Our model shows the explicit coupling of the piezoelectric physics with the fluid dynamics physics to simulate the interaction between the piezoelectric and the fluid forces that contribute to the deformation of a flexible membrane in the adaptive lens. Furthermore, the simulation model is extended to describe the membrane deformation by additional fluid forces from the fluid thermal expansion. Subsequently, the simulation model is used to study the refractive power of the adaptive lens as a function of internal fluid pressure and analyze the effect of the fluid thermal expansion on the refractive power. Finally, the simulation results of the refractive power are compared to the experimental results at different actuation levels and temperatures validating the coupled COMSOL model very well. This is explicitly proven by explaining an observed positive drift of the refractive power at higher temperatures.In this paper, we present a finite-element simulation of an adaptive piezoelectric fluid-membrane lens for which we modelled the fluid-structure interaction and resulting membrane deformation in COMSOL Multiphysics The expression adaptive optics was initially termed for the technology used in telescopes to deform the mirrors for phase correction of the incoming light . Soon, aThe developed adaptive lens consists of a piezoelectric actuator, a fluid chamber, and a transparent flexible membrane, as shown in ®  to define the refractive power linearly as a function of both the fluid pressure and temperature.To address the non-linear response and hence to compensate for the hysteresis and the temperature effect on the refractive power, it is essential to determine the combined influence of piezoelectric actuation and temperature on the membrane deformation. Hence in this paper, we present a finite-element simulation of the adaptive lens modelled in COMSOL Multiphysics® is based on the finite-element method (FEM), which solves engineering problems such as structural mechanics, fluid dynamics, heat transfer by a numerical approach. In FEM, the complex geometry is divided into simpler domains. These domains are defined with the elementary partial differential equations based on the physics. Then the elementary equations are combined to form a system of global equations, which represent the complex geometry [® offers a methodological environment to access elementary equations and then couple them with a wide range of available physics modules [®, authors in [® does not provide a direct feature to couple the piezoelectric with the fluid-structure and heat transfer physics modules. Hence, in this paper, we present the explicit coupling of multiple physics modules to simulate the membrane deformation due to the fluid forces from both the piezoelectric actuation and the thermal expansion.COMSOL Multiphysicsgeometry . The sysgeometry . To simu modules . Using Cthors in ,12,13 sithors in ,15 simulthors in ,17 simulthors in ,15,16,17We describe the physical design and working principle of the adaptive lens in The piezoelectric bi-morph actuator has a circular ring-shaped design with the two piezoelectric ceramic layers glued together in an anti-parallel polarization configuration. The fluid chamber and the flexible membrane are integrated with the actuator using micro-molding techniques to form an active lens chamber . The actThe manufactured adaptive lens with the actuator diameter of 20 vex lens a, and thvex lens b.® inbuilt material library [To reduce the complexity of a ive lens  with the library . The matThe adaptive lens uses the inverse piezoelectric property of the actuator to vary the refractive power. To model the inverse piezoelectric effect, the piezoelectric devices module is used. The module couples the solid mechanics Equation  and the x is the displacement, s is the stress, and E is the electric field, and V is the electric potential.The combined behavior is modelled through the coupled Equations  and 4)  4) in stS and stress T, the electrostatic parameters are electric field E and electric displacement field D, and the piezoelectric material parameters are compliance coefficient tivity ϵ . In the tivity ϵ .The piezoelectric actuator in the adaptive lens deforms the fluid chamber and varies the internal fluid pressure. The varied internal fluid pressure results in fluid forces, which act on the flexible membrane. The fluid forces contribute to the deformation of the flexible membrane to an aspherical surface. The fluid-structure interaction (FSI) physics module models the fluid forces acting on the membrane by coupling the solid mechanics Equation  and the u is the fluid velocity, F is the external force and g is the gravity. The FSI Multiphysics module couples the fluid inertial forces in Equation  and heaQ is the heat source, T is the temperature, S is the solid stress tensor, p is the fluid pressure, and u is the fluid velocity.Q that contributes to set the complete adaptive lens domain to the required temperature T. Equation   7) definmembrane .®, the coupling of the piezoelectric effect and the fluid-structure interaction is not possible through a direct Multiphysics feature. Hence, the moving mesh physics module is used to couple the piezoelectric forces with the fluid forces and apply the resultant on the flexible membrane. The explicit coupling of piezoelectric and laminar flow physics is performed in a way such that the solid domain velocities Equations (The adaptive lens working mechanism relies on the transfer of piezoelectric forces to the flexible membrane through the fluid forces. In COMSOL Multiphysicsquations  and 9)  ®, the cEquations  and 9)  9) equatEquation  of the fEquation . In thisIn the solid mechanics interface, the glass substrate is selected in the fixed constraint condition, as shown in The explicit coupling of the piezoelectric forces with the fluidic forces is achieved through the mesh velocities applied on the walls of the fluid chamber c. Hence The time-dependent study was selected in the simulation as the velocities, which are used in the moving mesh module, are time-dependent values, and as the stationary study does not compute these instantaneous velocities. In the study, the time range was selected from 0 rization . A sinusThe volume plots in The surface plots in The heat transfer interface for solids and fluids was used to set the adaptive lens to a temperature ranging from 20 °C–80 °C. The surface plot in The refractive power of the adaptive lens in the simulation  was calcFurthermore, to verify the simulation results, we characterized the adaptive lens at different applied voltages and temperatures . The adaA sinusoidal voltage was applied to the piezoelectric actuator as was assumed in the simulation. A voltage driver was used to limit the negative voltage to The simulated and measured refractive power of the adaptive lens at 25 °C, 50 °C and 75 °C with different applied voltages are compared in Our simulation model successfully couples the piezoelectric physics with the laminar flow and heat transfer physics modules. Both prove that the adaptive lens was simulated at different voltages and temperatures to determine the actuator deflection, the fluid pressure, and the refractive power. The simulated results are in close agreement with the experimental results. The adaptive lens can vary the refractive power from


Pituitary adenomas (PA) have an increased potential for relapse in one to 5 years after resection. In this study, we investigated the genetic differences in genomic DNA of primary and rapidly recurrent tumours in the same patient to explain the causality mechanisms of PA recurrence.The patient was a 69-year-old female with non-functional pituitary macroadenoma with extension into the left cavernous sinus (Knosp grade 2) who underwent craniotomy and partial resection in August 2010. Two years later, the patient had prolonged tumour growth with an essential suprasellar extension (Knosp grade 2), and a second craniotomy with partial tumour resection was performed in September 2012. In both tumours, the KI-67 level was below 1.5%. Exome sequencing via semiconductor sequencing of patient germline DNA and somatic DNA from both tumours was performed. Tmap alignment and Platypus variant calling were performed followed by variant filtering and manual review with IGV software. We observed an increased load of missense variants in the recurrent PA tumour when compared to the original tumour. The number of detected variants increased from ten to 26 and potential clonal expansion of four variants was observed. Additionally, targeted SNP analysis revealed five rare missense SNPs with a potential impact on the function of the encoded proteins.HRAS is the most likely candidate inducing rapid PA progression. The relapsed PA tumour had a higher variation load and fast tumour recurrence in this patient could be caused by clonal expansion of the leftover tumour tissue.In this case study, an SNP located in  Pituitary adenomas (PA) are neoplasms of the adenohypophyseal cells with benign characteristics but without clear markers for enhanced expansion or tumour regrowth after an operation. Clinically significant adenomas are rare and affect about one in 1000 to 1300 individuals , althougBoth genetic and epigenetic factors are involved in the development of PA . HoweverGNAS, PI3KCA and USP8, as well as known familial PA genes (such as MEN1 and AIP), that often harbouring missense and nonsense SNVs in sporadic tumours [Known causal genes for sporadic PA include  tumours –15.TRIP12 and IARS had variants shared with adrenocorticotropic hormone (ACTH)-secreting PA and prolactin (PRL)-secreting PA, respectively, providing insight into potential general genetic drivers of PA development. The median somatic novel variant rate per NFPA exome was 4.3 (range 0–13) [CDH23) in a family with inherited PA, and the gene was later screened in familial PA, sporadic PA and healthy controls. The results revealed that four out of 12 families (33%) and 15 out of 125 (12%) sporadic PA patients had variants in CDH23, providing yet another candidate for the development of PA [Recently, several studies have been performed to search for novel PA variants in genomic and tumour DNA pairs using whole-exome and genome sequencing. Newey et al. in 2013 sequenced the exomes of seven NFPA and blood-derived DNA pairs. They found low levels of somatic variants, which correspond to the benign nature of PA. The average novel variant rate was 3.5 per adenoma (with a range of 1–7) and no overlapping mutated genes were found in the follow-up group consisting of 24 PA cases . A studyge 0–13) . A separnt of PA . The rolMany studies of malignant tumour types have sought to gain insight into the process of carcinogenesis using massively parallel genomics to assess several tumours from the same individual , revealing major intratumoural heterogeneity that guides tumour evolution . It has In this study, we used a rapid recurrence case of NFPA to gain insight into potential intratumoural genetic evolution within the same individual using exome sequencing of a tumour’s somatic DNA. The presented study is the first to report an exome scale profile of somatic variants in PA in a primary and recurrent tumour and indicates the contributing factors for PA clonal evolution and tumour relapse.nervus opticus right side atrophy and left side sub-atrophy.The patient was a 69-year-old female who was diagnosed with pituitary macro-adenoma in 2010. At the time of diagnosis, the patient complained of a visual disturbance. The investigation revealed bi-temporal hemianopsia, A hormonal investigation showed an NFPA. Preoperative magnetic resonance imaging (MRI) demonstrated an endo-, supra- and parasellar macroadenoma with extension into the left cavernous sinus (Knosp grade 2) with a total CC dimension of 3,86 cm and a large suprasellar component Fig. . In AuguImmunohistochemical analysis of the tumour tissue showed negative immunostaining for p53 protein expression, PRL, growth hormone (GH), ACTH, thyroid-stimulating hormone (TSH), follicle-stimulating hormone beta-subunit (FSH), somatostatin receptor 5 (SSTR5) and T-box transcription factor TBX19 (T-Pit); mild immunostaining for POU domain class 1 transcription factor 1 (PIT1); moderate immunostaining for steroidogenic factor 1 (SF1); and strong positive immunostaining for luteinizing hormone beta subunit (LH), glycoprotein hormones alpha subunit (CGA), somatostatin receptor 2 (SSTR2) and aryl hydrocarbon receptor-interacting protein (AIP). The distribution of cytokeratin-8 (CK8) was diffuse throughout the tumour, the KI-67 level was 1.5%. Haematoxylin and eosin staining of the tumour is presented in Fig. Two years later, an MRI of the pituitary gland Fig.  revealedThe patient was lost to follow-up, as she rarely attends her family doctor and does not want further special examination. A detailed description of additional clinical data, materials, methods and timeline following the CARE guidelines are presented in Additional file Final average exome (defined by UCSC Genome Browser GRCh37/hg19)  interval7/hg19  iC11orf57 from 5.3% (4 reads at 76X depth) to 24.3% (17 reads at 70X) and MED24 from 3.2% (2 reads at 62X) to 22.2% (14 reads at 63X). An additional 16 variants were found in the second tumour but not in the exome of the WBC or in the exome of the first tumour. However, it should be mentioned that six  of these 16 positions had lower than 10X coverage in the first tumour sequencing. Additionally, two genetic variants were represented in the germline DNA derived from WBC by one sequencing read of 53  and 70 , respectively, and have an expanded fraction of mutant alleles in the exomes from the PA samples.The results of the exome-wide search for missense and nonsense variants are shown in Table ALKBH8 and AHNAK, contain a variant in the first tumour. RGS14 and C5 are involved in the G protein alpha signalling pathway, and APC and PCDHGA1 are involved in the Wnt signalling pathway, but the products of ENPP1 and PTPRK possess phosphatase activity. Three variants have been previously reported in COSMIC database PCDHGA1 (COSV65295567) in three cases - one prostate, one endometrium and one large intestine tumours. CLMN (COSV54187254) has been reported in one cervical cancer sample and ZNF320 (COSV67089305) in one thyroid carcinoma sample.Gene ontology analysis revealed that three of the genes are associated with the RNA binding process and two of them, CDH23 was the only gene that has two SNPs  recognized by both algorithms as severely affecting protein function.We also performed a targeted analysis of SNPs located in a gene set compiled from the literature on PA genetics, tumour suppression and genome and exome sequencing. By searching the literature with the keywords “pituitary adenoma genetics”, “pituitary adenoma exome sequencing”, “pituitary adenoma gwas” and “tumour suppressor genes” on 15th of May 2018, a list of 403 genes was compiled  left five SNPs as the top candidates possibly contributing towards characteristics and development of PA Table . Four SNHere we present the first study performing exome sequencing of recurrent PA from the same patient. Although the remission rate of NFPA after surgery is 44,4% , to the The number of variants in primary PA is low, is consistent with the literature reported in other exome sequencing studies on PA , 26 and WDFY3, ENPP1, C11orf57 and MED24) with a low amount of the mutated reads in the germline DNA or the first tumour could be attributed to the allele-specific replication of the germline and/or the first tumour during library preparation.It is unlikely that the variants identified are the cause of the tumours either alone or in a compound fashion, and the most likely explanation is that these are somatic “passenger” variants. Four genes  that are missense and predicted to be damaging to the protein function. CDH23 encodes cadherin 23, which is involved in cell to cell adhesion [CDH23 variant p.Arg1379Leu was found in a PA-affected family, and further screening showed that 33% of familial PA patients and 125 of sporadic PA patients carry functional variants compared to 0.8% of controls [CDH23 missense SNPs (a population chance of 0.6%) could contribute to the quick PA regrowth in the patient studied via disrupted contact inhibition.A targeted study of genes compiled from the literature on PA genetics and tumourigenesis revealed several interesting facts. adhesion  and hearadhesion . Cadheriadhesion . Additiocontrols . TherefoZFYVE26, JPH2, OR5M1, NPTXR and HRAS. All SNPs were in the heterozygous state. Three of the genes JPH2, OR5M1 and NPTXR have had a somatic variant  in previous PA exome sequencing studies in the literature [HRAS could be a novel candidate that influences PA. A cosmic somatic variant (COSV54248437) found in our PA patient has been previously found in cervix cancer [The five other SNPs identified in the targeted gene search are located in terature , and furterature , but theterature  but alsoterature , bladderterature . Having x cancer . TogetheThis study has some limitations. One limitation is that exome sequencing may miss important variants outside the coding regions that may contribute to PA development. Whole-genome sequencing would overcome this limitation. Similarly, although we had good sequencing coverage in our samples, increased depth would provide more precision for variants identified in a low percentage of reads. Additional sequencing, however, is not possible due to the low amount of initial tumour material available and the division of this material for the clinical archive and other research activities. We also did not perform Sanger sequencing validation as in other cancer studies where the overall variant percentage in the tumour somatic material could be low, as these may not be detectable by Sanger sequencing , 26, 37.In conclusion, we show that in this relapse case, the regrowth of PA is accompanied by the increase of the tumour novel variant load, which could be caused by clonal expansion of the tumour leftover tissue.Additional file 1. Timeline following the CARE guidelines. Additional clinical data. A detailed description of Materials and Methods used in the study.Additional file 2. Interval file of HG19 exome coordinates. This reference exome version was used to search for variants and CNVs.Additional file 3. Document file (30 pages) describing alignment quality metrics for each sample (10 pages per sample).Additional file 4. Excel spreadsheet with the list of genes used for targeted PA genetic marker search.


This suggests that the efficacy of XRT can be optimized before treatment in order to yield longer survival times. However, while current efforts focus on optimal scheduling of radiotherapy treatment, they do not include a similarly sophisticated spatial optimization. In an effort to improve XRT, we present a method for the spatial optimization of radiation profiles. We expand upon previous results in the general problem and examine the more physically reasonable cases of 1-step and 2-step radiation profiles during the first and second XRT fractions. The results show that by including spatial optimization in XRT, while retaining a constant prescribed total dose amount, we are able to increase the total cell kill from the clinically-applied uniform case.Glioblastomas are the most common primary brain tumours. They are known for their highly aggressive growth and invasion, leading to short survival times. Treatments for glioblastomas commonly involve a combination of surgical intervention, chemotherapy, and external beam radiation therapy (XRT). Previous works have not only successfully modelled the natural growth of glioblastomas  Glioblastomas are the most aggressive, and unfortunately most common, form of primary brain tumour –5. They Non-uniform dose distributions are not a new concept in radiation oncology. Phenotypic variations across the volume of a tumour can result in differing levels of radiation effectiveness. In particular, hypoxic regions cause a difference in cell radio-sensitivity, making radiation less effective in those areas. This leads to a technique called “dose-painting” in which different regions are prescribed a different dose to combat the reduced effect  of tumour cells remaining after application of XRT; another is to minimize the tumour control probability (TCP), eN−  in addition to TCP , 13. Theρ and Dn, which describe growth and invasion processes respectively. The two mathematical models most commonly used to describe growth of tumours are the so-called exponential and logistic growth laws. The more general logistic growth naturally provides a better description of tumour proliferation and stabilization. However, during the relatively short time frame before the growth of the tumour begins to plateau, exponential growth is a reasonable approximation. Including a linear (Laplacian) diffusion term, commonly used to model tumour invasion, we arrive at the well-established equation for tumour growthd as the number of dimensions; d = 3 in three dimensions, while for certain computations we focus on the two dimensional case of d = 2. Exponential growth corresponds to a = 0, while a = 1 leads to logistic growth to a maximal density nmax.Naturally, when discussing optimization in a given system, mathematical modelling is an invaluable tool. In the context of brain tumours, mathematical models have been widely used by many different investigators . Whiρ and Dn can be estimated , leads tob = 0), andb = 1). We focus on the first and second fractions of XRT and further impose a simple upper bound for C. The final constraint on Consider a tumour that has evolved according to N(T), obtained by integrating the tumour cell density asOur goal is to determine the function eN(T)− where N(T) is the number of cells surviving the treatment. Regarding N(T) is equivalent to maximizing eN(T)−. Furthermore, for the simplest case, we indeed achieve the same result.To contrast, Brahme and Agren  instead We begin by analysing continuous cytotoxic profiles for one fraction of radiation. In the case of exponential death, the result matches that of previous studies, and from it we can derive a precise shape of the profile. In the case of logistic death, the resulting profile is more complex, but remains mathematically consistent with the previous case. A similar analysis of the second fraction of radiation is significantly more challenging as the effect of normal tumour progression must be taken into account. While it is possible, the results are far less interesting since the optimal profile will leave a uniform (or flat-topped) cell density (proof of this in supporting information). The second fraction is mathematically examined in the supporting information for the case of exponential death. The second fraction for the logistic death case.γ = Δt = 1 for convenience. Solving the resulting Euler-Lagrange equation for ρ and Dn. The appearance of the logarithm is merely a consequence of the killing effect of therapy being proportional to the number of existing cells, with the cytotoxic profile appearing in the exponent of To proceed in the case of exponential cytotoxic action, we impose the first constraint in et al . Note that we assume the lengths of the two fractions to be the same. Defining f during the separate fractions asWe next consider application of a second fraction of radiation, with dosage separately constrained on each fraction. Describing the second fraction requires introducing four new variables to fully parametrize In this section, we consider the fractions constrained individually, such thatτ between the fractions is small enough to neglect spatial migrations described by the diffusion term . If so, the density profile simply grows exponentially, by a factor eρτ without changing its spatial form, and immediately before the second fraction is given bySince our constraint on r11, r21, r12, and r22, the cell density is a piecewise continuous function. The total number N can then be obtained as before by integration, as an explicit analytic expression. For the same initial combinations of  as above, we search for the radii  that optimize the second fraction using our Monte Carlo method  are naturally the same as obtained previously in For each set of radii, Note that if diffusion is ignored, the final cell density after a second fraction of radiation is given by F′ for F′) this is exactly the search that would be performed for a single fraction with a 4-step profile. The optimal values of these parameters are given in As a final example within this class, with non-diffusive exponential growth between the two fractions, we consider the case when the overall dose is constrained, i.e. asσ, the optimal N with the single overall constraint is either better, or the same as, in the individually constrained case. From the perspective of optimization, this is not unexpected as the latter also explores the subset of the space available to the former. In view of this, the surprising result may appear to be that for σ = 1 and 2 . We are thus unable to conclude if the unequal partition of flux between the two fractions  is correct or a computational artifact .Observe that for each nd 2 see  the minia = 1 in a1, b1, and c1 are fit parameters. Logistic growth causes the tumour to form a flat-top profile as the density in the centre approaches nmax. The Gaussian density profiles employed to model the initial cell densities above are appropriate only for small undeveloped tumours. For contrast, in this section we consider density profiles resulting from the logistic growth a = 1 in . Such prWe consider the same radial step-functions as previous, and the optimization procedures are carried out in the same manner as before. The results for application of a single 2-step fraction are reported in b = 1), then some aspects of such tendency are reproduced. This qualitative behavior is important to incorporate because the vast majority of tumours exhibit some form of treatment resistance. This resistance is conferred to a tumour through heterogeneities of various traits across its volume, such as cell-type, phenotypic expression, and stem-ness. Of particular interest to radiation therapy, tumour hypoxia is a prominent feature that leads to increased radioresistance. As we will see, inclusion of logistic cytotoxic action reproduces this behavior and dramatically changes the results. We note that this is a purely phenomenological effect and not meant to describe the underlying biology at play. We make the same simplifications as before leading to the piecewise equivalent to The previously examined cases of exponential cytotoxic action do not incorporate the phenomenon of radiation having a larger effect on faster-proliferating cells than on slower-proliferating cells due to the cell’s position in the cell cycle and factors such as oxygen concentration . If we iMathematically, the results here differ dramatically from the exponential case in which the optimal profile focused the radiative strength in the center of the tumour where the cell-density was larger. With the incorporation of logistic cell death, the effectiveness of radiation in the center of the tumour diminishes. The optimal profile must now balance this with still attacking areas with high cell densities. We see that in the case with the smallest initial spread of cells, the optimal cytotoxic profile achieves this by focusing strength in a ring through the middle of the tumour. For the other two cases, the density was far more spread out initially, leading to an optimal profile which focused on cells at the outside of the tumour. This was because the effect of the logistic death was stronger than the decreased cell density.In the case of exponential death, we were able to continue our discussion and optimize the second fraction as we did the first. In the logistic death case, the computations in the optimization method become significantly more challenging. For that reason, we do not pursue the second fraction of radiation here.(i) how the tumour grows in time; (ii) how it responds to treatment; and (iii) what constraints apply to radiation dosage. Answers to all questions need to be expressed in mathematical terms, which necessitates simplifications and approximations. We have relied on assumptions and mathematical models commonly used in the literature, and hope our general results are insensitive to choice of model.In this paper we pose the question of how to spatially shape a sequence of XRT treatments to best eliminate tumour cells. To answer this question, we need to know f will not lead to optimal cell kill. Using a spatially optimized f can reduce the total number of cells within a tumour significantly from what is currently done clinically.The most important result follows from the assumption that the effect of XRT is to destroy a fraction of existing tumour cells, proportional to its strength. This assumption is embodied by the term The metric of TCP is not the only quantity that can be used to measure radiation efficacy. Others such as normal tissue complication probability (NTCP), conformity index, homogeneity index, and survival time have been used by other researchers –26. We fρ, Dn and nmax. In the various studies above, we have mostly neglected the change in the shape of the tumour between two fractions. However, this needs to be included in a more comprehensive study. Given all our results, we can propose a procedure for spatial optimization of radiation as follows:For more than one fraction of XRT, it is necessary to account for the growth of the tumour in between the two treatments. A simple commonly used model is logistic growth, depending on three parameters ρ, Dn, and nmax. The most important ingredient for shaping the optimal beam is the cell density Image tumour twice. The change in shape of the tumour can then be used to model its growth mode; e.g. in order to deduce the parameters Fn} and the time intervals between fractions, {τn}.Determine dose prescription and treatment schedule for the tumour. This provides constraints on individual and total allowed dosage, {Determine the physical limitations of the radiation apparatus; e.g. how many radial steps is the apparatus capable of accurately producing and superposing.Optimize the first radiation fraction using the above optimization procedure.Use the growth model deduced from the initial two images to model the growth of the tumour cells between fractions. The deduced cell density profile prior to each fraction can then be used as input to optimize the shape of the beam in that fraction. The assumptions on evolution of the profile after a fraction and in between fractions are likely to introduce errors. Ideally, more imaging can be done to obtain more precise cell density profiles at intermediate times.This exploratory work examines spatial variations in the shape of radiation beams, and proposes improvements to radiation therapy by shaping beams according to the pre-treatment cell-density. The advantage of this method is the opportunity to reduce the total tumour cell number below that obtained in uniform radiation. In addition to the initial tumour density profile, the method relies only on few tumour-specific parameters in order to carry out the optimization. In its current implementation, the method does not take into account other factors in radiation planning such as nearby organs at risk, scheduling, or other scoring indices used to compare dose distributions. Such factors could potentially be included in a more elaborate model, a direction that we hope to pursue in future. A major limitation of the model is the exclusion of heterogeneity across the tumour volume as tumours usually vary in cell type, stemness, phenotypic expression, and perhaps most importantly, hypoxia. Although we added a logistic cytotoxic action term to account for different radiation efficacy across the area, this is relatively simplistic and could be improved with a more thorough specification of tumour heterogeneity. Another direction that was not examined here is the interaction of this spatially-varying radiation treatment with other therapies such as chemotherapy. We hope that this exploratory work sheds light on the spatial variation of radiation beams and inspires further work in the area.S1 File(PDF)Click here for additional data file.S1 Fig(EPS)Click here for additional data file.S2 Figσ with red for σ = 1, blue for σ = 2, green for σ = 3, teal for σ = 4, and purple for σ = 5. The dots correspond to individual runs of the pseudo-spectral method.The solid lines correspond to different values of (EPS)Click here for additional data file.S3 Figσ = 1, σ = 2, σ = 3, σ = 4, and σ = 5. The red dots are those below the detectable threshold in imaging, of 5 cells/mm2, and the blue dots those above. Note the different y-axis scales to highlight the resulting shape.Cell densities resulting from the optimal radiation profiles from one 1-step fraction of exponential growth and death for the initial density deviations of (from top left to bottom right) (EPS)Click here for additional data file.S4 Figσ = 1, σ = 2, σ = 3, σ = 4, and σ = 5. The red dots are those below the detectable threshold in imaging, of 5 cells/mm2, and the blue dots those above. Note the different y-axis scales to highlight the resulting shape.Cell densities resulting from the optimal radiation profiles from one 2-step fraction of exponential growth and death for the initial density deviations of (from top left to bottom right) (EPS)Click here for additional data file.S5 Figσ = 1, σ = 2, σ = 3, σ = 4, and σ = 5. The red dots are those below the detectable threshold in imaging, of 5 cells/mm2, and the blue dots those above. Note the different y-axis scales to highlight the resulting shape.Cell densities resulting from the optimal radiation profiles from two 2-step fraction of exponential growth and death for the initial density deviations of (from top left to bottom right) (EPS)Click here for additional data file.S6 Figσ = 1, σ = 2, σ = 3, σ = 4, and σ = 5. The red dots are those below the detectable threshold in imaging, of 5 cells/mm2, and the blue dots those above. Note the different y-axis scales to highlight the resulting shape.Cell densities resulting from the optimal radiation profiles from two 2-step fraction of exponential growth and death for the initial density deviations of (from top left to bottom right) (EPS)Click here for additional data file.S7 Figσ = 1, σ = 3, and σ = 5. The red dots are those below the detectable threshold in imaging, of 5 cells/mm2, and the blue dots those above. Note the different y-axis scales to highlight the resulting shape.Cell densities resulting from the optimal radiation profiles from one 2-step fraction of logistic growth and exponential death for the initial density deviations of (from left to right) (EPS)Click here for additional data file.S8 Figσ = 1, σ = 3, and σ = 5. The red dots are those below the detectable threshold in imaging, of 5 cells/mm2, and the blue dots those above. Note the different y-axis scales to highlight the resulting shape.Cell densities resulting from the optimal radiation profiles from two 2-step fractions of logistic growth and exponential death of (from left to right) (EPS)Click here for additional data file.S9 Figσ = 1, σ = 3, and σ = 5. The red dots are those below the detectable threshold in imaging, of 5 cells/mm2, and the blue dots those above. Note the different y-axis scales to highlight the resulting shape.Cell densities resulting from the optimal radiation profiles from one 2-step fraction of logistic growth and death of (from left to right) (EPS)Click here for additional data file.


This review is a “Pro-Con” discussion about the optimal fluid volume in critically ill patients in the intensive care unit (ICU). This article argues that fluids should be aggressively managed in critically ill patients.In recent years, restrictive fluid management has been thought to be beneficial for critically ill patients. Thus, to investigate whether fluid volumes have actually been restricted in practice, fluid volumes were compared between those used in the early goal-directed therapy (EGDT) study by Rivers et al. performed in 2001 and those used in the Protocolized Care for Early Septic Shock (ProCESS), Australasian Resuscitation in Sepsis Evaluation (ARISE), and Protocolized Management in Sepsis (ProMISe) studies performed between 2014 and 2015. The later studies did not have lower total fluid volumes than those in the EGDT study. This finding shows that the importance of administering a sufficient fluid volume before admission to the ICU has become widely accepted.Fluid management strategies for critically ill patients can be divided into the following four phases: rescue , optimization, stabilization, and de-escalation. Fluid therapy administered within 6 h of presentation covers the rescue and optimization phases. Because hemodynamic instability is observed in these phases, sufficient fluid should be administered for lifesaving and organ rescue purposes. As a strategy, water may be removed during the hemodynamically stable later phase after sufficient fluid volumes were given during the hemodynamically instable early phase.Performing aggressive fluid management is important to infuse a sufficient fluid volume proactively during the hemodynamically instable early phase of a critical illness. Fluid therapy is an important treatment method for patients in shock because it improves microvascular blood flow and increases cardiac output. However, some problems related to fluid overload in the intensive care unit (ICU) have been highlighted in recent years . There iThis review is a “Pro-Con” discussion about the optimal fluid volume in critically ill patients in the ICU, and it argues that fluids should be aggressively managed in critically ill patients.According to the systematic review reported by Malbrain et al. in 2014, which included 11 randomized controlled trials and 24 observational studies, the water balance 1 week after ICU admission was 5.48 L lower in the restrictive fluid management group than in the liberal group. Mortality was also significantly lower in the restrictive group  [Fluid volumes were compared between the early goal-directed therapy (EGDT) study performed by Rivers et al. in 2001  and the p < 0.001) [The fluid management strategy for critically ill patients can be divided into four phases, namely, rescue , optimization, stabilization, and de-escalation , 9. Flui< 0.001) .The ProCESS , ARISE , and ProAs a treatment strategy, water can be removed during the hemodynamically stable later phases  after the administration of sufficient fluid volume in the hemodynamically instable early phases (corresponding to the rescue and optimization phases). The efficacy of this strategy has been demonstrated by the Fluid and Catheter Treatment Trial (FACTT) . In the Proactively administering a sufficient fluid volume is important during the early phases (rescue and optimization phases) of a critical illness, during which the hemodynamics are instable; fluid administration should not be restricted in this stage. Restrictive fluid therapy should only be started in the later phases when the hemodynamics stabilize.


In animal models, dissolved compounds in the subarachnoid space and parenchyma have been found to preferentially transport through the cortex perivascular spaces (PVS) but the transport phenomena involved are unclear.In this study two hydraulic network models were used to predict fluid motion produced by blood vessel pulsations and estimate the contribution made to solute transport in PVS and parenchyma. The effect of varying pulse amplitude and timing, PVS dimensions, and tissue hydraulic conductivity on fluid motion was investigated.3 and 10−1 respectively. Peak fluid velocity in the PVS and parenchyma tended to increase with increasing pulse amplitude and vessel size, and exhibited asymptotic relationships with hydraulic conductivity.Periodic vessel pulses resulted in oscillatory fluid motion in PVS and parenchyma but no net flow over time. For baseline parameters, PVS and parenchyma peak fluid velocity was on the order of 10 μm/s and 1 nm/s, with corresponding Peclet numbers below 10Solute transport in parenchyma was predicted to be diffusion dominated, with a negligible contribution from convection. In the PVS, dispersion due to oscillating flow likely plays a significant role in PVS rapid transport observed in previous in vivo experiments. This dispersive effect could be more significant than convective solute transport from net flow that may exist in PVS and should be studied further. Since the 1970s the perivascular spaces (PVS) surrounding blood vessels have been thought to play a role in solute transport through brain tissue, specifically as conduits for rapid transport . The PVS3 times greater that net axial flow, evidence against net convective solute transport by peristalsis.Despite discrepancies in the literature with regard to the direction of solute transport and the anatomical structures involved, strong correlation with vascular pulsatility is a point of agreement . PulsatiIliff et al.  proposedAsgari et al.  modeled In this study, a one vessel and two vessel hydraulic network model was developed to explore how pulsatility may drive fluid motion within cortical PVS and parenchyma of the rat. The one vessel model parameters such as pulse amplitude, PVS size, and tissue hydraulic conductivity were varied to predict their effect on fluid motion and solute transport. A two vessel model was also developed to study the effect of pulse amplitude and timing differences between arteries and veins in proximity. A 2D resistance network is a simple tool that captures the essential physics involved, reveals the effect of varying tissue properties, and can help validate future CFD models. Unlike previous resistance network and CFD models –20, the Δp is the pressure difference across the resistor, q is the volumetric flow rate through the resistor, and R is the reciprocal of the hydraulic conductivity, or the hydraulic resistance. The one and two vessel models were implemented and run in MATLAB R2018a .Two hydraulic network models of the PVS and surrounding parenchyma in rat cortex were developed to simulate the fluid motion produced by vascular pulsations: a one vessel model of an arteriole segment, and a two vessel model of arteriole and vein segments Fig. . The vesA cylindrical segment of a penetrating arteriole with a baseline radius of 10 μm  and its The PVS hydraulic resistance was derived from the Navier–Stokes solution for steady pressure-driven flow through a straight annulus .2\documeμ, l, Ro, and E are the fluid dynamic viscosity, the PVS length modeled by the resistor, the PVS outer radius, and the ratio of PVS inner to outer radius, respectively. Parameters and their values are listed in Table Here The parenchyma hydraulic resistance was derived by simplifying Darcy’s law for flow through rigid porous media to one-dimensional radial flow through a cylindrical shell.RoPCY, RiPCY, h, KPCY, are the outer and inner radii of the parenchymal cylindrical shell, the shell height, and the parenchyma hydraulic conductivity, respectively [Here ectively . The outVolumetric fluid sources were introduced into the network to account for fluid displaced by the arterial pulses in the cardiac cycle Fig. a. No preq, V, l, and ri are the volumetric flow rate, volume contained by the PVS inner boundary, the segment length modeled by the fluid source, and the PVS inner radius as a function of time, respectively.Here f and b are the frequency and amplitude of inner wall motion, or the pulse frequency and amplitude. Ri is the time-averaged PVS inner radius value. Substituting Eq. The inner radius varied in time according tob/Ri, the first term dominates when b is much smaller than Ri and the flow rate is approximatelyρ is the fluid density, approximately that of water at body temperature [α is small, oscillatory flow can be approximated by the steady-state profile corresponding to the instantaneous axial pressure gradient in the segment [is small . Twice tis small  and ρ isperature . When PV segment . The pulTo account for the presence of solid components in the PVS, an alternative resistance was derived by simplifying Darcy’s law for axial flow through an annulus of rigid porous media.l, Ro, Ri, KPVS, are the PVS length modeled by the resistor, the PVS outer radius, the PVS inner radius, and the PVS hydraulic conductivity, respectively.A planar portion of tissue which included segments of a cortical arteriole and vein, surrounding PVS and parenchyma were modeled as a network with 25 resistors Fig. b. VesselAccordingly, axial flow along half the PVS was modeled for the arteriole and the vein. The PVS resistances were therefore double those derived in the one vessel model because only half the annulus was available for flow.The flow rate for each venous volumetric fluid source was determined by considering the pulsatility ratio between cortex arterioles and veins where pulsatility is defined as.T is the measurement interval. Substituting Eq. b/πf. The ratio of venous to arterial pulsatility, ξ, was used to determine the venous pulse amplitude for a given arterial pulse amplitude. Substituting the venous pulse amplitude into Eq. This formulation for pulsatility is based on Iliff et al.  where T ϕ and D* are the parenchyma porosity and solute diffusivity, respectively. The Peclet number formulation for the PVS, Eq. LPVS, the full vessel segment length, and v, the average axial velocity. Two Peclet number formulations, Eqs. LPCY, the distance between the arteriole and vein [η, an estimate of the parenchyma pore size [To assess the mode of solute transport in both the models, the Peclet number was computed for the PVS and parenchyma.mentclasspt{minimaand vein , and theore size .θ, to the venous fluid production function.Parameter sweeps were conducted to explore their effect on fluid motion in PVS and parenchyma. Parameters such as pulse amplitude, PVS inner and outer radius, and PVS and parenchyma hydraulic conductivity were varied for both the one vessel and two vessel models. In addition, the pulsatility ratio and pulse timing between arterial and venous pulses were varied in the two vessel model. Pulse timing was varied by adding a phase shift, When a particular parameter(s) was varied the others remained at baseline values Table  except iThe authors use the term “oscillatory fluid motion”, “net fluid motion”, and “net flow” to refer to movement of fluid and reserve “solute transport”, “diffusion”, “dispersion,” and “convection” for the transport of solutes in the fluid medium. Oscillatory fluid motion is fluid motion that does not displace the mean position of the fluid over time unlike net fluid motion and net flow. Diffusion is the solute transport due to random molecular motion. Dispersion in this context is enhanced diffusion due to oscillatory fluid motion, and convection is solute transport along with a fluid undergoing net flow.3 μm2/s were mostly below 10−1 in the parenchyma indicating transport of physiological solutes there was diffusion dominated  in any direction. Peak fluid velocity and pressure in the PVS were about 30 μm/s and 60 mPa, respectively Fig.  a, b. Pe3 μm2/s were above 1 in the PVS , peak fluid velocity in the parenchyma droped three orders of magnitude and fluid velocity in the PVS remained of order 10 μm/s  as in many other experiments and models [−1 for a pressure difference of 1 mmHg/mm between arterial and venous PVS was recently predicted in a porous media computational model [−3 mmHg/mm  that the main solute transport mode was diffusion (Pe < 10d models , 17–19. /mm Fig. a, increa/mm Fig. e, increa/mm Fig. b becauseges Fig. c. Computges Fig. d. Delayiges Fig. f.While the results show no net flow over time in the PVS Fig. b, they dWhile the one and two vessel hydraulic resistance networks developed here are a coarse discretization of the flow domain they can nonetheless capture the effects of vessel diameter variation and tissue property changes on fluid motion within the PVS and parenchyma simultaneously. Because the parenchyma was modeled as rigid porous media, these models did not capture parenchyma deformation expected to accompany vessel volume change in vivo which might result in unsteady variation in PVS hydraulic conductivity. Non-linear, viscoelastic tissue properties might play a role in producing net fluid motion as hydraulic conductivity could vary with unsteady deformation rates during the cardiac cycle. CFD models that account for interaction between fluid–solid interfaces and viscoelastic tissue properties would provide further insight into fluid motion and solute transport.Two hydraulic network models were developed to predict the fluid motion produced by blood vessel pulsations in PVS and parenchyma. Periodic changes in vessel volume resulted in oscillatory fluid motion in PVS and parenchyma but no net flow over time. Peclet numbers indicated solute transport is diffusion dominated in parenchyma but might be enhanced by dispersion in PVS. Peak fluid velocity in the PVS tended to increase with increasing pulse amplitude and vessel size. While these results to do not rule out possible net flow in the PVS due to unsteady PVS hydraulic resistance and non-linear tissue properties, they do encourage further investigation into dispersion as an alternative mechanism for rapid solute transport in PVS.


There were no significant differences between clean eating and control recipes with respect to the energy , carbohydrate , sugar , and sodium content . Less than 10% of clean eating and control recipes met the WHO constraints for proportions of energy from fat and sugar intake. A simulated nutrient profile of an average clean and control recipe shows that nutrients for both are similarly classified as moderate to high in fat, saturated fat, salt, and sugar. Foods with clean eating claims contained the same amount of energy, sugar, and sodium as foods without those claims. Clean eating claims are potentially misleading for consumers who may believe these foods are healthy alternatives, potentially undermining people’s efforts to eat a healthy diet.Food blogs are an increasingly popular source of information about food and nutrition. There is a perception that foods published on clean eating blogs, which promote unprocessed foods, are healthier than comparable foods without these claims. However, foods with these claims and their nutrient composition have not previously been evaluated. The purpose of the study was to describe the nutritional content of clean eating recipes compared to recipes without clean eating claims and the nutritional guidelines published by the World Health Organisation (WHO). Clean eating recipes were systematically selected from 13 popular clean eating blogs and were described and compared with control recipes without clean eating claims. The nutrient profiles from the included recipes were summarised and evaluated against criteria from WHO recommendations for chronic disease prevention and criteria from the U.K. Food Standards Agency. Data for 86 clean eating recipes were extracted that represented five food categories: breakfast, snacks, treats, desserts, and smoothies. These were matched with 86 control recipes without clean eating claims. The clean eating recipes, per portion, provide the equivalent of 15% of daily energy intake. The average serving sizes were not significantly different between clean eating and control recipes. Overall, the clean eating recipes contained significantly more protein (8.1 ± 7.3 g vs. 5.7 ± 4.1 g,  In recent years, millions of people have turned to the Internet as a rapidly accessible source of health information, including information about diet. Websites and blogs devoted to food and nutrition have become increasingly popular, especially blogs promoting clean eating. Clean eating can be defined as choosing whole and minimally processed foods, and limiting consumption of artificial or processed foods . Clean eClean eating blogs are not usually authored by people qualified to give individual nutrition advice, with the majority of bloggers writing because of their passion for food ,4. DespiNo previous research has investigated the influence that this online information may have on people’s understanding about the healthfulness of foods. Ho and Chang Chien  found thThere are also concerns regarding the scientific validity and safety of some of the nutrition advice found on social media content, particularly regarding the encouragement of dietary restraint and restrictive eating patterns that focus on the elimination of many foods ,9. The iThere has only been one other analysis of the nutritional content of recipes published on food blogs, but none to date have looked at clean eating blogs. The authors found that the recipes on popular food blogs exceeded recommendations for daily sodium and saturated fat intake . There hEvaluation of the recipes presented on clean eating blogs is important for a number of reasons. Clean eating emphasises restrictive eating practices of varying intensity. In some cases, extreme dietary restrictions may adversely affect an individuals’ nutrient and energy intakes over time, especially among vulnerable groups . No prevTo address this gap, we evaluated the nutritional content of foods from clean eating blogs online and compared them to the nutritional content of foods without clean eating claims, using recommendations for chronic disease prevention published by the World Health Organisation (WHO) . We alsoWe performed a cross-sectional content analysis to examine the nutritional values of recipes found on popular clean eating blogs. Following the search methodology used previously by Boepple and Thompson , web seaUp to eight recipes were selected from each of the final 13 blogs. These met the criteria of being classified as breakfast recipes, snacks, smoothies, desserts, and treats and were posted within the previous 12 months. The categories selected represented the most popular types of recipes for foods promoted on clean eating sites. We did not consider other main meal categories or recipes as these were not a common feature or category of foods published on clean eating blogs. Any recipes for special occasions, e.g., birthdays or holidays such as Christmas and Easter, were excluded.A separate systematic search was conducted using Google to match and select control recipes for analysis based on recipe names within each food category. Using the name of the clean eating recipe, we conducted a search using Google with the keywords in the recipe as search terms. For example, for a clean recipe labelled “raw chocolate cheesecake”, the search terms, “chocolate cheesecake recipe” were used. The first page of the results was captured and the recipes were selected if they were the highest-ranking recipe returned on the first page of results. Recipes were screened for eligibility and included if they did not describe a diet or food philosophy on the blog or website they were published on . Overall, 86 recipes were matched across the five categories of recipes.A total of 172 recipes were included for analysis (86 clean eating recipes and 86 control recipes). For each recipe, information was collected about the type and quantity of ingredients and serving sizes. The information was entered into FoodWorks  for analysis. Foods were standardised as much as possible when entering the recipes to ensure similarity across the recipes for the nutrition analysis and comparison. For example, peanut butter was listed in recipes under several different names, so the same brand name was entered into FoodWorks. Proprietary foods and foods not found in FoodWorks databases, such as a brand name protein powders, had nutrient information imputed using the branded nutrient content information published online. The recipes were rechecked (by M.S.W.) after entry to ensure accuracy.t-tests to compare the difference in nutrient content per serving for each recipe. Using Chi-squared tests, we compared the percentage contribution to daily energy and other key nutrients such as sugar, total fat, saturated fat, and sodium per serving, referring to guidelines published by the WHO for chronic disease prevention [n or (%) for frequencies and mean ± standard deviation where normally distributed and p < 0.05 was considered statistically significant. Statistical analyses were conducted using IBM SPSS version 22 .For each recipe, we calculated the nutritional content per serving by dividing the total recipe by the number of servings described in the recipes. We used independent evention . For eacevention . This syn = 10), one was authored by a male and female couple, and two blogs were authored by multiple people. The blogs were predominantly from the United States (n = 9), followed by Australia (n = 1), and the U.K. (n = 1). Geographic locations could not be determined for two of the blogs. Of the 86 clean recipes selected for analysis, 12.8% were classified as breakfast recipes (n = 11), 12.8% as desserts (n = 11), 29.1% as treats (n = 25), 33.7% as snacks (n = 29), and 11.6% as smoothies (n = 10). A comparison of the most frequent ingredients used in the clean and control recipes is reported in A total of 172 recipes were selected for analysis across five product categories. The majority of the clean eating blogs was authored by one woman only  among the clean eating recipes. The higher protein and fibre content of the clean recipes may have implications for appetite and body weight. In epidemiologic studies, higher fibre intakes are associated with lower body weight ; howeverWe speculate that consumers may infer health benefits about foods labelled as “clean” because of a “halo” effect. This refers to a consumer tendency of inferring health benefits above and beyond attributes that the claim communicates . The halAs clean eaters tend to fixate on the techniques and ingredients used in food preparation, consumers may perceive foods in their more “natural” state to be healthier and to contain fewer calories than the same food that has been processed mechanically. This was evaluated in a series of studies by Szocs et al. , who tesOne of the strengths of this study was the systematic process used to select popular clean eating blogs. The sampling method was based on previous methods used for the content analysis of healthy living blogs . We sampIt is important to note that the we evaluated the nutrient composition of recipes consumed as a single food, not that of meals or the daily intake of food of an individual, which would comprise combinations of multiple foods. Therefore, the comparison of the recipes according to the percentage of energy from macronutrients should be viewed with caution. Depending on what other foods an individual usually consumes over the course of a day, their overall intake may fall within these constraints.We did not impose any geographic restrictions on the blogs eligible for inclusion in the study. However, the final sample featured blogs published mainly in the U.S.A., so findings may not be generalisable to other countries. The average serving sizes within a food product category did not significantly differ, so it was appropriate that the nutrient content of the recipes was comparable per portion consumed.This research provides important information about the health and nutrition information landscape on social media and the web, which is an increasingly popular avenue the general public are turning to for advice. It can inform practitioners and policy-makers about some of the messages on social media and some of the information being circulated. In turn, this can inform health promotion strategies for communicating messages about food and nutrition. This research is useful to clinicians trying to understand the healthfulness of popular health and nutrition content online so they can better inform and educate their patients about the quality of the information available. It also highlights an opportunity for health professionals to harness the influence of social media/online space to provide credible nutrition information. There may be some lessons to learn from bloggers on how health professionals can effectively communicate with consumers as trusted sources of information. The clean eating recipes evaluated had a small, but significantly higher protein, fat, and fibre content than foods not published on clean eating blogs, but were similar in overall energy and sugar content. As such, following clean eating recipes is unlikely to confer any additional health benefits to the average person. The consumption of processed and discretionary foods needs to decrease at a population level and clean eating alternatives promoted online may not represent healthier alternatives.


In the paper by Ning et al. , a fundiThis work was supported by the Fundamental Research Funds for the Provincial Universities; the Scientific Research Fund of Harbin Medical University‐Daqing (Grant No. DQXN201706); the National Natural Science Foundation of China (Grant Nos 81572341 and 61601150); the Natural Science Foundation of Heilongjiang Province (Grant No. JJ2016ZR1232/F2016031); Yu Weihan Outstanding Youth Training Fund of Harbin Medical University; Wu Liande Youth Science Research Fund of Harbin Medical University (Daqing) (Grant No. DQWLD201703); Innovative Scientific Research Fund of Harbin Medical University (Grant No. 2016JCZX03); and the National Science Foundation of Heilongjiang Province (Grant No. YQ2019C013).


In this paper, the correlation coefficients and the total scattering cross sections (TSCSs) for different types of metasurfaced stirrers and the traditional metallic stirrer, and the effects on field uniformity when such stirrers are used in reverberation chambers, are analyzed. Three metasurfaced stirrers are considered: A stirrer with two unit cells arranged alternatively (#1), a stirrer with two unit cells arranged in a chessboard-like manner (#2), and a stirrer with two unit cells in random arrangement (#3). From the correlation coefficient and TSCS results obtained in simulations, it follows that metasurfaced stirrer #1 is the best option. Field uniformity analysis of the resulting metasurface reverberation chambers (MRC) equipped with the different stirrers also supports this conclusion. In general, a reverberation chamber (RC) consists of a metal shielded chamber containing stirrers, antennas, a piece of equipment under test, as well as other devices. Formally, an RC can be defined as an electrically large, high quality factor (Q), multimode cavity that uses mode stirring to create changing boundary conditions in order to obtain a statistically uniform electromagnetic field ,2. RCs, In the past, many efforts have been focused on trying to optimize the performance of metallic stirrers in conventional RCs. Mainly through the application of empirical techniques and common sense, heuristic guides, which define and adopt many design criteria, have been proposed. For instance, stirrers should be greater than or equal to the wavelength of the lowest usable frequency (LUF), stirrers should be shaped such that a non-repeating field pattern is obtained in one rotation, etc. In this sense, references ,9,10,11 Despite the efforts directed towards stirrer optimization, certain limitations and constraints arise in real-life scenarios . To date, few efforts have been concentrated on alternative stirring methods which may provide a solution to the previous limitative aspects. In this regard, the concept of a metasurfaced reverberation chamber (MRC), with stirrers based on metasurfaces, has been recently proposed  as an alIn , we usedIn this work, we study and compare three different types of rotating metasurfaced stirrer  on the basis of their influence on RC performance. The key performance indicators are the correlation coefficients and total scattering cross section (TSCS).λ = 0.375 m, where λ was the wavelength of the LUF . It was at least half a meter from all other metallic surfaces and it remained the same for all the simulated configurations, for the sake of comparison, even though for some analyzed configurations it could have been greater.The simulated RC was 1.2 m long, 0.8 m wide, and 1.2 m high, with a transmitting antenna as shown in The considered metasurfaced stirrers in the present study were based on two types of unit cells, with “0” and “π” phase responses to mimic the “0” and “1” elements of the 1-bit digital coding metasurface . The de® . The different stirrers generated a diffuse far-field scattering pattern, as depicted in In order to analyze the scattering characteristic of the stirrers, we first simulated the far-field pattern of the stirrers by means of CST Microwave StudioTo evaluate whether a stirrer provides independent field conditions for the different rotation positions, the correlation coefficient is the key parameter. It is assumed that uncorrelated stirrer positions yield independent field conditions . Thus, t®  was employed. Nevertheless, the theoretical foundations of TSCS are given as follows. The expression giving the mean value of the E-field ηE(t)  over the sources α , probes β  and over the various object locations γ  at time t, is as follows [The TSCS reveals an interesting criterion to quantify the target scattering ability. In the EMC regard, the TSCS of an RC provides an indication of the capability of the chamber to generate statistical field uniformity, through stirring efficiency ,18,19,20 follows :(1)〈〈Eη and c is the speed of light in vacuum. After rewriting (1), we can define the ratio C(t) as follows:The TSCS can be inferred from the scattering damping time sτ can be linearly derived from relations (1) and (3) according to:C(t) is inferred through the CST simulation.Therefore, the scattering damping time C(t) corresponding to the four stirrers . After the estimation of the damping time (sτ), the TSCS was computed for the four stirrers . Note that for a high Q cavity, waves outperform many bounces within the cavity before they decay. Thus, the higher the Q value, the longer the sτ [sτ is associated with significant stirring. From the results of C(t) of stirrers #1 and #3 reduces sharply, as compared to the metallic stirrer and stirrer #2. In other words, the stirrers #1 and #3 exhibited better TSCS and stirring efficiency. Note that sτ can be extracted from the least-square fit of the logarithm of C(t) in (3) [2 , 0.195 m2 (metasurface stirrer #1), 0.123 m2 (metasurface stirrer #2), 0.189 m2 (metasurface stirrer #3). In r the τs . In othe) in (3) ,24, thusTo further verify our optimization results for the metasurfaced stirrers, some standard EMC tests  were carIn this paper, we have analyzed the effects of introducing different types of metasurface stirrers in reverberation chambers, compared to the traditional metallic stirrer. Three metasurface stirrers have been studied: one with two unit cells arranged alternatively (#1), another one with two unit cells arranged in a chessboard-like manner (#2), and a third one with two unit cells in random arrangement (#3). From the correlation coefficient and TSCS results obtained, we can conclude that the field uniformity is somehow improved for the RC with metasurfaced stirrer #1. Since this stirrer is comprised of a metasurface with negligible volume , the test volume of the RC is significantly extended. The volume extension is dependent on the dimensions of the mechanical stirrer.


In both tables, the sample sizes should not have appeared in the headings for the first 2 data columns, and the word “unweighted” should not have appeared in the spanning heading above those columns because the data are weighted. This article has been corrected.1In the Original Investigation titled “Patterns in Outpatient Benzodiazepine Prescribing in the United States,”


Instead of “[grant no. (2019) 1209], it should have been written as “[grant no. (2019) The authors apologize to the funders of their research project, and to the readership of the Journal for any inconvenience caused.


Social media is increasingly playing a critical role for direct communication. One such example is Twitter, which is an online social media networking and microblogging service that enables users to send and read short 140-character messages called “tweets.” Registered users can read and post tweets, but unregistered users can only read them. The conversations on Twitter are often formed around hashtags (#) that can enable connections between people, foster the effective sharing of ideas, and help entire online communities form and flourish. As the fastest growing social media site , TwitterFigure 1 .Notably, we are facing a new era of communication. Whereas previous shifts included the telephone, which enabled one-to-one communication possible; the television, which ensured broadcasting to millions of people; and the Internet, which gave us access to countless websites; social media and Twitter, in particular, represents a new wave. With social media, it is possible to select people to follow and to receive direct messages as part of mass communication and stages of communication that are partly public and transparent and partly private. Furthermore, a vast amount of communication takes place in networks and the communication is briefer. People can choose large networks with shorter, more to-the-point conversation, rather than smaller networks with longer conversations. Lastly, communication channels have opened radically, providing open channels to, for instance, world leaders. It means people are reachable in more ways than ever . TwitterIn recent months, we have experienced how “twiplomacy” has become of utmost importance in the political landscape. Twiplomacy refers to the use of Twitter and other social media sites by government agencies and officials to engage with the public, disperse information, and even leverage global influence. The term was coined by Burson-Marsteller, who studied world leaders on Twitter and attempted to illustrate how social media is closing the gap between these leaders and the public they serve . For insTwitter, as a ground-breaking microblogging site, can be regarded as a powerful tool for democracy  and disAn example could be when new health care reforms are discussed regarding the impact of the shift from “Obamacare” to “Trumpcare.” Along these lines, research suggests that users searching for health information on Twitter would need certain literacy skills to interpret it correctly , and tweWhen Twitter received an award for societal impact in 2013, it was stated that “Twitter is the pulse of the planet” . Hence, Taking the recent developments in the policy arena into account, there is no doubt that health literacy, in particular, health twitteracy and eHealth literacy, defined as the ability to seek, find, understand, and appraise health information from electronic sources and apply the knowledge gained to addressing or solving a health problem , will be


Surgery is the initial and most important mode of treatment for glioma, the most common primary brain tumor. The greatest possible extent of resection and preservation of neurological functions are both the primary goals, although they tend to be in the trade-off relationship. Several surgical adjuncts have been developed for maximal safe resection, which include electrophysiological monitoring, navigation system, intraoperative imaging, and fluorescent probes. Intraoperative imaging such as MRI and ultrasound tend to overcome inacuracy due to brain shift during tumor resection. However, these devices tend to be costly. In contrast, fluorescent probes can be implemented to surgery by simply attaching an excitation and emission filters to a preexisting microscope, achieving high versatility with low cost. Fluorescence-guided surgery has been proven effective for radical tumor resection; fluorescent probes effectively visualize the tumor intraoperatively.Fluorescence probes are useful indicators for biologically relevant targets, being sensitive, rapidly responsive, and capable of affording high spatial resolution via microscopic imaging without destroying structures . In surgThree types of fluorescent probes are in use in neurosurgical procedures: 5-aminolevulinic acid (5-ALA), indocyanine green (ICG), and fluorescein sodium . ICG andp = 0.0003). The complete resection rate of contrast enhancing tumor in the fluorescence-guided surgery group compared favorably with that in the conventional surgery group . They have shown that the use of 5-ALA resulted in a higher complete resection rate and a longer progression-free survival. Of note, no significant differences in overall survival, neurological deficit, or toxic effects were noted between the two groups. 5-ALA is now routinely used in clinical practice for high-grade glioma surgery. On the contrary, it fails to identify low-grade gliomas. There are some limitations in its use as well, which would include false positivity, false negativity, the need for preoperative oral administration, and the inability for re-administration  probes as activatable fluorescent probes for rapid cancer detection with topical spray . They arirmation –18.These HMRG probes can be applied for the detection of a brain tumor. Some probes fluorescence glioma tissue more than the surrounding normal brain tissue after their topical application . The bigWe believe that these novel fluorescent probes have a potential as probes complementary to 5-ALA in high-grade glioma surgery. As discussed earlier, 5-ALA is highly effective and routinely administered for resection of high-grade gliomas, but these probes would be worth a try when the tumor does not fluorescence with 5-ALA or when 5-ALA fluorescence has significantly diminished at the end of tumor resection. In addition, they would be a breakthrough in low-grade glioma surgery, where 5-ALA is largely ineffective. Moreover, they are potentially applicable to virtually all types of brain tumors including malignant lymphoma and brain metastasis, which are the top differential diagnoses of glioma. Novel HMRG probes which specifically detect malignant lymphoma or brain metastasis are currently under investigation. Last but not the least, a larger clinical study is warranted to assess the clinical utility of our probes in brain tumor surgery.YKi, ShoT, MK, and YU wrote the manuscript. YKu, KY, AO, TN, RM, TK, TH, SatT, MN, ShuT, AM, and NS carefully reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cancer immunotherapy has experienced remarkable advances in recent years. Striking clinical responses have been achieved for several types of solid cancers  after treatment of patients with T-cell checkpoint blockade therapies. These have been shown to be particularly effective in the treatment of cancers with high mutation burden, which places tumour-mutated antigens (neo-antigens) centre stage as targets of tumour immunity and cancer immunotherapy. With current technologies, neo-antigens can be identified in a short period of time, which may support the development of complementary, personalized approaches that increase the number of tumours amenable to immunotherapeutic intervention. In addition to reviewing the state of the art in cancer immunotherapy, we discuss potential avenues that can bring the immunotherapy revolution to a broader patient group including cancers with low mutation burden. In the late nineteenth century, William Coley treated cancer patients by local injection with bacterial toxins, which provoked anti-tumour immune responses in some patients . In the The transition to targeted immunotherapy was made with the development of the hybridoma technology, in 1975, which supported the production of monoclonal antibodies . RapidlyMore recently, a number of antibodies targeting cellular immune checkpoints (e.g. PD-1/PD-L1 and CTLA-4) have been developed to promote the activation of T cells and subsequent tumour control. This treatment strategy has been shown to be particularly effective in tumours with high mutation burden, putting tumour-mutated antigens (neo-antigens) centre stage in cancer immunotherapy –19.2.+ T cells [+ and CD8+ T cells [+ (cross-presentation) and CD4+ T cells, respectively [Antigen processing and presentation enables the immune system to monitor cellular processes and to act accordingly upon expression of aberrant/foreign proteins. Human leukocyte antigen (HLA) class I molecules present antigens at the surface of most cells throughout the organism. Such antigens can, theoretically, be derived from most cellular proteins as these are processed by the (immuno) proteasome and broken down to peptides . Subsequ T cells . Neverth T cells . In ordeectively . HLA claectively ,27.Antigens that are considered to evoke anti-tumour immune responses and which are therefore suitable as immunotherapeutic targets can be divided into three groups: tumour-mutated antigens (or neo-antigens), tumour-associated antigens and cancer-testis antigens . Viral apassenger mutations which are highly variable between cancers and patients [In silico tools aiming at identifying neo-antigens more likely to constitute good immunotherapy targets are also under constant development [Neo-antigens are by definition tumour-specific as they arise from somatic mutations that are not present in healthy tissue. Theoretically, they constitute ideal targets for immunotherapy because no off-target reactivity and central tolerance of T cells are expected . The accpatients . The development –44.BRAF and KRAS, accumulated evidence suggests that such mutations are seldom immunogenic [The requirement of a personalized approach to target neo-antigens can be a time-consuming and onerous procedure. While this limitation could be circumvented by the targeting of recurrent mutations at driver genes such as unogenic ,46. In funogenic ,48. On tunogenic . Anotherunogenic . However3.T cells are key players in anti-tumour immunity and, therefore, the bulk of cancer immunotherapy research has focused on inducing T-cell-mediated anti-tumour responses. The current breakthrough in cancer immunotherapy results from the identification and subsequent targeting of checkpoint mechanisms in T cells with antibodies against CTLA-4, PD-1 and PD-L1 –53. CTLA+ T cells to fulfil their cytotoxic activity, they must infiltrate tumour tissues and subsequently recognize cancer antigens loaded on HLA class I molecules. Therefore, defects in the antigen processing and presentation machinery are often observed as immunoediting phenotypes in tumour cells [IFNGR1/2, IRF1 and JAK2 [JAK1/2 [Treatment with checkpoint blocking antibodies has been approved for a number of cancers including melanoma, urothelial bladder cancer, head and neck squamous cell carcinoma, non-small cell lung cancer and classical Hodgkin lymphoma, while positive indications has been found for many other malignancies ,58–62. Iur cells –69. Addiand JAK2 . Similar [JAK1/2 ,72. Neo- [JAK1/2 ,74.ex vivo expansion of tumour-reactive T cells and their reinfusion back in the patient [et al. reported on the successful treatment of a metastatic melanoma patient with CD4+ and CD8+ tumour-specific T cells [+ T-cell product derived from TIL, resulting in stable disease [a priori which patients may benefit from it.Spontaneous, neo-antigen-driven, anti-tumour responses arise in many cancer patients, as demonstrated by the isolation of neo-antigen-reactive tumour-infiltrating lymphocytes (TIL) . Further patient . The inf patient ,80. ACT- patient ,80–83. V T cells ,80. In a disease . These fToday, many ongoing clinical trials are investigating the clinical effect of combining different immunotherapies. The use of anti-CTLA-4 in addition to anti-PD-1 antibodies resulted in increased overall survival rates in previously untreated melanoma patients ,85. Furt+ and CD8+ anti-tumour T-cell responses against several epitopes. Four out of six patients had no recurrence after 25 months; two patients with tumour recurrence received subsequent anti-PD1 therapy leading to complete tumour regression [TP53) with recurrent mutations [passenger mutations.Other avenues like therapeutic vaccination with synthetic peptides corresponding to neo-antigens are being explored. This strategy aims to prime autologous T cells from cancer patients against tumour-specific antigens to unleash anti-tumour immune responses. In addition to providing neo-antigens as immunotherapy products, several co-stimulatory factors are needed to induce an effective anti-tumour T-cell response , includigression . In anotgression . Both vagression ,100. Nevutations . Therefoζ signalling domain for T-cell activation. Investigations in larger cohorts showed clinical responses [The requirement that neo-antigens are presented in complex with HLA class I hinders the widespread application of neo-antigen-targeted therapies in the form of peptide vaccination or ACT. Therefore, CAR T cells were designed to enable the targeting of any cell surface molecule, in an HLA non-restricted fashion . This stesponses ,103, butesponses –106. Theesponses ,108. In esponses –112. Furesponses ,113,114.esponses . On the 4.As discussed, neo-antigens constitute attractive targets for immunotherapy and clinical responses with checkpoint blockers have been correlated to the mutation burden of tumours ,62. CancMedulloblastoma, the most common brain tumour in children, has a low mutation burden, but was found to upregulate IDO1 expression . IDO1 en5.et al. [in silico prediction models for antigen processing and HLA binding affinity might not be necessary for a first T-cell reactivity screening using long peptides, because the number of mutations is low and all neo-antigens can be tested for their ability to induce T-cell activation. However, to directly investigate T-cell reactivity against short peptides, in silico tools are still required.Previous works by Tran et al. ,127 suppet al. ,127,128.Immunotherapies have a high synergistic potential with standard chemo- and radiotherapies as these are known to induce immunogenic cell death ,130. Thi+ T-cell infiltration in ovarian cancer and the immunogenicity of colorectal cancer cells was increased upon treatment with DNA-demethylating agents [Another avenue that may lead to the sensitization of additional tumours to immunotherapeutic intervention is epigenetic modulation of cancer cells . Epigeneg agents ,147. EpiAnother obstacle to employing immunotherapies for the treatment of tumours with low mutation burden relates to the fact that they are usually poorly infiltrated by immune cells. The initiation of an adaptive anti-tumour immune response probably relies on a robust inflammatory trigger that is absent in poorly immunogenic tumours. On the other hand, such inflammatory threshold in tumours with high mutation burden is most likely reached due to the abundance of mutated antigens. A strategy to artificially induce an inflammatory response that complements immunotherapeutic approaches is oncolytic virotherapy . Talimog6.et al. 2018, unpublished data). These findings underscore the relevance of developing neo-antigen targeting immunotherapies for low mutation burden tumours by tuning anti-tumour inflammatory responses. ‘Cold’, poorly immunogenic, tumours will require rationale-based interventions that make use of combinatorial therapies, including radio/chemotherapy or oncolytic viruses, to switch cancer immune microenvironments to a ‘hot’ state.Immunotherapy, particularly checkpoint blockade, can induce robust and durable anti-tumour responses in a significant proportion of patients, predominantly when applied for the treatment of cancers with high mutation burden. Until today, the applicability of these treatments for other cancer types is very limited. During the last decade, different groups have demonstrated the possibility of identifying neo-antigen-targeted immune cell repsonses in tumours with intermediate/low mutation burden. Recent work in our laboratory confirms that neo-antigen-reactive T cells are present in low mutation burden, mismatch repair-proficient colorectal carcinomas (van den Bulk


Correspondingly, the microstructures of the samples, including the phase fraction, crystal size, orientation factor, fibril radius, fibril length and misorientation angle, have been investigated. It was fortunate that the supercritical carbon dioxide fluid could be used as a medium during the hot-stretch process to improve the mechanical performance of F-III fibers, although the treatment temperature was lower than the glass transition temperature of the F-III fibers.F-III fibers were treated at different pressures in supercritical carbon dioxide fluid and all samples including untreated and treated F-III fibers were characterized by a mechanical performance tester, wide-angle X-ray scattering and small-angle X-ray scattering. By studying the relationship between mechanical performance and microstructural changes of the samples, it was found that microstructural change was the main cause of variation in mechanical performance. Results revealed that the maximum tensile strength and modulus of F-III fibers were acquired at 14 MPa within the pressure range of 8 MPa to 16 MPa when the temperature, tension and time were 250 °C, 6 g·d The discovery of high-performance product named aramid fibers (AFs) has brought infinite vitality to military, aerospace, electronic appliances, cables, sports equipment, fiber reinforced matrix composites and other excavated and unexcavated application fields ,2,3,4. AHot-stretch treatment of AFs has been studied by many researchers in the last few decades. In this process, the improvement of the mechanical performance of AFs mainly lies in the amelioration of the microstructure. For instance, Ran and Lee ,8 pointe2) fluid is famous for its excellent swelling and plasticizing characteristics [2 fluid to carry the hexamethylene diisocyanate into the amorphous regions of AFs to improve tensile strength and modulus [2 fluid could enhance tensile strength and elastic modulus of polyethylene terephthalate fibers [2 fluid, which is not available in other media [2 fluid at temperatures lower than the Tg of F-III fibers.Supercritical carbon dioxide  with a purity of 99.99% was purchased from Sinopharm Chemical Reagent Co., Ltd., Shanghai, China.The untreated F-III fiber made up of 150 monofilaments with the denier of 44 tex and the Tg of 275 °C was provided by Inner Mongolia Aerospace New Materials Technology Co., Ltd., Inner Mongolia, China. Carbon dioxide  reflections, the value of the constant k is 1, λ is 0.124 nm, β is the integral width of the reflection peak and θ is the half value of the diffraction angle. Similarly, the orientation factor of specific crystal planes was referenced in Herman’s equation reported by Yu et al. [c is the orientation factor of the crystal plane, ω is the angle between the c-axis crystal unit and the fiber axis, (cos2ω) is the orientation parameter for the reflection (110), and (cos2ω110) can be determined by Equation (3):110 is the azimuthal angle of (110) reflection and I (β110) is the intensity of the azimuthal angle of (110) reflection.Wide-angle X-ray scattering (WAXS) measurement was performed on a beam line (BL14B) at Shanghai Synchrotron Radiation Facility. The wavelength dimension of the X-ray was 0.124 nm and the distance between the detector (Mar 345) and the sample was 120.5 mm. The crystal, mesomorphic and amorphous fractions of each sample were acquired from the 2D WAXS pattern analyzed by Xpolar software which was purchased from Precision Machinery Co., Ltd., NY, USA. The average crystallite size was calculated according to the Scherrer equation reported by Gupta , as showu et al. , as presf is the length of the fibrils in F-III fiber, Bφ is the angle between the scattering object and the fiber axis, s is the scattering object, and s is acquired using s = 2sin θ/λ, Bobs is the full width at the half maximum of the azimuthal profile.Small-angle X-ray scattering (SAXS) measurement was performed on a beam line (BL14B) with the same wavelength dimension as WAXS. The distance between the detector (Mar CCD 165) and the sample was 1950 mm, which was different from the WAXS measurement. The resulting analysis of the SAXS pattern was also performed by Xpolar software and the radiuses of scattering objects in F-III fibers were calculated according to the paper written by Guinier and Fournet , as revey Ruland , as depi−1 at the College of Textile, Donghua University, Shanghai, China. The average values of these parameters were chosen from at least 30 effective data. The units of tensile strength and modulus were converted using Equation (6):−1 are two kinds of representations of tensile strength and modulus units. The value of ρ was 1.44 g·cm−3.Mechanical performance including tensile strength, modulus, and elongation at break was tested using a single-filament strength tester named XQ-1A  which had a gauge length of 20 mm and a speed of 10 mm·min−1 and a time of 40 min in Sc-CO2 fluid.The 1D WAXS patterns of all samples in the direction of equator and meridian are displayed in 2 fluid could dissolve in fiber interiors, increase the free volume of fibers [2 fluid played a plasticizing role [2 fluid [2 fluid played a leading role within a certain pressure range, however, the static pressure could not be ignored beyond a certain pressure [The qualitative calculations of phase fractions and crystallite sizes of (110) and (002) crystal planes as well as orientation factors of (110) and (002) crystal planes are shown in f fibers , reduce ing role ,32 and sing role ,34,35. H[2 fluid . Howeverpressure . Crystalpressure ,39. It c2 fluid was gradually enhanced as the pressure increased, and the molecular chains of fibers moved and rearranged along the direction of the external force, so the degree of orientation of crystal was gradually increased. However, the Sc-CO2 fluid would inhibit the movement of molecular chains when the pressure was too high.The crystalline size of (110) crystal plane in the equatorial direction showed an upward trend within the pressure range, while the crystalline size of (002) crystal plane in the meridional direction decreased continuously. This was because the particles grew naturally without tension in the equator, while the particles were restricted under certain external forces along the meridian. On the whole, the crystal particles with large sizes tended to be acquired along the fiber axis. The variation tendency of particle sizes could also reflect the change trend of crystallinity to a certain extent. The orientation factors in The fibril radius, fibril length and misorientation angle calculated from SAXS patterns are displayed in 2 fluid. The maximum tensile strength and modulus were obtained at 14 MPa, which were 4.8 GPa and 100.3 GPa, respectively. Unfortunately, the tensile strength and modulus began to fall when the pressure rose to 16 MPa, and the change tendency of mechanical performance corresponded to the variation trend of crystallinity and degree of orientation. The elongation at break, as an important index to evaluate the toughness of fibers, is shown in The tensile strength, tensile modulus and elongation at break of all samples are presented in 2 fluid when the temperature, tension and time were 250 °C, 6 g·d−1 and 40 min, respectively. Throughout the full text, results showed that tensile strength increased from 1.2 GPa to 4.8 GPa and tensile modulus increased from 41.7 GPa to 100.3 GPa when the pressure was 14 MPa. The WAXS results showed that crystallinity increased from 37.12% to 49.38%, the orientation factor of crystal of (110) crystal plane increased from 79.43% to 92.17% and the orientation factor of crystal of (002) crystal plane increased from 83.18% to 94.37% at 14 MPa. Overall, Sc-CO2 fluid can be used as a medium to improve the mechanical performance of F-III fibers, although the temperature needs to be lower than the Tg of F-III fibers.In this paper, F-III fibers were treated with pressure ranging from 8 MPa to 16 MPa in Sc-CO