Impact of target point deviations on control and complication probabilities in stereotactic radiosurgery of AVMs and metastases.

OBJECTIVE: Determination of the impact of inaccuracies in the determination and setup of the target point in stereotactic radiosurgery (SRS) on the expectable complication and control probabilities. METHODS: Two randomized samples of patients with arteriovenous malformation (AVM) (n=20) and with brain metastases (n=20) treated with SRS were formed, and the probability for complete obliteration (COP) or complete remission (CRP), the size of the 10 Gy-volume in the brain tissue (VOI10), and the probability for radiation necrosis (NTCP) were calculated. The dose-effect relations for COP and CRP were fitted to clinical data. Target point deviations were simulated through random vectors and the resulting probabilities and volumes were calculated and compared with the values of the treatment plan. RESULTS: The decrease of the relative value of the control probabilities at 1mm target point deviation was up to 4% for AVMs and up to 10% for metastases. At 2 mm the median decrease was 5% for AVMs and 9% for metastases. The value for the target point deviation, at which COP and CRP decreased about 0.05 in 90% of the cases, was 1.3 mm. The increase of NTCP was maximally 0.0025 per mm target point deviation for AVMs and 0.0035/mm for metastases. The maximal increase of VOI10 was 0.7 cm(3)/mm target point deviation in both patient groups. CONCLUSIONS: The upper limit for tolerable target point deviations is at 1.3mm. If this value cannot be achieved during the system test, a supplementary safety margin should be applied for the definition of the target volume. A better accuracy level is desirable, in order to ensure optimal chances for the success of the treatment. The target point precision is less important for the minimization of the probability of radiation necroses.     

Recent Advances in Archaeological Science Techniques Special Feature: Dating the emergence of dairying by the first farmers of Central Europe using 14C analysis of fatty acids preserved in pottery vessels

Direct, accurate, and precise dating of archaeological pottery vessels is now achievable using a recently developed approach based on the radiocarbon dating of purified molecular components of food residues preserved in the walls of pottery vessels. The method targets fatty acids from animal fat residues, making it uniquely suited for directly dating the inception of new food commodities in prehistoric populations. Here, we report a large-scale application of the method by directly dating the introduction of dairying into Central Europe by the Linearbandkeramik (LBK) cultural group based on dairy fat residues. The radiocarbon dates (n = 27) from the 54th century BC from the western and eastern expansion of the LBK suggest dairy exploitation arrived with the first settlers in the respective regions and were not gradually adopted later. This is particularly significant, as contemporaneous LBK sites showed an uneven distribution of dairy exploitation. Significantly, our findings demonstrate the power of directly dating the introduction of new food commodities, hence removing taphonomic uncertainties when assessing this indirectly based on associated cultural materials or other remains.

The introduction of new food commodities into the human diet at the very beginnings of plant and animal domestication is one of the most critical questions in the Neolithization process, having far reaching consequences for human evolution and environmental change. Of major importance is milk exploitation, as it relates to animal domestication but also the ability of adult humans to digest lactose (1, 2). Clearly, identifying the beginnings of the exploitation of domesticated animals for their secondary products (i.e., those obtained during the life of animals, such as milk, wool, or blood) as opposed to primary products (i.e., those obtained by the death of the animal such as meat, skin, teeth, or horn) makes it extremely important to establish when and how dairying began (3, 4). Directly dating the introduction of a new food commodity is nonetheless challenging.Evidence for dairy exploitation in prehistory can be interpreted from iconography, diagnostic ceramics, or domesticated animal slaughter patterns based on sex and ages (3, 4). Additionally, direct evidence for dairy exploitation can be derived from lipid analyses of food residues preserved in pottery vessels. By determining the stable carbon isotope values of the two fatty acids (FAs) (C_16:0 and C_18:0) characteristic of degraded animal fats, dairy products can be distinguished from carcass products (5). Recent combined lipid residue analyses of pottery vessels and animal management assessments based on faunal remains (stable isotopes, butchery practices, kill-off patterns, and calving patterns) have provided invaluable knowledge of early dairying practices at archaeological sites. Currently, the earliest evidence for milk use from lipid residues and faunal assemblages recovered during the Neolithic was found in Anatolia during the 7th millennium BC (6), from several regions in the Balkans, eastern Europe, and the Mediterranean during the 6th millennium BC (7–12), in Saharan Africa (Libya and Algeria) during the 5th millennium BC (13–15), from the beginning of the Neolithic in Britain, Ireland, and Scandinavia during the 4th millennium BC (5, 16–19), and in the Baltic countries during the 3rd millennium BC (16). The dates of the introduction of dairying in these regions have been established largely indirectly based on associated materials (e.g., animal bone collagen, charcoal, charred seeds, etc.) recovered from the same archaeological contexts as the pottery yielding milk fat residues. However, uncertainties exist with indirect dating due to possible intrusion or residuality of datable materials, resulting from the disturbance of archaeological layers and the requirement for the datable materials to be short-lived and truly contemporaneous in date with the pottery vessels containing the dairy residues.Thus, the application of recently developed methods for the direct dating of lipids from pottery food residues offers a unique approach to obtain accurate and precise dates for the introduction of new food commodities. The direct ¹⁴C dating of dairy fat residues avoids all the aforementioned uncertainties, offering an unprecedented opportunity to accurately date the start of dairying practices. At the University of Bristol, United Kingdom, we recently reported a method for radiocarbon dating pottery vessels from their absorbed food residues. Our compound-specific radiocarbon analysis (CSRA) approach is based on the isolation of the C_16:0 and C_18:0 FAs from the clay matrix and freeing them from exogenous organic contaminants (20, 21). We have successfully applied this approach to a small number of dairy residues from the Libyan Sahara and Central Europe, with one of the oldest dated dairy residues coming from the 6th millennium in the Balkans (11, 22). Hence, this dating method offers the opportunity to directly date residues identified as dairy fats based on the compound-specific δ¹³C values of the C_16:0 and C_18:0 FAs, avoiding taphonomic uncertainties arising from dating-associated materials.In this paper, we focus on the Linearbandkeramik (LBK) culture, the first farming society in Central Europe, which emerged and expanded over much of northern Europe in the middle of the 6th millennium BC (23). This culture has been divided into five main phases: Earliest (I), Early (II), Middle (III), Late (IV), and Final (V) LBK, known as the Meier-Arendt chronology, whose timing and evolution differed in the different regions of the LBK (24). Hence, the ceramic phases discussed in the remainder of this paper use the regional and site classifications for the chronology of earliest, early, middle, and Late LBK, which are not necessarily contemporaneous. For example, phase I in Poland and phase I in Cuiry-lès-Chaudardes refer to the Earliest and Late LBK phases, respectively, in the Meier-Arendt chronology.Dairy residues were identified in varying quantities at LBK sites across Central Europe. Some sites show only a weak dairy signal (1 to 2 potsherds only), while others display much higher recovery, with over 20% of the residues displaying dairy fat molecular and carbon isotope characteristics. These results emphasize the spatial disparity in the exploitation of cattle and caprines for their milk in this period. We do not exclude the possibility that the use of organic containers other than clay vessels for dairy products at some sites may affect the overall dairy lipid recovery observed. Diachronic studies in certain regions also revealed dairy practices evolving from being nonexistent or at very low levels at LBK sites but becoming much more abundant in the following Middle Neolithic cultures [e.g., the Rössen culture in Lower Alsace, France (22) or Funnel Beaker culture at the site of Kopydłowo, Poland (25)]. Dating of dairy residues recovered from the earliest phases of the sites would provide calendar ages for the emergence of dairying between LBK regions based directly on the commodity itself rather than on associated materials. Critically, some sites cannot be dated by conventional materials due to their poor preservation, while at other sites where dairy evidence is scarce, the possibility exists for false-positive signal arising due to stratigraphic perturbations. In reporting here the application of our recently developed CSRA method to a wide range of potsherds, we begin to resolve the timing of appearance of dairying practices by LBK farmers during the Neolithic in the diverse regions of the settlements.     

Predictive Factors for Bilateral Disease in Papillary Microcarcinoma: A Retrospective Cohort Study

Background: Based on risk stratification, the therapeutic options in papillary microcarcinoma (PTMC) can be active surveillance or surgery. Multifocal tumor occurrence can be decisive in determining the treatment strategy. The objective of this study was to identify risk factors for bilateral tumor occurrence in PTMC to enable individual therapy planning. Methods: A total of 545 PTMC patients who underwent thyroidectomy from 2008 to 2020 were retrieved. Univariate and multivariate analyses were performed to evaluate risk factors for bilateral PTMC. Results: 25.1% (n = 137) of all patients had multifocal PTMC, and 13.2% (n = 72) bilateral PTMC, respectively. In contrast to the maximum tumor size, the total tumor size significantly influenced a bilateral tumor manifestation (median total tumor size 5 mm versus 8.5 mm for bilateral PTMC, p < 0.001). A cut-off level for the total tumor size of >10 mm resulted in a sensitivity and specificity of 29.2% and 94.7%, respectively, in predicting a bilateral tumor manifestation, AUC 0.680 (95% CI, 0.611–0.748, p < 0.001). A cut-off of >4 tumors showed a sensitivity of 99.4% and a specificity of 97.5%, AUC 0.897 (95% CI, 0.870–0.924, p < 0.001) in predicting bilaterality. Conclusion: We could demonstrate for the first time that a total tumor size of >10 mm and more than four tumors significantly increased the risk of bilateral PTMC tumor involvement. These findings enable a risk-adjusted patient treatment.     

Immunophenotyping does not improve predictivity of the local lymph node assay in mice

The local lymph node assay (LLNA) is a regulatory accepted test for the identification of skin sensitizing substances by measuring radioactive thymidine incorporation into the lymph node. However, there is evidence that LLNA is overestimating the sensitization potential of certain substance classes in particular those exerting skin irritation. Some reports describe the additional use of flow cytometry‐based immunophenotyping to better discriminate irritants from sensitizing irritants in LLNA. In the present study, the 22 performance standards plus 8 surfactants were assessed using the radioactive LLNA method. In addition, lymph node cells were immunophenotyped to evaluate the specificity of the lymph node response using cell surface markers such as B220 or CD19, CD3, CD4, CD8, I‐A^κ and CD69 with the aim to allow a better discrimination above all between irritants and sensitizers, but also non‐irritating sensitizers and non‐sensitizers. However, the markers assessed in this study do not sufficiently differentiate between irritants and irritant sensitizers and therefore did not improve the predictive capacity of the LLNA. Copyright © 2014 John Wiley & Sons, Ltd.     

Gas Atomization of Duplex Stainless Steel Powder for Laser Powder Bed Fusion

Duplex stainless steel powders for laser additive manufacturing have not been developed extensively. In this study, the melts of a super duplex stainless steel X2CrNiMoCuWN25-7-4 (AISI F55, 1.4501) were atomized with different process gases (Ar or N₂) at different atomization gas temperatures. The process gas N₂ in the melting chamber leads to a higher nitrogen dissolution in the steel and a higher nitrogen content of the atomized powders. The argon-atomized powders have more gas porosity inside the particles than the nitrogen-atomized powders. In addition, the higher the atomization gas temperature, the finer the powder particles. The duplex stainless steel powders showed good processability during PBF-LB/M (Laser powder bed fusion). The gas entrapment in the powder particles, regardless of the gas chemistry and the gas content, appears to have a negligible effect on the porosity of the as-built parts.     

A partially aromatic urethane dimethacrylate as a new substitute for Bis-GMA in restorative composites.

OBJECTIVES: The objective of this study was to investigate the use of a new, partially aromatic urethane dimethacrylate in visible-light cured resin-based composite restoratives. Selected mechanical properties, such as flexural strength and flexural modulus of elasticity, of model monomer mixtures and composites containing the new urethane dimethacrylate were investigated and compared to the properties of materials that are based on Bis-GMA, at present the most frequently used cross-linker in restorative composites. In addition, the polymerization shrinkage and the water sorption of selected composites were determined. METHODS: The flexural strength, flexural modulus of elasticity, and the water sorption were determined according to ISO 4049:2000. Test specimens (rods: 2 mmx2 mmx25 mm; discs: d=15 mm and h=1 mm) of the investigated composites were prepared in stainless steel molds and light-cured (150 mW/cm2, 2x180 s). The flexural strength and flexural modulus of rods were measured after the samples had been stored under dry conditions or in water for 24 h at 37 degrees C as well as after they had been stored in water for 7 days at 37 degrees C. The water sorption was determined with discs. The polymerization shrinkage was calculated from the densities of the uncured composite pastes and cured composites. RESULTS: Visible light cured mixtures of dimethacrylate diluents with the new urethane dimethacrylate and composites based on these mixtures show a reactivity, flexural strength, flexural modulus of elasticity, polymerization shrinkage and water sorption similar to those of materials that are based on Bis-GMA. The composites did not show any strong deterioration of the mechanical properties after water storage.     

Transplanted human cones incorporate into the retina and function in a murine cone degeneration model

Once human photoreceptors die, they do not regenerate, thus, photoreceptor transplantation has emerged as a potential treatment approach for blinding diseases. Improvements in transplant organization, donor cell maturation, and synaptic connectivity to the host will be critical in advancing this technology for use in clinical practice. Unlike the unstructured grafts of prior cell-suspension transplantations into end-stage degeneration models, we describe the extensive incorporation of induced pluripotent stem cell (iPSC) retinal organoid–derived human photoreceptors into mice with cone dysfunction. This incorporative phenotype was validated in both cone-only as well as pan-photoreceptor transplantations. Rather than forming a glial barrier, Müller cells extended throughout the graft, even forming a series of adherens junctions between mouse and human cells, reminiscent of an outer limiting membrane. Donor-host interaction appeared to promote polarization as well as the development of morphological features critical for light detection, namely the formation of inner and well-stacked outer segments oriented toward the retinal pigment epithelium. Putative synapse formation and graft function were evident at both structural and electrophysiological levels. Overall, these results show that human photoreceptors interacted readily with a partially degenerated retina. Moreover, incorporation into the host retina appeared to be beneficial to graft maturation, polarization, and function.     

Evolution of thrombolytic therapy in patients with HeartWare ventricular assist device thrombosis: a single-institutional experience

Open in a separate window OBJECTIVESPump thrombosis remains a major challenge in heart failure patients with left ventricular HeartWare assist device. Current International Society for Heart and Lung Transplantation recommendations favour surgical pump exchange over lysis because safety and efficacy of lysis has been controversially reported. This study summarizes our experience on our HeartWare thrombosis prevention strategy as well as thrombolysis through implementation of our institutional standardized HeartWare assist device protocol.METHODSOutcomes of all HeartWare thrombosis patients admitted between 2010 and 2020 were analysed. Thrombolysis therapy using tissue plasminogen activator was used as the first-line therapy in this study and thrombolysis therapy efficacy was defined as freedom from stroke, bleeding, recurrent HeartWare assist device thrombosis or surgical device exchange within 30 days after lysis application.RESULTSA total of 507 patients have been included in this study and 66 patients (13%) collectively developed a first HeartWare-thrombosis after a median of 12 months (8–22 months) after HeartWare implantation. Forty patients were treated with unstandardized lysis, of whom 7 patients had thrombolysis associated complications, such as incomplete thrombus resolution requiring surgical pump exchange in 4 patients, but also intracranial haemorrhage occurring in 3 patients. Three patients died in the non-protocol group. Eight device thrombosis patients were treated according to our protocol, showing no lysis-associated complication.CONCLUSIONSDespite current recommendations, preferring surgical HeartWare pump exchange in thrombosis, thrombolysis therapy for first HeartWare thrombosis can be safe and effective in a standardized protocol setting, including anticoagulation adjustment and intensified blood pressure control management.