Search

People are infected with Leishmania donovani when the parasite is deposited in the dermis during the blood meal of the sand fly vector. Most infected people develop a subclinical latent infection, but some develop progressive visceral leishmaniasis. Malnutrition is a risk factor for the development of active VL. We previously demonstrated increased parasite dissemination from the skin to visceral organs in a murine model of malnutrition. Here we investigated the mechanism of early parasite dissemination. After delivery of L. donovani to the skin, we found enhanced capture of parasites by inflammatory monocytes and neutrophils in the skin of malnourished mice. However, parasite dissemination in malnourished mice was driven primarily by infected inflammatory monocytes, which showed increased CCR7 expression, greater intrinsic migratory capacity, and increased trafficking from skin to spleen. PGE2 production, which was increased at the site of skin infection, increased monocyte CCR7 expression and promoted CCR7-related monocyte-mediated early parasite dissemination in malnourished mice. Parasite dissemination in monocytes was reduced by inhibition of PGE2, knockdown or silencing of CCR7 in monocytes, and depletion of inflammatory monocytes through administration of diphtheria toxin to CSFR1-DTR transgenic mice that have monocyte-specific DT receptor expression. CCR7-driven trafficking of infected inflammatory monocytes through the lymph node was accompanied by increased expression of its ligands CCL19 and CCL21. These results show that the CCR7/PGE2 axis is responsible for the increased trafficking of L. donovani-infected inflammatory monocytes from the skin to the spleen in the malnourished host. Undernutrition and production of PGE2 are potential targets to reduce the risk of people developing VL. Nutritional interventions that target improved immune function and reduced PGE2 synthesis should be studied in people at risk of developing VL. Author summary: This study established that inflammatory monocytes contribute to the visceralization of L. donovani parasites in the malnourished host. We found that the prostaglandin E2 produced during the first 72 hours of infection amplified the parasite burden at the site of skin infection and induced a high expression of CCR7 receptor in inflammatory monocytes. CCR7-bearing inflammatory monocytes carried L. donovani parasites via enhanced migration from the skin infection site to the viscera of malnourished mice. This dissemination of Leishmania parasites was abrogated in CCR7 deficient inflammatory monocytes and in mice treated with a prostaglandin E synthase inhibitor. We conclude that PGE2 contributes to monocyte-mediated parasite dissemination through the expression of CCR7 and its ligands in malnourished mice. [ABSTRACT FROM AUTHOR]

Purpose: Due to the electron return effect (ERE) during magnetic resonance imaging guided radiotherapy (MRIgRT), rectal gas during pelvic treatments can result in hot spots of over‐dosage in the rectal wall. Determining the clinical impact of this effect on rectal toxicity requires estimation of the amount and mobility (and stability) of rectal gas during treatment. We therefore investigated the amount of rectal gas and local inter‐ and intra‐fractional changes of rectal gas in pelvic cancer patients. Methods: To estimate the volume of gas present at treatment planning, the rectal gas contents in the planning computed tomography (CT) scans of 124 bladder, 70 cervical and 2180 prostate cancer patients were calculated. To estimate inter‐ and intra‐fractional variations in rectal gas, 174 and 131 T2‐w MRIs for six cervical and eleven bladder cancer patients were used. These scans were acquired during four scan‐sessions (~20–25 min each) at various time‐points. Additionally, 258 T2‐w MRIs of the first five prostate cancer patients treated using MRIgRT at our center, acquired during each fraction, were analyzed. Rectums were delineated on all scans. The area of gas within the rectum delineations was identified on each MRI slice using thresholding techniques. The area of gas on each slice of the rectum was used to calculate the inter‐ and intra‐fractional group mean, systematic and random variations along the length of the rectum. The cumulative dose perturbation as a result of the gas was estimated. Two approaches were explored: accounting or not accounting for the gas at the start of the scan‐session. Results: Intra‐fractional variations in rectal gas are small compared to the absolute volume of rectal gas detected for all patient groups. That is, rectal gas is likely to remain stable for periods of 20–25 min. Larger volumes of gas and larger variations in gas volume were observed in bladder cancer patients compared with cervical and prostate cancer patients. For all patients, local cumulative dose perturbations per beam over an entire treatment in the order of 60 % were estimated when gas had not been accounted for in the daily adaption. The calculated dose perturbation over the whole treatment was dramatically reduced in all patients when accounting for the gas in the daily set‐up image. Conclusion: Rectal gas in pelvic cancer patients is likely to remain stable over the course of an MRIgRT fraction, and also likely to reappear in the same location in multiple fractions, and can therefore result in clinically relevant over‐dosage in the rectal wall. The over‐dosage is reduced when accounting for gas in the daily adaption. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is characterized by expansion of myeloid cells in the liver and spleen, which leads to a severe splenomegaly associated with higher risk of mortality. This increased cellularity is thought to be a consequence of recruitment of cells to the viscera. We studied whether the local proliferation of splenic myeloid cells contributes to increased splenic cellularity. We found that a monocyte-like population of adherent splenic cells from Leishmania donovani-infected hamsters had enhanced replicative capacity ex vivo and in vivo (BrdU incorporation, p<0.0001). In vitro assays demonstrated that proliferation was more pronounced in the proinflammatory M1 environment and that intracellular infection prevented proliferation. Secondary analysis of the published splenic transcriptome in the hamster model of progressive VL revealed a gene expression signature that included division of tumoral cells (Z = 2.0), cell cycle progression (Z = 2.3), hematopoiesis (Z = 2.8), proliferation of stem cells (Z = 2.5) and overexpression of proto-oncogenes. Regulators of myeloid cell proliferation were predicted in-silico (CSF2, TLR4, IFNG, IL-6, IL-4, RTK signaling, and STAT3). The in-silico prediction was confirmed with chemical inhibitors of PI3K/AKT, MAPK and STAT3 which decreased splenic myeloid cell division ex vivo. Hamsters infected with L. donovani treated with a STAT3 inhibitor had reduced in situ splenic myeloid proliferation (p = 0.03) and parasite burden. We conclude that monocyte-like myeloid cells have increased STAT3-dependent proliferation in the spleen of hamsters with visceral leishmaniasis and that inhibition of STAT3 reduces myeloid cell proliferation and parasite burden. [ABSTRACT FROM AUTHOR]

Current drug therapies for cutaneous leishmaniasis are often difficult to administer and treatment failure is an increasingly common occurrence. The efficacy of antileishmanial therapy relies on a combination of anti-parasite activity of drugs and the patient's immune response. Previous studies have reported in vitro antimicrobial activity of histamine 1-receptor antagonists (H1RAs) against different pathogens. We used an ex vivo explant culture of lymph nodes from mice infected with Leishmania major to screen H1RAs compounds. Azelastine (AZ) and Fexofenadine (FX) showed remarkable ex vivo efficacy (EC50 = 0.05 and 1.50 μM respectively) and low in vitro cytotoxicity yielding a high therapeutic index. AZ significantly decreased the expression of H1R and the proinflammatory cytokine IL-1ẞ in the ex vivo system, which were shown to be augmented by histamine addition. The anti-leishmanial efficacy of AZ was enhanced in the presence of T cells from infected mice suggesting an immune-modulatory mechanism of parasite suppression. L. major infected BALB/c mice treated per os with FX or intralesionally with AZ showed a significant reduction of lesion size (FX = 69%; AZ = 52%). Furthermore, there was significant parasite suppression in the lesion (FX = 82%; AZ = 87%) and lymph nodes (FX = 81%; AZ = 36%) with no observable side effects. AZ and FX and potentially other H1RAs are good candidates for assessing efficacy in larger studies as monotherapies or in combination with current anti-leishmanial drugs to treat cutaneous leishmaniasis. Author summary: Cutaneous leishmaniasis (CL) is a parasitic disease present in more than 90 countries. Different species of Leishmania produce skin ulcers upon infection through the bite of infected sand fly vectors. There are several drugs used to treat CL but most of them are toxic or difficult to administer and there is increasing drug resistance leading to treatment failure. Therefore, new drugs are needed for treating CL. The objective of this study was to determine the antileishmanial efficacy of antihistamine drugs. Using cell cultures of lymph nodes obtained from Leishmania major infected mice, we evaluated the parasiticidal activity of the antihistamine drugs azelastine and fexofenadine. Both drug showed high efficacy against L. major and low toxicity for a human cell line. Treatment of mice infected in the skin with L. major indicated that both azelastine and fexofenadine significantly reduced the size of the lesions and suppressed parasite multiplication. Consequently, these two drugs are good candidates to further evaluate their efficacy as monotherapies or in combination with other antileishmanial drugs. [ABSTRACT FROM AUTHOR]

Purpose: Dose deposition around unplanned air cavities during magnetic resonance‐guided radiotherapy (MRgRT) is influenced by the electron return effect (ERE). This is clinically relevant for gas forming close to or inside organs at risk (OARs) that lie in the path of a single beam, for example, intestinal track during pelvic treatment. This work aims to verify Monte Carlo calculations that predict the dosimetric effects of ERE around air cavities. For this, we use GafChromic EBT3 film inside poly‐methyl methacrylate (PMMA) –air phantoms. Method: Four PMMA phantoms were produced. Three of the phantoms contained centrally located spherical air cavities (0.5, 3.5, 7.5 cm diameter), and one phantom contained no air. The phantoms were split to sandwich GafChromic EBT3 film in the center. The phantoms were irradiated on an Elekta Unity system using a single 10 × 10 cm2 7‐MV photon beam under the influence of a 1.5‐T transverse magnetic field. The measurements were replicated using the Elekta Monaco treatment planning system (TPS). Gamma analysis with pass criteria 3%/3 mm was used to compare the measured and calculated dose distributions. We also consider 3%/2 mm, 2%/3 mm, and 2%/2 mm pass criteria for interest. Results: The gamma analysis showed that >95% of the points agreed between the TPS‐calculated and measured dose distributions, using 3%/3 mm criteria. The phantom containing the largest air cavity had the lowest agreement, with most of the disagreeing points lying inside the air cavity (dose to air region). Conclusions: The dose effects due to ERE around spherical air cavities are being calculated in the TPS with sufficient accuracy for clinical use. [ABSTRACT FROM AUTHOR]

Inter-observer variability (IOV) in target volume delineation is one of the largest sources of uncertainty in radiotherapy. It can be reduced by following guidelines and training, but the effects of training fade over time. Our aim was to evaluate a tool that provides automatic feedback during delineation and its impact on breast and lymph node IOV, using contouring workshops. Automatic online feedback was presented via warning annotations displayed on the delineated contours when the observer crossed medial, lateral and skin limits. These limits were generated based on a machine learning solution that learnt guideline limits from 150 expertly contoured cases. Warning annotations were also shown when the users were using incorrect local window/level settings, based on analysis of the displayed grey values close to the contour. The system was tested in two 2-day contouring workshops (WS1, WS2). During WS1, we assessed acceptability of the tool via qualitative feedback. Prior to WS2, participants were asked to contour two cases (breast and lymph nodes). During the first day, training was provided on breast delineation following international guidelines. The participants then delineated two additional cases. The final day included additional training, discussions, and general feedback. For each workshop, the tool was enabled for one case. To evaluate IOV, the standard deviation (SD) of the perpendicular distances from every point on each observer's contour to the median of the contours was calculated. SDs for the cases with/without feedback were compared pairwise per observer and volume. We report changes in SD before and after training, and defined improvement when SD reduced by >2mm. Feedback after WS1 showed acceptability of the tool and its potential to influence observers even with minimal training. In WS2, 10 participants, out of 16, delineated all cases (138 contours). Training improved consistency in 23% of analyzed contours for cases when the tool was disabled, and only in 14% when the tool was enabled. SD changes <2mm were 63% for both cases. Real-time automated feedback during contouring is feasible and has the potential to reduce IOV. Our results suggest that it can have similar effects to training. Its use for day-to-day contouring could act as a permanent reminder of guidelines, which may mitigate the fading effect seen after training. This could help to improve contouring by automatically providing anatomical limits to clinically defined target volumes and promoting correct window-level usage. [ABSTRACT FROM AUTHOR]

This work presents a system of two optical microcavities made of mesoporous silicon that have been analyzed as a platform for either chemical sensing or biosensing. When a porous microcavity is exposed to an analyte, the effective refractive index of its layers change, and its optical transmittance shifts towards lower wavenumbers. We constructed a device that employs two identical porous silicon microcavities, one of them is allowed to be in contact with the analyte, whereas the other remains unexposed. The transmitted intensity of the system results in the integrated product of the transmittances of both multilayers, which can be approximated to the autocorrelation function of the transmittance of the microcavity. Its value depends on the analyte concentration, so it can be used for sensing purposes. This results in a sensor that requires neither a wavelength-sensitive detector nor a monochromatic source of illumination, and is robust to changes in temperature, because it only depends on the relative changes in the microcavities. The sensor's response can be optimized by modifying the angular position of the second microcavity. A sensor based on this principle is demonstrated for isopropyl alcohol detection. The minimum concentration change that can be measured is about 30 ppm, which is equivalent to a minimum measurable change of refractive index of 5 × 10 −5 . [ABSTRACT FROM AUTHOR]

The aim of this study was to ascertain whether zinc may improve the repair ability of demineralized dentin. Dentin disks were demineralized by phosphoric acid during 15 s and immersed in artificial saliva, remineralizing solution, a zinc chloride solution and a zinc oxide solution. Dentin specimens were analyzed after 24 h and 1 month of storage. Surface morphology was assessed by atomic force and scanning electron microscopy, mechanical properties were analyzed by nanohardness testing in a TriboIndenter, and chemical changes at the surfaces were determined by X-ray diffraction, Raman and energy-dispersive elemental analyses. After phosphoric acid application, dentin was only partially demineralized. Demineralized dentin was remineralized after 24 h of storage in any of the tested solutions (nanohardness increased and hydroxylapatite formation was detected by Raman). Remineralization was maintained up to 1 month in dentin stored in remineralizing solution, zinc chloride and zinc oxide. Zinc and phosphate were important for hydroxylapatite homeostasis. Scholzite formation was encountered in dentin stored in zinc-containing solutions. Zinc might allow to reach the balance between dentin demineralization and remineralization processes. [ABSTRACT FROM AUTHOR]

The aim of this study was to ascertain whether zinc may improve the repair ability of demineralized dentin. Dentin disks were demineralized by phosphoric acid during 15 s and immersed in artificial saliva, remineralizing solution, a zinc chloride solution and a zinc oxide solution. Dentin specimens were analyzed after 24 h and 1 month of storage. Surface morphology was assessed by atomic force and scanning electron microscopy, mechanical properties were analyzed by nanohardness testing in a TriboIndenter, and chemical changes at the surfaces were determined by X-ray diffraction, Raman and energy-dispersive elemental analyses. After phosphoric acid application, dentin was only partially demineralized. Demineralized dentin was remineralized after 24 h of storage in any of the tested solutions (nanohardness increased and hydroxylapatite formation was detected by Raman). Remineralization was maintained up to 1 month in dentin stored in remineralizing solution, zinc chloride and zinc oxide. Zinc and phosphate were important for hydroxylapatite homeostasis. Scholzite formation was encountered in dentin stored in zinc-containing solutions. Zinc might allow to reach the balance between dentin demineralization and remineralization processes. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Host arginase 1 (arg1) expression is a significant contributor to the pathogenesis of progressive visceral leishmaniasis (VL), a neglected tropical disease caused by the intracellular protozoan Leishmania donovani. Previously we found that parasite-induced arg1 expression in macrophages was dependent on STAT6 activation. Arg1 expression was amplified by, but did not require, IL-4, and required de novo synthesis of unknown protein(s). To further explore the mechanisms involved in arg1 regulation in VL, we screened a panel of kinase inhibitors and found that inhibitors of growth factor signaling reduced arg1 expression in splenic macrophages from hamsters with VL. Analysis of growth factors and their signaling pathways revealed that the Fibroblast Growth Factor Receptor 1 (FGFR-1) and Insulin-like Growth Factor 1 Receptor (IGF-1R) and a number of downstream signaling proteins were activated in splenic macrophages isolated from hamsters infected with L. donovani. Recombinant FGF-2 and IGF-1 increased the expression of arg1 in L. donovani infected hamster macrophages, and this induction was augmented by IL-4. Inhibition of FGFR-1 and IGF-1R decreased arg1 expression and restricted L. donovani replication in both in vitro and ex vivo models of infection. Inhibition of the downstream signaling molecules JAK and AKT also reduced the expression of arg1 in infected macrophages. STAT6 was activated in infected macrophages exposed to either FGF-2 or IGF-1, and STAT6 was critical to the FGFR-1- and IGF-1R-mediated expression of arg1. The converse was also true as inhibition of FGFR-1 and IGF-1R reduced the activation of STAT6 in infected macrophages. Collectively, these data indicate that the FGFR/IGF-1R and IL-4 signaling pathways converge at STAT6 to promote pathologic arg1 expression and intracellular parasite survival in VL. Targeted interruption of these pathological processes offers an approach to restrain this relentlessly progressive disease. [ABSTRACT FROM AUTHOR]

Poster: Physics track: Intra-fraction motion management PO-1651: Inter and intra-fractional stability of rectal gas in cervical cancer patients J. Shortall, E. Vasquez Osorio, A. Cree, M. Dubec, R. Chuter, A. McWilliam, K. Kirkby, R. Mackay, M. Van Herk. [Extracted from the article]

The clinicopathological features of the hamster model of visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that the inability to control parasite replication in VL could be related to ineffective classical macrophage activation. Therefore, we hypothesized that the pathogenesis of VL might be driven by a program of alternative macrophage activation. Indeed, the infected hamster spleen showed low NOS2 but high arg1 enzyme activity and protein and mRNA expression (p,0.001) and increased polyamine synthesis (p,0.05). Increased arginase activity was also evident in macrophages isolated from the spleens of infected hamsters (p,0.05), and arg1 expression was induced by L. donovani in primary hamster peritoneal macrophages (p,0.001) and fibroblasts (p,0.01), and in a hamster fibroblast cell line (p,0.05), without synthesis of endogenous IL-4 or IL-13 or exposure to exogenous cytokines. miRNAi-mediated selective knockdown of hamster arginase 1 (arg1) in BHK cells led to increased generation of nitric oxide and reduced parasite burden (p,0.005). Since many of the genes involved in alternative macrophage activation are regulated by Signal Transducer and Activator of Transcription-6 (STAT6), and because the parasite-induced expression of arg1 occurred in the absence of exogenous IL-4, we considered the possibility that L. donovani was directly activating STAT6. Indeed, exposure of hamster fibroblasts or macrophages to L. donovani resulted in dose-dependent STAT6 activation, even without the addition of exogenous cytokines. Knockdown of hamster STAT6 in BHK cells with miRNAi resulted in reduced arg1 mRNA expression and enhanced control of parasite replication (p,0.0001). Collectively these data indicate that L. donovani infection induces macrophage STAT6 activation and STAT6-dependent arg1 expression, which do not require but are amplified by type 2 cytokines, and which contribute to impaired control of infection. [ABSTRACT FROM AUTHOR]

Abstract: We present results of numerical simulation of optimized porous silicon (PS) multilayers used as antireflection coatings. For the simulations we introduce a figure of merit, which has into account the transmittance of PS multilayers, the solar cell internal spectral response and the solar spectrum. Using a realistic range of porosities in the simulations (from 40% to 90%) we found an optimal three layers configuration, which transfers to the cell 95.7% of the whole usable power. This value represents the 99.8% of the maximum attainable using the complete porosity range (from 0% to 100%). We fabricate the optimal PS three layers, achieving power transference to the substrate of 95.2%. In addition, taking advantage of the PS fabrication characteristics, we transferred a PS multilayer with specific optical response onto a crystalline silicon solar cell. This allows obtaining a tunable spectral response of the solar cell demonstrating the feasibility of transfer the porous antireflection coating onto any optical device. [Copyright &y& Elsevier]

Abstract: Objectives: To determine the bond strength of seven adhesive systems to human cementum, and to assess the promoted surface roughness. Methods: Extracted human canines were used for the present study. The mesial surface from the cervical third of the roots were ground flat with wet 600-grit silicon carbide paper and bonded. Seven adhesive systems were employed: an etch-and-rinse adhesive (Single Bond), two two-step self-etching (Clearfil SE Bond and Resulcin Aquaprime) and four one-step self-etching (One-up Bond F, Prompt-L-Pop, Etch and Prime 3.0 and NRC+Prime&Bond NT). Composite build-ups were constructed and stored in a humid environment for 24h at 37°C. Specimens were sectioned into 1mm2 beams and tested for microtensile bond strength (MTBS). Additional surfaces were conditioned for atomic force microscopy (AFM) analysis. Results were analyzed with ANOVA and Student–Newman–Keuls tests (P <0.05). Results: Single Bond showed the highest MTBS values. No differences were found between Resulcin Aquaprime, One-up Bond and Prompt-L-Pop. Clearfil SE Bond, Etch and Prime and NRC+Prime&Bond NT obtained the lowest bond strength values. H3PO4 acid treatment of cementum and Resulcin Aquaprime showed the highest nanoroughness parameters and One-up Bond the lowest. Conclusion: The etch-and-rinse adhesive and the two-step self-etching adhesive with the lowest pH value promoted the highest bond strength to human cementum surfaces. [Copyright &y& Elsevier]

Abstract: In this work we provide evidence that granulocytes produce macrophage colony-stimulating factor (M-CSF) in the band cell stage and secrete it upon sodium caseinate-mediated differentiation to polymorphonuclear cells. We identified M-CSF in an enriched population of myeloid band cells from murine bone marrow using a chromophore-labeled monoclonal anti-M-CSF antibody. An ELISA assay was then used to detect secreted M-CSF in culture supernatants of enriched band cells differentiated to mature neutrophils using sodium caseinate. Colony formation in vitro by the supernatants from differentiating band cells was blocked by anti-M-CSF, thus suggesting that this factor is the only one responsible for this activity. Our data imply that casein can modulate hematopoiesis possibly via M-CSF production. Finally we discuss the possibility whether this M-CSF in concert with G-CSF could establish a cellular communication network between macrophages and granulocytes allowing them to simultaneously arrive at the inflammatory site. [Copyright &y& Elsevier]

Purpose/objective(s): Lymphopenia during radiotherapy (RT) may be related to adverse outcome for head and neck cancer and is a theoretical concern for effectiveness of adjuvant immunotherapy. Prevention may be possible via plan adaptation if the relationship between RT dose distribution and incidence of lymphopenia is known. This work utilized image-based data mining to identify anatomical regions associated with development of lymphopenia during RT.Materials/methods: 639 oropharyngeal cancer patients treated from 2005-2016 at a single institution with curative intent RT and baseline lymphocytes ≥ 0.5 × 109/L were studied. To control for co-founders and improve data mining sensitivity, two matched groups were defined - patients with and without lymphopenia (defined as Grade 3 or higher based on lymphocytes at nadir during RT < 0.5 × 109/L according to CTCAE v5.0) - matched on target volume, baseline lymphocytes, and prescribed dose (propensity score matching, M = 1:1, caliper = 0.2). Following matching, 309 patients remained, and image-based data mining was used to identify regions where dose correlates with lymphopenia. EQD2 dose matrices (α/β = 10) were mapped onto a reference patient using deformable registration of the planning CT images. L-R mirrored images were included in the cohort to compensate for potential laterality bias. Mean dose distributions for the groups with/without lymphopenia were calculated and regions with significant differences between the mean dose of the two groups detected using permutation testing with 1000 permutations. Multivariable logistic analysis was conducted for the full cohort including mean dose to the identified region, along with age, gender, smoking, performance status, HPV status, stage, histology, target volume, prescribed dose, RT modality, RT duration, baseline lymphocytes, and chemotherapy delivery to generate a predictive model for development of lymphopenia.Results: 74% of the patients developed lymphopenia ≥ G3 during RT. An association with dose to a discrete anatomical region was found. Of interest, this location corresponds to dense lymphoid tissue, bone marrow reserve, and numerous blood vessels. Following elastic-net least absolute shrinkage and selection operator regression, bootstrapped 100 times, a model including baseline lymphocytes (HR = 0.43, P < 0.001) and mean dose to the identified region (HR = 1.02 Gy-1, P = 0.006) adjusted for age (HR = 0.98, P = 0.09) and target volume (HR = 1.83, P = 0.07) was proposed. The Hosmer-Lemeshow test indicated that the model was a good fit, C-statistics 94%.Conclusion: In this large oropharynx cohort, RT related lymphopenia ≥ G3 was associated with dose to a discrete anatomical region including structures containing blood, lymphoid tissue, and bone marrow that may offer a mechanistic explanation. While hypothesis generating, this suggests the possibility that treatment related lymphopenia may be mitigated by prioritizing dose reduction to this region. Further confirmatory studies are indicated. [ABSTRACT FROM AUTHOR]

Abstract: Combustion at programmed temperature in a thermobalance is a common test for the rapid assessment of coal combustibility. In this study two series of blends (low rank/medium rank coal-AB and low rank/petroleum coke-AC) with the low rank coal in three different proportions (1/4, 2/4 and 3/4) have been tested. Samples have been ground and sieved to 20–75μm after blend preparation. The combustion profiles indicated different behaviour for the two series of samples: the AB series showed wide curves with the presence of shoulders whereas the AC series showed two maxima corresponding to the component fuels. The comparison of the calculated and experimental curves indicated different effects of blending on the relevant temperatures and reactivity of the blends. In the AB blend most relevant parameters were similar than expected and only a slight reduction of burnout temperature was observed. In the AC series the difference between calculated and experimental values was large with higher initiation temperatures, lower burnout temperatures and higher reactivity in the experimental curves. This indicates synergistic effects for the combination of subbituminous/petroleum coke blends. In order to visualize the relative combustibility of the coals the reaction was stopped at 50% conversion and the samples were examined through the microscope. The combustion of the particles followed a shrinking core pattern in which the core of the low rank particles remained isotropic whereas anisotropy development was observed in the medium rank coal. The reflectance of the coals increased with increasing the temperature at which the reaction was stopped regardless the rank of the parent coal following a linear trend. The consumption rate of the low rank coal increased with temperature rise. [Copyright &y& Elsevier]

To describe a simple variation of burr hole craniostomy for the management of chronic subdural hematoma (CSDH) that uses a frontal drainage system to facilitate timely decompression in the event of tension pneumocephalus and spares the need for additional surgery. We conducted a retrospective analysis of 20 patients with CSDH who underwent burr hole craniostomy and 20 patients who underwent the same procedure alongside the placement of a 5 Fr neonatal feeding tube as a backup drainage for the anterior craniostomy. Depending on the situation, the secondary drain stayed for a maximum of 72 hours to be opened and used in emergency settings for drainage, aspiration, or as a 1-way valve with a water seal. The outcomes of 20 patients who underwent this procedure and 20 controls are described. One patient from each group presented tension pneumocephalus. One was promptly resolved by opening the backup drain under a water seal to evacuate pneumocephalus and the other patient had to undergo a reopening of the craniostomy. The described variation of burr hole craniostomy represents a low-cost and easy-to-implement technique that can be used for emergency decompression of tension pneumocephalus. It also has the potential to reduce reoperation rates and CSDH recurrence. Prospective controlled research is needed to validate this approach further. [ABSTRACT FROM AUTHOR]

PO-1755: Use of "Jigsaw puzzles" to train convolutional neural networks for segmentation with limited data Poster: Physics track: Imaging acquisition and processing PO-1755: Use of â Jigsaw puzzlesâ to train convolutional neural networks for segmentation with limited data E. Henderson, E. Vasquez Osorio, M. Van Herk, A. Green. [Extracted from the article]

Poster: Physics track: Radiobiological and predictive modelling, and radiomics PO-1569: Early prediction of tumour-response to radiotherapy in NSCLC patients. L.M. Amugongo, E. Vasquez Osorio, A. Green, D. Cobben, M. Van Herk, A. McWilliam. [Extracted from the article]

A. Cree, E. Vasquez Osorio, G. Price, M. Van Herk, P. Hoskin, A. Choudhury, A. McWilliam, Poster Highlights: Poster highlights 13 CL: Gynaecology PH-0401: What are the main causes of interfraction motion of the uterine fundus and cervix?. [Extracted from the article]

The authors present results on electromigrated Au nanojunctions broken near the conductance quantum of 77.5 μS. At room temperature it is found that wires, initially narrowed by an actively-controlled electromigration technique down to a few conductance quanta, continue to narrow after removing the applied voltage. Separate electrodes form as mobile gold atoms continuously reconfigure the constriction. They find, from results obtained on over 300 samples, no evidence for gold cluster formation in junctions broken without an applied voltage, implying that gold clusters may be avoided by using this self-breaking technique. [ABSTRACT FROM AUTHOR]

Summary: Realising the benefits of systematic secondary fracture prevention requires supporting local sites to get started and becoming effective. We here describe the development, implementation and impact of a regional fracture liaison service (FLS) mentorship programme in Latin America that led to 64 FLS getting started and coverage of 17,205 patients. Introduction: Despite treatments and service models to deliver effective secondary fracture prevention, most patients are left untreated after a fragility fracture. To improve the capability to get FLS started and more effective, we describe the development, implementation and evaluation of an international programme to develop national communities of FLS mentors as part of the Capture the Fracture Partnership in Latin America. Methods: The IOF regional team and the University of Oxford developed the curriculum and associated resources for training mentors in setting up FLS, service improvement and mentorship. Mentors were selected during a preparatory meeting, trained using live online sessions followed by regular mentor-led post-training meetings. The programme was evaluated using a pre-training needs assessment and post-training evaluation based on Moore's outcomes. Results: The mentorship programme was initiated in Mexico, Brazil, Colombia and Argentina. The mentors were multidisciplinary, including orthopaedic surgery, rehabilitation, rheumatology, endocrinology, geriatrics, gynaecology and internal medicine. There was 100% participation in training sessions and reported satisfaction with the training. Since the initiation of the training programme, 22 FLS have been set up in Mexico, 30 in Brazil, 3 in Colombia and 9 in Argentina, in comparison with two in Chile and none in any other LATAM countries that were not involved in the mentorship programme. This equates to approximately 17,025 additional patients identified from 2019 to 2021 after initiation of mentorship. The mentors have engaged with 58 FLS for service development. Post-training activities include two published national best practice guidelines and other country-specific resources for FLS in the local language. Conclusion: Despite the COVID pandemic, the mentorship pillar of the Capture the Fracture Partnership has developed a community of FLS mentors with measurable improvement in national FLS provision. The programme is a potentially scalable platform to develop communities of mentors in other countries. [ABSTRACT FROM AUTHOR]

Image-based data mining (IBDM) is a novel technique to identify dose-response relationships (DRRs) in radiotherapy. IBDM comprises two steps: spatial normalisation of patient data to a reference anatomy using deformable image registration, and 'per-voxel' dose comparison. The main advantage of IBDM is the possibility of identifying DRRs at the sub-organ level and in structures that are not routinely contoured, depending on the image registration accuracy. Computed Tomography (CT)-based IBDM has been successfully applied in adults; however, for children with brain tumours, Magnetic Resonance (MR) imaging is indicated due to superior anatomical definition. We evaluate the accuracy of spatial normalisation using MR images to determine the feasibility of MR-based IBDM in children with brain tumours. We used MR images and radiotherapy contours from 129 children previously treated on the SJMB03 protocol for medulloblastoma. The patient with the median brain volume was selected as the reference anatomy for deformable image registration (NiftyReg software). We analysed registration accuracy, comparing each patient's deformed contours to the reference contours, in 5 brain structures (Table 1) via 95%-Hausdorff (HD95%), average-contour (MeanDTA) and centre-of-mass (CoM) distances. Based on previous results in CT data, meanDTA accuracy <3mm was considered acceptable. 16/129 cases required manual adjustments to fix registration errors, commonly arising due to enlarged ventricles or large rotations compared to the reference anatomy. MeanDTA for all structures was <2.1mm and all metrics <6mm (Table 1). Accurate spatial normalisation was achieved using MR images from paediatric brain tumour patients, suggesting that MR-based IBDM is feasible in this patient group. [ABSTRACT FROM AUTHOR]

Current medical guidelines consider pregnant women with COVID-19 to be a high-risk group. Since physiological gestation downregulates the immunological response to maintain "maternal-fetal tolerance", SARS-CoV-2 infection may constitute a potentially threatening condition to both the mother and the fetus. To establish the immune profile in pregnant COVID-19+ patients, a cross-sectional study was conducted. Pregnant women with COVID-19 (P-COVID-19+; n = 15) were analyzed and compared with nonpregnant women with COVID-19 (NP-COVID-19+; n = 15) or those with physiological pregnancy (P-COVID-19-; n = 13). Serological cytokine and chemokine concentrations, leucocyte immunophenotypes, and mononuclear leucocyte responses to polyclonal stimuli were analyzed in all groups. Higher concentrations of serological TNF-α, IL-6, MIP1b and IL-4 were observed within the P-COVID-19+ group, while cytokines and chemokines secreted by peripheral leucocytes in response to LPS, IL-6 or PMA-ionomicin were similar among the groups. Immunophenotype analysis showed a lower percentage of HLA-DR+ monocytes in P-COVID-19+ than in P-COVID-19- and a higher percentage of CD39+ monocytes in P-COVID-19+ than in NP-COVID-19+. After whole blood polyclonal stimulation, similar percentages of T cells and TNF+ monocytes between groups were observed. Our results suggest that P-COVID-19+ elicits a strong inflammatory response similar to NP-COVID19+ but also displays an anti-inflammatory response that controls the ATP/adenosine balance and prevents hyperinflammatory damage in COVID-19. [ABSTRACT FROM AUTHOR]

Poster discussion: PH: Radiobiological and predictive modelling, and radiomics 1 PD-0428: Large scale evaluation of sarcopenia as prognostic factor in lung cancer radiotherapy patients A. Green, M. Van Herk, E. Vasquez Osorio, J. Weaver, A. McWilliam. [Extracted from the article]

Background: Dentine matrix metalloproteinases (MMPs) play an important role in the dentine caries process. Aims: To determine if MMP-mediated collagen degradation of acid-demineralized dentine may be inhibited by zinc or zinc chelators. Methods: Human dentine specimens were demineralized by phosphoric acid (PA), ethylenediaminetetraacetic acid (EDTA), Clearfil SE Bond primer (SE), or Xeno V (XE) and stored in artificial saliva. Chlorhexidine digluconate (CHX), doxycycline, EDTA, or ZnCl2 was added. C-terminal telopeptide determinations (ICTP) were performed by radioimmunoassay after 24 h and 4 weeks. Results: Collagen degradation was prominent in PA-demineralized (ICTP values from 74.01 μg/l at 24 h to 202.46 μg/l after 4 weeks) and EDTA-demineralized dentine (ICTP values from 83.93 μg/l at 24 h to 158.82 μg/l after 4 weeks) stored in artificial saliva. Doxycycline fully blocked proteolysis. CHX and EDTA reduced collagen degradation only at 24 h. Zinc in excess strongly inhibited hydrolysis of collagen in all tested groups (ICTP values were: PA, 13.56 μg/l; EDTA, 11.21 μg/l; SE, 1.52 μg/l, and XE, 2.37 μg/l) and its effect was maintained for up to 4 weeks, except for EDTA-treated dentine (ICTP values were: PA, 40.76 μg/l; EDTA, 79.15 μg/l; SE, 5.29 μg/l, and XE, 6.38 μg/l). Conclusion: EDTA and CHX exerted time-limited MMP inhibition, and excess zinc served as an effective inhibitor of MMP-mediated collagen degradation in strong or mildly demineralized dentine. MMP degradation of collagen was reduced in resin-infiltrated dentine; the presence of excess zinc chloride exerted an additional protective effect. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: Dentin matrix metalloproteinases are implicated in the pathogenesis of caries and contribute to collagen degradation in resin-dentin interfaces. The objective was to determine if collagen degradation may be modulated by an excess of zinc or zinc chelators.Methods: Mineralized and phosphoric acid demineralized human dentin specimens were tested. Chlorhexidine digluconate, doxycycline or ZnCl₂ were added to the media. In half of the groups, active exogenous metalloproteinase-2 was incorporated into the solution. C-terminal telopeptide determinations (radioimmunoassay) were performed after 24 h, 1 and 3 weeks.Results: Collagen degradation was prominent in demineralized dentin. Doxycycline fully blocked dentin proteolysis. Chlorhexidine digluconate reduced the degradation at the 24-h period. Zinc in excess strongly inhibits hydrolysis of collagen and its effect was maintained for 3 weeks.Conclusions: Zinc in excess reduces MMP-mediated collagen degradation. The hypothesis that binding of zinc to collagen results in protection of sensitive cleavage sites of metalloproteinases requires further validation. [ABSTRACT FROM AUTHOR]

Abstract Oxidative stress (OxS) and inflammation are physiopathological mechanisms related to diabetes and aging. We evaluated the additive effect of diabetes and aging on OxS and inflammation in a cross-sectional comparative study of 228 subjects: (1) 56 healthy adults (mean age, 47 ± 7 years); (2) 60 diabetic adults (mean age, 52 ± 6 years); (3) 40 healthy elderly adults (mean age, 67 ± 7 years); and (4) 72 diabetic elderly adults (mean age, 68 ± 7 years). We measured levels of glycosylated hemoglobin (HbA1c), plasma lipid peroxides, superoxide dismutase, glutathione peroxidase, total antioxidants, and tumor necrosis factor-alpha (TNF-[alpha]). The results indicate that diabetes is a risk factor for subjects with high serum levels of TNF-[alpha] (odds ratio [OR] = 12.1; 95% confidence interval [95% CI], 5.0-28; p < 0.001); this correlation becomes stronger when it is also associated with aging (OR = 14; 95% CI, 3.7-53.7; p < 0.05). Likewise, we observed that diabetes is an independent risk factor for OxS (OR = 2.1; 95% CI, 1.2-3.8; p < 0.05), and a stronger factor in older patients (OR = 3.1; 95% CI, 1.3-7.5; p < 0.05). Our findings suggest that aging, in concert with diabetes, exerts an additive effect on OxS and inflammation. [ABSTRACT FROM AUTHOR]

Inflammation is necessary for survival, but it is also an important cause of human morbidity and mortality, as exemplified by sepsis. During inflammation, cells of the innate immune system are recruited and activated in response to infection, trauma or injury. These cells are activated through receptors, such as Toll-like receptors (TLRs), which recognize microbial ligands such as lipopolysaccharide (LPS). Triggering receptor expressed on myeloid cells (TREM)-1 amplifies the inflammatory response initiated by TLRs, and its expression on the surface of monocytes increases in the presence of TLR ligands. Here we have shown that in monocytes TREM-1 mRNA levels, measured by reverse transcription–polymerase chain reaction (RT–PCR), remained unchanged and TREM-1 protein levels, measured by flow cytometry, increased, indicating that LPS increases TREM-1 expression by a post-transcriptional mechanism. We also showed that TREM-1/Fc fusion protein decreased the ability of the sera of some patients with sepsis to activate monocytes, indicating that the TREM-1 ligand, whose identity is unknown, may be present in the sera of some of these patients. We describe a mechanism for the regulation of TREM-1 expression on monocytes and the possible presence of its ligand in serum; these findings help to explain the contribution of TREM-1 during systemic inflammation. [ABSTRACT FROM AUTHOR]

Objectives. The purpose of this study was to analyze the behavior in water, related to mechanical properties, of experimental composites for dental restoration.Methods. The studied materials were composed of a visible-light-curing monomer mixture (Bis-GMA and TEGDMA or HEMA) and micrometric, nanometric or a mixture of both sizes hydroxyapatite particles as a reinforcing filler. Filler particles were modified with a coupling agent (citric, hydrosuccinic, acrylic or methacrylic acid or silane). The hydrolytic stability of the evaluated materials was studied through total elution and water-uptake tests. Percent net-mass variation was daily monitored and analyzed as a function of time. Mechanical performance was examined through flexural properties and Vickers hardness. Morphological surface changes were observed with scanning electron microscopy. ANOVA statistical analysis was performed (P<0.05).Results. In general, the use of HEMA instead of TEGDMA did not substantially worsen the composite quality. Dental composites containing only nanometric particles of hydroxyapatite as a filler are unsuitable for clinical performance. Midway-filled composite resins loaded with micro-HAP particles, coated with citric, acrylic or methacrylic acid displayed low percent elution and water-uptake values. Mechanical properties were similar or even superior to those measured for silane treated particles.Significance. More research is needed to further improve the interaction of nano-HAP particles with the polymeric matrix, either as a single filler or, preferentially, mixed with micro-HAP, that will allow to increase the total loading of reinforcing filler and, hence, to improve the mechanical properties. [Copyright &y& Elsevier]

A simple and selective new technique for atomic hydrogen flux measurements in a hydrogen plasma environment is introduced and demonstrated in this work. This technique works by measuring the etching rate of an amorphous carbon film and translating this to an incoming hydrogen radical flux through a well-defined carbon etch yield per radical. Ions present in the plasma environment have a much higher etch yield than radicals do. For that reason, suppression of the ion flux toward the carbon film is crucial to ensure that the observed carbon etch rate is dominated by atomic hydrogen etching. It is demonstrated that this can be achieved using a simple cylindrical pipe (hereinafter "chimney") in which a bend is introduced to enforce ion–wall collisions, neutralizing the ions. The chimney is made out of Macor, a material with low catalytic surface activity, to preserve the incoming atomic hydrogen flux while effectively suppressing ions. Ultimately, the etching sensor is deployed in a radio frequency inductively coupled hydrogen plasma operated at low pressure (1–10 Pa). Atomic hydrogen fluxes are measured and compared with heat flux sensor and vacuum ultraviolet absorption spectroscopy measurements in the same setup. All sensors agreed within a factor 4 in the atomic hydrogen flux range 1019 to 1021 m−2 s−1. [ABSTRACT FROM AUTHOR]