen labels is printed. Handwritten text varies much more and does not conform to standard shapes and sizes of individual characters, which poses an additional challenge for OCR. Recently, deep learning has allowed for significant advances in this area. Google's Cloud Vision, which is based on deep learning, is trained on large-scale datasets, and is shown to be quite adept at this task. This may take us some way towards negating the need for humans to routinely transcribe handwritten text.Determining the countries and collectors of specimens has been the goal of previous automated text digitisation research activities. Our approach also focuses on these two pieces of information. An area of Natural Language Processing (NLP) known as Named Entity Recognition (NER) has matured enough to semi-automate this task. Our experiments demonstrated that existing approaches can accurately recognise location and person names within the text extracted from segmented images via Tesseract version 4.0.0.We have highlighted the main recommendations for potential pipeline components. The paper also provides guidance on selecting appropriate software solutions. These include automatic language identification, terminology extraction, and integrating all pipeline components into a scientific workflow to automate the overall digitisation process.

DiSSCo, the Distributed System of Scientific Collections, is a pan-European Research Infrastructure (RI) mobilising, unifying bio- and geo-diversity information connected to the specimens held in natural science collections and delivering it to scientific communities and beyond. Bringing together 120 institutions across 21 countries and combining earlier investments in data interoperability practices with technological advancements in digitisation, cloud services and semantic linking, DiSSCo makes the data from natural science collections available as one virtual data cloud, connected with data emerging from new techniques and not already linked to specimens. These new data include DNA barcodes, whole genome sequences, proteomics and metabolomics data, chemical data, trait data, and imaging data (Computer-assisted Tomography (CT), Synchrotron, etc.), to name but a few; and will lead to a wide range of end-user services that begins with finding, accessing, using and improving data. DiSSCo will deliver the diagnostic information required for novel approaches and new services that will transform the landscape of what is possible in ways that are hard to imagine today.With approximately 1.5 billion objects to be digitised, bringing natural science collections to the information age is expected to result in many tens of petabytes of new data over the next decades, used on average by 5,000 – 15,000 unique users every day. This requires new skills, clear policies and robust procedures and new technologies to create, work with and manage large digital datasets over their entire research data lifecycle, including their long-term storage and preservation and open access. Such processes and procedures must match and be derived from the latest thinking in open science and data management, realising the core principles of 'findable, accessible, interoperable and reusable' (FAIR).Synthesised from results of the ICEDIG project ("Innovation and Consolidation for Large Scale Digitisation of Natural Heritage", EU Horizon 2020 grant agreement No. 777483) the DiSSCo Conceptual Design Blueprint covers the organisational arrangements, processes and practices, the architecture, tools and technologies, culture, skills and capacity building and governance and business model proposals for constructing the digitisation infrastructure of DiSSCo. In this context, the digitisation infrastructure of DiSSCo must be interpreted as that infrastructure (machinery, processing, procedures, personnel, organisation) offering Europe-wide capabilities for mass digitisation and digitisation-on-demand, and for the subsequent management (i.e., curation, publication, processing) and use of the resulting data. The blueprint constitutes the essential background needed to continue work to raise the overall maturity of the DiSSCo Programme across multiple dimensions (organisational, technical, scientific, data, financial) to achieve readiness to begin construction.Today, collection digitisation efforts have reached most collection-holding institutions across Europe. Much of the leadership and many of the people involved in digitisation and working with digital collections wish to take steps forward and expand the efforts to benefit further from the already noticeable positive effects. The collective results of examining technical, financial, policy and governance aspects show the way forward to operating a large distributed initiative i.e., the Distributed System of Scientific Collections (DiSSCo) for natural science collections across Europe. Ample examples, opportunities and need for innovation and consolidation for large scale digitisation of natural heritage have been described. The blueprint makes one hundred and four (104) recommendations to be considered by other elements of the DiSSCo Programme of linked projects (i.e., SYNTHESYS+, COST MOBILISE, DiSSCo Prepare, and others to follow) and the DiSSCo Programme leadership as the journey towards organisational, technical, scientific, data and financial readiness continues.Nevertheless, significant obstacles must be overcome as a matter of priority if DiSSCo is to move beyond its Design and Preparatory Phases during 2024. Specifically, these include:Organisational:Strengthen common purpose by adopting a common framework for policy harmonisation and capacity enhancement across broad areas, especially in respect of digitisation strategy and prioritisation, digitisation processes and techniques, data and digital media publication and open access, protection of and access to sensitive data, and administration of access and benefit sharing.Pursue the joint ventures and other relationships necessary to the successful delivery of the DiSSCo mission, especially ventures with GBIF and other international and regional digitisation and data aggregation organisations, in the context of infrastructure policy frameworks, such as EOSC. Proceed with the explicit aim of avoiding divergences of approach in global natural science collections data management and research.Technical:Adopt and enhance the DiSSCo Digital Specimen Architecture and, specifically as a matter of urgency, establish the persistent identifier scheme to be used by DiSSCo and (ideally) other comparable regional initiatives.Establish (software) engineering development and (infrastructure) operations team and direction essential to the delivery of services and functionalities expected from DiSSCo such that earnest engineering can lead to an early start of DiSSCo operations.Scientific:Establish a common digital research agenda leveraging Digital (extended) Specimens as anchoring points for all specimen-associated and -derived information, demonstrating to research institutions and policy/decision-makers the new possibilities, opportunities and value of participating in the DiSSCo research infrastructure.Data:Adopt the FAIR Digital Object Framework and the International Image Interoperability Framework as the low entropy means to achieving uniform access to rich data (image and non-image) that is findable, accessible, interoperable and reusable (FAIR).Develop and promote best practice approaches towards achieving the best digitisation results in terms of quality (best, according to agreed minimum information and other specifications), time (highest throughput, fast), and cost (lowest, minimal per specimen).FinancialBroaden attractiveness (i.e., improve bankability) of DiSSCo as an infrastructure to invest in.Plan for finding ways to bridge the funding gap to avoid disruptions in the critical funding path that risks interrupting core operations; especially when the gap opens between the end of preparations and beginning of implementation due to unsolved political difficulties.Strategically, it is vital to balance the multiple factors addressed by the blueprint against one another to achieve the desired goals of the DiSSCo programme. Decisions cannot be taken on one aspect alone without considering other aspects, and here the various governance structures of DiSSCo (General Assembly, advisory boards, and stakeholder forums) play a critical role over the coming years.

Abstract Invasive motor Cortex Stimulation (iMCS) was introduced in the 1990’s for the treatment of chronic neuropathic orofacial pain (CNOP), although its effectiveness remains doubtful. However, CNOP is known to be a heterogeneous group of orofacial pain disorders, which can lead to different responses to iMCS. Therefore, this paper investigated (1) whether the effectiveness of iMCS is significantly different among different CNOP disorders and (2) whether other confounding factors can be impacting iMCS results in CNOP. A systematic review and meta-analysis using a linear mixed-model was performed. Twenty-three papers were included, totaling 140 CNOP patients. Heterogeneity of the studies showed to be 55.8%. A visual analogue scale (VAS) measured median pain relief of 66.5% (ranging from 0–100%) was found. Linear mixed-model analysis showed that patients suffering from trigeminal neuralgia responded significantly more favorable to iMCS than patients suffering from dysfunctional pain syndromes (p = 0.030). Also, patients suffering from CNOP caused by (supra)nuclear lesions responded marginally significantly better to iMCS than patients suffering from CNOP due to trigeminal nerve lesions (p = 0.049). No other confounding factors were elucidated. This meta-analysis showed that patients suffering from trigeminal neuralgia and patients suffering from (supra)nuclear lesions causing CNOP responded significantly more favorable than others on iMCS. No other confounding factors were found relevant.

Multi-echo gradient echo (ME-GRE) magnetic resonance signal evolution in white matter has a strong dependence on the orientation of myelinated axons with respect to the main static field. Although analytical solutions have been able to predict some of the white matter (WM) signal behaviour of the hollow cylinder model, it has been shown that realistic models of WM offer a better description of the signal behaviour observed.In this work, we present a pipeline to (i) generate realistic 2D WM models with their microstructure based on real axon morphology with adjustable fiber volume fraction (FVF) and g-ratio. We (ii) simulate their interaction with the static magnetic field to be able to simulate their MR signal. For the first time, we (iii) demonstrate that realistic 2D WM models can be used to simulate a MR signal that provides a good approximation of the signal obtained from a real 3D WM model derived from electron microscopy. We then (iv) demonstrate in silico that 2D WM models can be used to predict microstructural parameters in a robust way if ME-GRE multi-orientation data is available and the main fiber orientation in each pixel is known using DTI. A deep learning network was trained and characterized in its ability to recover the desired microstructural parameters such as FVF, g-ratio, free and bound water transverse relaxation and magnetic susceptibility. Finally, the network was trained to recover these micro-structural parameters from an ex vivo dataset acquired in 9 orientations with respect to the magnetic field and 12 echo times. We demonstrate that this is an overdetermined problem and that as few as 3 orientations can already provide comparable results for some of the decoded metrics.

Purpose: To investigate the effect of patient specific vessel cooling on head and neck hyperthermia treatment planning (HTP). Methods and materials: Twelve patients undergoing radiotherapy were scanned using computed tomography (CT), magnetic resonance imaging (MRI) and contrast enhanced MR angiography (CEMRA). 3D patient models were constructed using the CT and MRI data. The arterial vessel tree was constructed from the MRA images using the ‘graph-cut’ method, combining information from Frangi vesselness filtering and region growing, and the results were validated against manually placed markers in/outside the vessels. Patient specific HTP was performed and the change in thermal distribution prediction caused by arterial cooling was evaluated by adding discrete vasculature (DIVA) modeling to the Pennes bioheat equation (PBHE). Results: Inclusion of arterial cooling showed a relevant impact, i.e., DIVA modeling predicts a decreased treatment quality by on average 0.19 °C (T90), 0.32 °C (T50) and 0.35 °C (T20) that is robust against variations in the inflow blood rate (|ΔT| 0.5 °C) were observed. Conclusion: Addition of patient-specific DIVA into the thermal modeling can significantly change predicted treatment quality. In cases where clinically detectable vessels pass the heated region, we advise to perform DIVA modeling.

The lamina cribrosa (LC) is an active structure that responds to the strain by changing its morphology. Abnormal changes in LC morphology are usually associated with, and indicative of, certain pathologies such as glaucoma, intraocular hypertension, and myopia. Recent developments in optical coherence tomography (OCT) have enabled detailed in vivo studies about the architectural characteristics of the LC. Structural characteristics of the LC have been widely explored in glaucoma management. However, information about which LC biomarkers could be useful for the diagnosis, and follow-up, of other diseases besides glaucoma is scarce. Hence, this literature review aims to summarize the role of the LC in nonophthalmic and ophthalmic diseases other than glaucoma. PubMed was used to perform a systematic review on the LC features that can be extracted from OCT images. All imaging features are presented and discussed in terms of their importance and applicability in clinical practice. A total of 56 studies were included in this review. Overall, LC depth (LCD) and thickness (LCT) have been the most studied features, appearing in 75% and 45% of the included studies, respectively. These biomarkers were followed by the prelaminar tissue thickness (21%), LC curvature index (5.4%), LC global shape index (3.6%), LC defects (3.6%), and LC strains/deformations (1.8%). Overall, the disease groups showed a thinner LC (smaller LCT) and a deeper ONH cup (larger LCD), with some exceptions. A large variability between approaches used to compute LC biomarkers has been observed, highlighting the importance of having automated and standardized methodologies in LC analysis. Moreover, further studies are needed to identify the pathologies where LC features have a diagnostic and/or prognostic value.

The United Nations’ sustainable development goals (SDGs) set ambitious policy targets for 2030 to overcome poverty while preserving the planet. These goals are not perfectly aligned; trade-offs emerge during implementation at regional and local levels, such as in a river basin. Here, we quantify important trade-offs between water, energy, and food-related SDGs in the Ganges–Brahmaputra–Meghna River basin, a climate vulnerability hotspot, using multi-objective optimisation based on detailed water resources and crop production modelling and accounting for uncertainties in the costs of water, labour, and land. The trade-off between food production and agricultural profit is strong; the amount of people fed would be reduced by more than two-thirds, were profitability maximized. However, we do see the potential to achieve higher profitability in agriculture against limited loss of food and hydropower production and limited impact on downstream environmental flows, although continued reliance on groundwater and energy, currently unsustainable, needs to be mitigated.

Upward soil water flow is a vital supply of water to crops. The purpose of this study is to determine if upward flow and recirculated percolation water can be quantified separately, and to determine the contribution of capillary rise and recirculated water to crop yield and groundwater recharge. Therefore, we performed impact analyses of various soil water flow regimes on grass, maize and potato yields in the Dutch delta. Flow regimes are characterized by soil composition and groundwater depth and derived from a national soil database. The intermittent occurrence of upward flow and its influence on crop growth are simulated with the combined SWAP-WOFOST model using various boundary conditions. Case studies and model experiments are used to illustrate the impact of upward flow on yield and crop growth. This impact is clearly present in situations with relatively shallow groundwater levels (85 % of the Netherlands), where capillary rise is a well-known source of upward flow; but also in free-draining situations the impact of upward flow is considerable. In the latter case recirculated percolation water is the flow source. To make this impact explicit we implemented a synthetic modelling option that stops upward flow from reaching the root zone, without inhibiting percolation. Such a hypothetically moisture-stressed situation compared to a natural one in the presence of shallow groundwater shows mean yield reductions for grassland, maize and potatoes of respectively 26, 3 and 14 % or respectively about 3.7, 0.3 and 1.5 t dry matter per hectare. About half of the withheld water behind these yield effects comes from recirculated percolation water as occurs in free-drainage conditions and the other half comes from increased upward capillary rise. Soil water and crop growth modelling should consider both capillary rise from groundwater and recirculation of percolation water as this improves the accuracy of yield simulations. This also improves the accuracy of the simulated groundwater recharge: neglecting these processes causes overestimates of 17 % for grassland and 46 % for potatoes, or 63 and 34 mm yr−1, respectively.

The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeutic efficacy, thereby enhancing tumor elimination and improving patient survival. Here, we demonstrate that cetuximab treatment combined with immunostimulatory agonists for Toll-like receptor (TLR) 2 induces profound immune responses. Natural killer (NK) cells, isolated from healthy individuals or patients with head and neck cancer, harbored enhanced cytotoxic capacity and increased tumor-killing potential in vitro. Additionally, combination treatment increased the release of several pro-inflammatory cytokines and chemokines by NK cells. Tumor-bearing mice that received cetuximab and the TLR2 ligand Pam3CSK4 showed increased infiltration of immune cells into the tumors compared to mice that received cetuximab monotherapy, resulting in a significant delay in tumor growth or even complete tumor regression. Moreover, combination treatment resulted in improved overall survival in vivo. In conclusion, combining tumor-targeting antibody-based immunotherapy with TLR stimulation represents a promising treatment strategy to improve the clinical outcomes of cancer patients. This treatment could well be applied together with other therapeutic strategies such as anti-PD-(L)1 checkpoint inhibition to further overcome immunosuppression.

Diffusion MRI is an exquisitely sensitive probe of tissue microstructure, and is currently the only non-invasive measure of the brain's fibre architecture. As this technique becomes more sophisticated and microstructurally informative, there is increasing value in comparing diffusion MRI with microscopic imaging in the same tissue samples. This study compared estimates of fibre orientation dispersion in white matter derived from diffusion MRI to reference measures of dispersion obtained from polarized light imaging and histology.Three post-mortem brain specimens were scanned with diffusion MRI and analyzed with a two-compartment dispersion model. The specimens were then sectioned for microscopy, including polarized light imaging estimates of fibre orientation and histological quantitative estimates of myelin and astrocytes. Dispersion estimates were correlated on region – and voxel-wise levels in the corpus callosum, the centrum semiovale and the corticospinal tract.The region-wise analysis yielded correlation coefficients of r = 0.79 for the diffusion MRI and histology comparison, while r = 0.60 was reported for the comparison with polarized light imaging. In the corpus callosum, we observed a pattern of higher dispersion at the midline compared to its lateral aspects. This pattern was present in all modalities and the dispersion profiles from microscopy and diffusion MRI were highly correlated. The astrocytes appeared to have minor contribution to dispersion observed with diffusion MRI.These results demonstrate that fibre orientation dispersion estimates from diffusion MRI represents the tissue architecture well. Dispersion models might be improved by more faithfully incorporating an informed mapping based on microscopy data.

Background: Destruction of the afferents by dorsal root entry zone (DREZ) surgery may be an effective treatment of intractable neuropathic pain, though it remains a high-risk surgical intervention. Potential complications due to the lesioning of structures within the cervical spinal cord other than the DREZ can be minimized by accurate knowledge of the optimal insertion angle [i.e., the angle between the DREZ and the posterior median sulcus (PMS)]. The employed insertion angle was based on measurements between the DREZ and the PMS on post-mortem transverse slices. However, new, more sophisticated imaging techniques are currently available and are thought to yield higher spatial resolution and more accurate images.Obejctive: This article measures the angle between the DREZ and the PMS on 11.7T post-mortem magnetic resonance images and compares these findings with polarized light imaging (PLI) microscopy images of the same specimens in order to quantify fiber orientation within the DREZ.Methods: To visualize the anatomy of the cervical DREZ, magnetic resonance imaging (MRI), diffusion-weighted MRI (dMRI), probabilistic tractography, and PLI were performed on three post-mortem human cervical spinal cords at level C5–C6. The MR data was used to measure the angle between the DREZ and the PMS. MR images were complemented by probabilistic tractography results. Then, the orientation of fibers within the DREZ was quantified by use of PLI microscopy.Results: Median angle between the DREZ and the PMS, as measured on MR-images, was found to be 40.1° (ranging from 34.2° to 49.1°) and 39.8° (ranging from 31.1° to 47.8°) in the left and right hemicord, respectively. Median fiber orientation within the DREZ, as quantified by PLI, was 28.5° (ranging from 12.0° to 44.3°) and 27.7° (ranging from 8.5° to 38.1°) in the left and right hemicord, respectively.Conclusion: Our study, which provides an improved understanding of the anatomy of the DREZ, the angle between the DREZ and the PMS and the median fiber orientation within the DREZ, could contribute to safer DREZ-lesioning surgery to treat chronic neuropathic pain in the future.

Motor cortex stimulation (MCS) was introduced as a last-resort treatment for chronic neuropathic pain. Over the years, MCS has been used for the treatment of various pain syndromes but long-term follow-up is unknown.This paper reports the results of MCS from 2005 until 2012 with a 3-year follow-up. Patients who suffered from chronic neuropathic pain treated with MCS were studied. The analgesic effect was determined as successful by decrease in pain-intensity on the visual analog scale (VAS) of at least 40%. The modifications in drug regimens were monitored with use of the medication quantification scale (MQS). Stimulation parameters and complications were also noted. Interference of pain with quality of life (QoL), the Quality of Life Index (QLI), was determined with use of a specific subset of questions from the MPQ-DLV score.Eighteen patients were included. Mean pre-operative VAS changed from 89.4 ± 11.2 to 53.1 ± 25.0 after three years of follow-up (P < 0.0001). A successful outcome was achieved in seven responders (38.9%). All patients in the responder group suffered from pain caused by a central lesion. With regard to all the patients with central pain lesions (n = 10) and peripheral lesions (n = 8), a significant difference in response to MCS was noticed (P = 0.002). MQS scores and QLI-scores diminished during the follow-up period (P = 0.210 and P = 0.007, respectively).MCS seems a promising therapeutic option for patients with refractory pain syndromes of central origin.