Based on the bibliometric method, the toxicity of aconite is analyzed and evaluated.  Studies on the toxicity of aconite were retrieved from CNKI, CQVIP, Chinese Biomedical Literature Service System, and PubMed, ranging from January 1985 to November 2020. All those studies were formed into the Database of Literature of Toxicity of Aconite (DLTA). Studies on the toxicity of aconite were retrieved from CNKI, CQVIP, SinoMed, and PubMed, respectively. Collecting relevant information in DLTA, we analyzed the hotspots, factors and mechanism of aconite toxicity, and attenuation methods.  A total of 445 studies on the toxicity of aconite have been collected. “Compatibility attenuation” and “Processing attenuation” have been the hotspots of aconite toxicity in recent years. Many studies support that the main toxic reactions of aconite are heart damage, liver toxicity, nephrotoxicity, and neurotoxicity. The toxic effect of aconite is related to the effect on the central nervous system. Exciting the vagus nerve reduces the autonomy of the sinus node and damages myocardial cells. The decoction time, dosage, and administration of aconite are the main factors of the toxicity of aconite. There are few studies about the effect of the origin of aconite and the specifications of the medicinal materials on toxicity. Therefore, it is impossible to analyze its relevance. At present, the commonly used methods to reduce the toxicity of aconite mainly include three methods: drug compatibility, processing, and decoction. The most common compatibility with aconite medicines includes licorice, dried ginger, ginseng, and ephedra. Black sliced aconite, steamed slices, and fried slices are less toxic than other processed products. Aconite decoction for more than 60 minutes can basically reach the safe range, and more than 2 hours of decoction may cause the loss of active ingredients.  The research on the mechanisms of aconite dosage-efficacy-toxicity, compatibility, processing, liver toxicity, and nephrotoxicity is still not comprehensive and in-depth. Researchers should perfect toxicity studies of aconite, remove the constraints that affect its clinical application, and promote the clinical use of aconite safely and reasonably. Aconitum carmichaelii Debx. and a plant of the Ranunculaceae family. It is an authentic medicinal material produced in Sichuan. It was first published in “Shennong's Classic of Materia Medica,” which records its spicy, sweetness, hot property, and toxicity  OR “附片” [All fields: intelligent] OR “盐附子” [All fields: intelligent] OR “白附片” [All fields: intelligent] OR “黑附子” [All fields: intelligent] OR “黑顺片” [All fields: intelligent] OR “黑片” [All fields: intelligent] OR “顺片” [All fields: intelligent] OR “熟附子” [All fields: intelligent] OR “熟片” [All fields: intelligent] OR “制附子” [All fields: intelligent] OR “制附片” [All fields: intelligent] OR “川附子” [All fields: intelligent] OR “淡附子” [All fields: intelligent] OR “淡附片” [All fields: intelligent] OR “炮附片” [All fields: intelligent] OR “泥附子” [All fields: intelligent] OR “炮天雄” [All fields: intelligent] OR “制天雄” [All fields: intelligent]) AND (“副作用” [All fields: intelligent] OR “毒” [All fields: intelligent] OR “不良反应” [All fields: intelligent] OR “毒效” [All fields: intelligent] OR “毒理” [All fields: intelligent] OR “毒副作用” [All fields: intelligent] OR “不良事件” [All fields: intelligent] OR “毒” [All fields: intelligent] OR “安全性” [All fields: intelligent] OR “中毒” [All fields: intelligent]).The following words are used as keywords or subject terms for literature retrieval in PubMed: (Aconitum [MeSH Terms]) OR (Aconite [Title/Abstract]) OR (Aconites [Title/Abstract]) OR (Radix Aconiti [Title/Abstract])) OR  OR  OR (Radix Aconitus [Title/Abstract]) OR (Aconitum napellus [Title/Abstract]) OR (Monkshood [Title/Abstract]) OR (Aconitums [Title/Abstract]) AND (poisoning [MeSH Terms]) OR (Side effects [MeSH Terms]) OR (adverse effect [Title/Abstract]) OR (side reaction [Title/Abstract]) OR (toxic effect[Title/Abstract]) OR (toxicity [Title/Abstract]).After deleting the duplicate studies, 445 studies related to the toxicity of aconite were obtained to form the Database of Literature of Toxicity of Aconite (DLTA).We evaluated the research hotspot of toxicity literature, toxicity classification, mechanism analysis, influencing factors of toxicity, and detoxification methods of aconite by the bibliometric method. The collected information included the annual publication of aconite toxicity literature, coword analysis, toxicity classification, toxicity mechanism, aconite varieties, origin, aconite usage, dosage, processing situation, compatible herbs, decoction method, and decoction time. Studies in the DLTA were screened and classified one by one and were structured according to the information collection table. Finally, the extracted data information was classified and analyzed, as shown in There were a total of 445 studies related to the toxicity of aconite in the DLTA. The annual number of publications on the toxicity of aconite from 1985 to 2020 was calculated, as shown in We performed clustering analysis through VOSviewer1.6.15 for coword analysis. Cluster analysis is a multivariate index statistical method that classifies multiple data according to the degree of distance relationship between objects . All stuIn A total of 223 studies on the action mechanism of aconite were collected. The toxic action mechanism of aconite was extracted and classified. Then, the statistical analysis was carried out. The toxic action mechanism of aconite that was reported only in one study was eliminated. The classification of its toxic mechanism is shown in From the statistical analysis of studies , there aWe analyzed the correlation between aconite toxicity and several factors, such as the origin, the specification, the decoction time, and the dosage of aconite. The bibliometric method was used to analyze the relationship between the origin of aconite, the specifications of medicinal materials, the decoction time, the dosage, and the toxicity of aconite.The sources of aconite medicinal materials in all studies of DLTA were analyzed, and the classification statistics were performed . Most ofIn DLTA, the extracted specifications of aconite medicinal materials include aconite, black aconite/sliced aconite, cooked aconite, prepared aconite, and prescriptions and medicines containing aconite . The claLiterature studies have shown that aconite medicinal materials have many specifications. Most of those specifications are toxic. However, in general, raw aconite has a higher toxicity than other specifications of aconite. Therefore, studies that use “raw aconite or aconite” as the research object are mostly aimed at analyzing its toxicity mechanism or reducing toxicity by compatibility, etc., and there are few clinical studies. The literature with “processed aconite” as the research object involves more clinical research.This study analyzed the decoction time of aconite in various studies , as showScholars generally believe that a decoction time of less than 30 minutes is likely to cause clinical toxic events. The decoction time should be extended as the dose of aconite increases. However, most clinicians rely on their own experience about the corresponding relationship between dosage and decoction time, and there is no standard for it. This is one of the reasons for the prone to poisoning reaction when using large doses of aconite . UsuallyThe current textbooks and pharmacopeias stipulate that the common dosage of aconite is 3–15 g/d , and acoIn addition, the factors affecting the toxicity of aconite are shown in Through the literature survey, it is found that the commonly used ways to reduce the toxicity of aconite mainly include three methods: drug compatibility, processing, and decoction.Glycyrrhiza uralensis Fisch, Zingiber officinale Roscoe, Panax ginseng C. A. Meyer, and Ephedra sinica Stapf, etc. The toxicity studies of the compatibility of other drugs with aconite are few. The chemical reaction between aconite and codecocting drugs can reduce toxicity by compatibility, thereby changing the structure of diester alkaloids and converting them into compounds with weaker toxicity [In DLTA, we collected the results and causes of the effects of compatible medicinal materials on the toxicity of aconite and analyzed them statistically, as shown in toxicity , or imprtoxicity .A total of 38 studies on the processing of aconite were collected in this study, and information analysis was performed . StudiesIn addition, although the safety of aconite is guaranteed, the medicine materials for disease treatment decrease due to overprocessing. Many experimental data supported this view , 102. OnThe diester alkaloids in aconite, such as aconitine, hypaconitine, and neoaconitine, are both effective and toxic components . The dieThrough literature surveys , it was Based on the bibliometric method, this study evaluated the publication trend and research hotspots of aconite toxicity in the past 35 years. In addition, this paper analyzed the common toxic reactions, toxic mechanisms, factors, and commonly used detoxification methods of aconite. This can provide a useful reference for clinical rational use of aconite and related research on its toxicity.Since the beginning of 1985, there have been research reports on the toxicity of aconite. The decoction time, dosage, and mode of administration of aconite are the main factors affecting the toxicity of aconite. There are few studies on the effect of the origin of aconite and the specifications of medicinal materials on toxicity, so it is impossible to analyze their relevance. At present, the commonly used methods to reduce the toxicity of aconite include three methods: drug compatibility, concoction, and decoction. The most common drugs compatible with aconite are licorice, dried ginger, ginseng, and ephedra. Black sliced aconite, steamed slices, and fried slices are less toxic than other processed products. Aconite decoction for more than 60 minutes can basically reach the safe range, and more than 2 hours of decoction may cause the loss of active ingredients.One problem is that the number of studies on the toxicity of aconite has declined in recent years. However, the toxicity of aconite has not been fully revealed. More experimental data and research are needed to confirm and answer: (1) overdose use of aconite (exceeding the pharmacopeia recommendation) is common, but there are few studies on the relationship between quantity and toxicity effect of aconite. When clinical use is caused, there is no uniform reference standard for indication dose, which could easily cause toxic reactions. (2) The reasonable decoction time of aconite is 30 minutes to 1 hour. This has been supported by many studies. However, there are also 2–4 hours of decoction cases in clinical practice, especially in the case of large-dose use. Although long-term decoction reduces the incidence of toxic reactions, does the effect of aconite change after long-term decoction? There are too few research data. The decoction time of large-dose aconite lacks a reference standard. (3) Although there are many studies about the processing and compatibility of aconite, there is a large convergence, the processing method is rarely innovative, and the compatibility research is mostly concentrated on several drugs such as licorice, and the compatibility evaluation with other drugs is less, leading to the lack of precise evidence to guide doctors when prescribing drugs in the clinic, and it is also easy to cause toxic events. (4) More and more reports show that aconite can cause adverse reactions such as kidney and liver damage, but the mechanism of its hepatotoxicity and nephrotoxicity is less. The exact toxicity mechanism needs further study. The researchers should be committed to improve the research of toxicity of aconite, remove the constraints for application, and promote the safe and reasonable use of aconite in the clinic. Researchers should improve various toxicity studies of aconite, remove the constraints that affect its clinical application, and promote the rational use of aconite.


Journal of Extracellular Vesicles, 9: 1795362. https://doi.org/10.1080/20013078.2020.1795362Elashiry, M., Elashiry, M.M., Elsayed, R., Rajendran, M., Auersvald, C., Zeitoun, R., Rashid, M.H., Ara, R., Meghil, M.M., Liu, Y., Arbab, A.S., Arce, R.M., Hamrick, M., Elsalanty, M., Brendan, M., Pacholczyk, R. and Cutler, C.W. (2020), Dendritic cell derived exosomes loaded with immunoregulatory cargo reprogram local immune responses and inhibit degenerative bone disease The authors inadvertently left the following grant information out of the Acknowledgments section of their article:The MicroCT data shown in Figure 10 was made possible through the support of an NIH S10 grant (S10 OD025177).The authors regret the error.


In this article, we consider the effects of double diffusion on magnetohydrodynamics (MHD) Carreau fluid flow through a porous medium along a stretching sheet. Variable thermal conductivity and suction/injection parameter effects are also taken into the consideration. Similarity transformations are utilized to transform the equations governing the Carreau fluid flow model to dimensionless non-linear ordinary differential equations. Maple software is utilized for the numerical solution. These solutions are then presented through graphs. The velocity, concentration, temperature profile, skin friction coefficient, and the Nusselt and Sherwood numbers under the impact of different parameters are studied. The fluid flow is analyzed for both suction and injection cases. From the analysis carried out, it is observed that the velocity profile reduces by increasing the porosity parameter while it enhances both the temperature and concentration profile. The temperature field enhances with increasing the variable thermal conductivity and the Nusselt number exhibits opposite behavior. Non-Newtonian fluids have gained great attention due to their immense applications in industrial and biomedical applications. The study concerning electrically conducting non-Newtonian fluids passing through a stretching sheet has been done by many researchers due to its vast engineering and industrial applications comprising plastic and metal extrusion, insulating materials, metal spinning, and in insulating materials. Sahoo  studied Double diffusion in fluid flow is a phenomenon that discusses a type of convection with two different density gradients both having different diffusive rates. This is a very important phenomenon and many researchers are driven to study it. Malik et al.  analyzedFluid flow via a porous medium has a significant amount of applications in petroleum engineering, geothermal and industrial operations. A porous medium is a solid matrix having a continuous network of pores. A porous medium which allows fluid flow can be natural including sand, wood, and human lungs or it can be synthetic such as ceramics, metal foams having high porosity, and composite materials. Pores and interconnected solid particles make up porous media which can be seen in electrochemical systems, steel and iron production, microchemical reactors, and renewable fuels. Traditionally, Darcy’s law is utilized mainly for computational and theoretical investigations of porous medium studies. Heat transfer effects and fluid flow through a porous medium are studied by numerous researchers. Khan et al.  studied The Carreau fluid flow model is a significant non-Newtonian fluid model. It effectively describes both shear thickening and shear thinning phenomena. At a high wall shear stress, the behavior of this fluid degenerates to a Newtonian behavior. This model considerately explains the rheological behavior of many industrial fluids such as foams, cosmetics, syrups, and biotechnological detergents. Khan et al.  discusseIn this article, we examine MHD Carreau fluid flow in permeable media over a stretched sheet. Double diffusion, variable thermal conductivity, and Darcy’s law are employed for porous medium in the modeling of the problem. Equations governing the considered Carreau fluid flow model problem are transformed to non-linear ordinary differential equations in dimensionless form by employing similarity transformations. The effects of pertinent parameters present in the problem for injection/suction cases on velocity, temperature, concentration, and on other physical quantities such as skin friction and Nusselt and Sherwood numbers are investigated, represented graphically, and discussed accordingly.The remaining article is organized as follows: The problem formulation is presented in x direction with stretching velocity y-axis. The geometry of the considered flow phenomena is depicted in We consider steady incompressible flow of a double diffusive Carreau fluid through porous medium over a stretching sheet in two dimensions. Assuming that the sheet is considered in the The corresponding conditions on the boundaries are as followsu, v represent components of velocity along x and y directions respectively, T, C, n is the power law index describing fluid characteristics, while In the above model,  is the cThe following similarity transformations are considered to transform the governing equationsSubject to these similarity transformations, Equation  is automn is called the power law index, Equations –9) are  are 9) aThe physical quantities such as skin friction, the Nusselt number and Sherwood number are given asHere Using  and 12)12), thesM, the Hartmann number, n, the power index, The non-linear transformed ODEs –9) alon alon9) aM, the Hartmann number, n, the power-law index. In M causes a reduction in velocity for both cases of suction and injection. As M corresponds to Lorentz force due to which for larger values of M the Lorentz force enhances and as this force is a resistive force acting against the motion of the fluid hence reduces the fluid’s velocity. n is displayed in n is increasing. This is because the non-linearity of the sheet is increased with the power-law index which reduces the resistant force and also the non-Newtonian behavior of the fluid is decreased.M and power-law index (n) are illustrated. It is deduced that M and reduces with n. Due to the greater magnitude of the Lorentz force depicted by higher M, the resistive force between the layers of the fluid results in an increase in the temperature.Variations in temperature profile (M), Dufour solutal Lewis number  and M produces more friction between layers and also with the surface of the sheet. The opposite impact of the power-law index (n) on the skin friction coefficient is observed in The behavior of the local Nusselt number versus different parameters is observed in In this article we studied a double-diffusive Carreau non-Newtonian fluid flow with variable thermal conductivity in a porous media. Similarity transformations are used to transform the governing Carreau fluid flow model equations into a system of non-linear ordinary differential equations. Physical quantities of primary interest are investigated for key parameters present in the study and a skin friction coefficient comparison has been carried out with the results available in  for variM) and porosity parameter (n).The velocity profile decelerates for increasing Hartmann number (M, and with the modified Dufour parameter (n.The temperature field increases with variable thermal conductivity (M, the Dufour solutal Lewis number The concentration profile reduces with the Lewis number (M and n.The local skin friction drag increases with The Nusselt number diminishes with The Sherwood number decreases with The presence of the suction parameter provides more resistance to the fluid flow as compared to injection.The yemperature and concentration of a fluid increase in the case of injection parameter.


Increased intracranial pressure is the source of most critical symptoms in patients with glioma, and often the main cause of death. Clinical interventions could benefit from non-invasive estimates of the pressure distribution in the patient's parenchyma provided by computational models. However, existing glioma models do not simulate the pressure distribution and they rely on a large number of model parameters, which complicates their calibration from available patient data. Here we present a novel model for glioma growth, pressure distribution and corresponding brain deformation. The distinct feature of our approach is that the pressure is directly derived from tumour dynamics and patient-specific anatomy, providing non-invasive insights into the patient's state. The model predictions allow estimation of critical conditions such as intracranial hypertension, brain midline shift or neurological and cognitive impairments. A diffuse-domain formalism is employed to allow for efficient numerical implementation of the model in the patient-specific brain anatomy. The model is tested on synthetic and clinical cases. To facilitate clinical deployment, a high-performance computing implementation of the model has been publicly released. Gliomas are divided into low- and high-grade tumours. High-grade gliomas (HGGs) are characterized by fast progression and poor prognosis with a median survival between 1 and 5 years, depending on the tumour subtype . Low-graComputational tumour models can provide valuable insights into the patient's state and forecast the disease progression to assist clinical interventions. Most glioma models are based on the Fisher–Kolmogorov equation, which describes tumour proliferation and infiltration into the surrounding tissue –24. Suchet al.  be a normalized tumour cell density at time t and voxel i ∈ {1, …, N} at location  ∈ Ω1(t). The dynamics of the tumour cell density Ω1(t) is modelled as: i at time t. The constants Dw and Dg describe the tumour infiltration rate in white and grey matter, respectively. Since the tumour cells infiltrate the white matter faster than the grey matter, it is assumed that ρ (1/day) is the proliferation rate. As the tumour grows, it exerts pressure on the surrounding tissue, which is deformed and displaced in response. The brain tissue displacement also causes displacement of the tumour cells infiltrated inside that tissue. This is modelled by the last term on the right-hand side of equation (Ω1(t). The tumour is initialized as a point source at voxel iic ∈ Ω1(t = 0) and its growth is modelled from the initial time t = 0 until the final time t = T (day).The glioma dynamic consists of tumour proliferation and infiltration into the surrounding brain tissue. Let 2 day−1) ,73. Let . 2.1.2t. The tumour-induced pressure Ω2: i at time t, while The pressure dynamics are determined by the growing tumour pressing on the surrounding brain tissue and the mechanical properties of the individual tissue constituents. The brain tissue acts as a viscoelastic material that partially relaxes the pressure from the tumour. The pressure relaxation is proportional to the tissue-specific mechanical properties—the softer the material the more pressure it relaxes. The remaining pressure results in tissue deformation. The deformation rate can be computed from the pressure gradient using Darcy’s law. Let orted in . This me. 2.1.3i ∈ Ω2 at time t. The dynamics of each tissue constituent s ∈ {w, g, c} is modelled by the following advection–convection equation: 2 The advection term describes tissue displacement, while the convection term models tissue compression. After each simulation time step, the percentage of each tissue component must be recomputed accordingly, i.e. for s ∈ {w, g, c}The growing tumour compresses and displaces the surrounding brain tissue. Let Let us note that in equation  the tumoequation .. 2.1.4The model can be further updated to account for the anisotropic tumour cell migration along the fibres in the white matter. This can be achieved by replacing the identity matrix us works ,75–78. PAdditional model updates can be achieved by including a damping effect in the diffusion term informed by von Mises stress, as presented in ,79. This. 2.2This section presents how the DDM can be deployed to reduce the computational intensity of the proposed model. Details of the numerical implementation are discussed afterwards.. 2.2.1Ω2 can be replaced by a new set of equations defined on regular domain Ω3 with a zero Dirichlet boundary condition on ∂Ω3, resulting in a system of linear equations with a symmetric matrix. The DDM method uses a so-called phase-field function Ω2 and Ω3. The phase-field function Ω2, i.e. ψi = 1 for i ∈ Ω2, ψi = 0 for ψ varies smoothly at the interface between the domains Ω2 and Ω3, such that ψ(i) = 0.5 for i ∈ ∂Ω2, as shown in Ω2, does not change over time since it is constrained by a rigid skull. The pressure computed by the above equations in domain Ω3 can be easily mapped to domain Ω2 (i.e. brain parenchyma) by multiplication with the characteristic function ɛ is the prescribed interface thickness. Taking The computational cost of the proposed model is largely determined by the numerical solution of the Helmholtz equations  and 2.1. Its numequation ,86,2.17∂1 For each new patient, the patient-specific phase-field function can be obtained by computing an affine registration, 2,3To simplify the process and to avoid re-computation of the phase-field function for each new patient, affine image registration can be used instead. More specifically, we provide the brain MRI atlas with the binary brain mask , Dg = 1.3 × 10−4 (cm2/day), ρ = 1.2 × 10−2 (1/day), Dw, Dg, ρ) were taken from [For the synthetic case, brain anatomy from a healthy subject provided by the SRI24 Atlas is used to simulate the disease progression over time. The brain tissue segmentation is provided together with the atlas. The tumour is initialized as a point source in the right frontal lobe and its progression is simulated over a period of 600 days using the following model parameters: ken from ,94 and M [M from , while vb, is directly derived from the growing tumour and is constrained by the patient-specific brain anatomy. The model identified the highest pressure accumulation in the frontal lobe, where the growing tumour compresses the brain tissue against the inner wall of the skull. On the other hand, the pressure in the ventricles is much lower, which is consistent with the capability of the CSF to relax the pressure [figure 2c, is most dominant at the interface between the tumour and the tissues, i.e. the region where the bulk tumour presses most on the surrounding tissue, while its effect decreases with increasing distance from the tumour. The model predictions can be used to assist clinical interventions, such as ICP management or surgery planning. The distribution of the ICP can be used to estimate the neurological symptoms caused by the increased pressure in the specific brain centres, as shown in figure 2d. For instance, in the presented case the pressure elevation in the frontal lobe, as seen in the initial stages of the disease, can affect the subject’s behaviour and concentration. As the pressure elevation progresses to the motor cortex, deterioration of motor functions can be expected, followed by impairment of perception caused by further disease progression to the sensory cortex in the parietal lobe. Interestingly, the identified ICP values are also comparable to the pathological values reported in Figures figure 2pressure . The def. 3.2a,b shows fluid-attenuated inversion recovery (FLAIR) and T1-weighted (T1w) MRI scans of two patients at the time of tumour detection. The FLAIR scan provides good contrast between healthy tissue and tumour (seen as bright enhancement), while the contrast between white and grey matter is less pronounced. On the other hand, the T1w MRI shows lower enhancement in the lesion but superior contrast between the distinct brain tissues. The FLAIR scan is therefore used to detect the tumour extent while the T1w MRI is deployed to estimate the brain anatomy.To assess the ability of the model to produce realistic brain deformations, the model is used to reproduce the tumour mass effect observed in MRI scans of patients diagnosed with HGG. Figure 43 The approximated healthy anatomies of both patients are shown in figure 4c. This approach provides a reasonable approximation of the deformation-free anatomy in most cases. However, the affine registration might not be sufficient to capture atypical anatomical morphologies, such as enlarged ventricles, which might require manual correction. In the simulation, the tumour is initialized as a point source at the centre of mass of the FLAIR-enhancing lesion. The time of the tumour growth, from its onset to detection, is not known in practice. However, from the simulation perspective, one can obtain the same tumour morphology with different combinations of time-dependent parameters, such as T and speed of growth, i.e. , as shown in [T, which is chosen manually by comparing the extent of the real and the predicted tumour.To perform the simulation, we would like to initialize the tumour in the patient’s tumour-free non-deformed anatomy and model the disease progression over time, until it reaches the state visible on the patient’s scans. Since the scans with the patient’s healthy anatomy are usually not available, we approximate the initial deformation-free anatomy through image registration. More specifically, the T1w MRI scan from the SRI24 atlas  is mappeshown in ,73. Sincd–f. The predicted tumour mass effect is in good qualitative agreement with the tumour-induced deformations observed in the patients’ MRI scans. In the case of patient 1, the model correctly predicts the midline displacement, while for patient 2 it accurately reproduces the compression of the ventricles. The simulated tumours have complex morphology similar to tumour patterns seen in the patients’ scans. Figure 4e shows the predicted ICP distribution overlaid on the patients’ T1w MRI scans. The estimated pressure distribution closely follows the morphology of the visible tumour, with the highest pressure accumulation mainly in the tumour core close to the skull. The high ICP values imply intracranial hypertension in both patients . The initial brain anatomy is obtained by mapping the brain atlas to the patient's T1w scan from the first time point, i.e. T1. The initial tumour location is chosen as the centre of mass of the tumour visible on the FLAIR scan from time T1. The tumour progression is simulated from the time of disease onset, i.e. t = 0 (days), through the time of the tumour detection at t = T1 (days) until the final time t = T2 (days) using the same parameter values as in the previous cases. The time points corresponding to the patient's scans were found manually by comparing the extent of the simulated and real tumour, and were estimated as T1 = 200 (days) and T2 = 700 (days). The additional benefit of this approach is that the model predictions can be evaluated at two different time points instead of one.We test the feasibility of the model to capture the disease progression over time in a patient case with MRI scans from two different time points. Figure 5T1 and T2 are shown in The results of the simulation at time points . 4This paper proposes a novel model coupling glioma progression, tumour mass effect and ICP dynamics. Synthetic and clinical cases are used to illustrate the model’s capability to capture realistic disease progression and brain deformations and to estimate the ICP distributions. The main advantage of the proposed approach is that the ICP is directly derived from the tumour dynamics and the patient-specific anatomy. This allows for estimates of critical conditions such as hypertension, brain midline shift or neurological impairments caused by high-pressure accumulation in specific brain areas. The distribution of ICP has further potential to guide surgical interventions.The model could also be used to guide deformable image registration of patients' brain scans from different time points. Another interesting application would be to deploy the model towards the discovery of novel prognostic markers. In particular, markers such as midline shift ,98 or laA limitation of the proposed model is that it does not account for the circulation of CSF within and outside of the brain. As a consequence, the model cannot capture swelling of the ventricles, which can happen in some patients owing to the presence of the tumour or as a response to the treatment. Future works should thus account for the role of CSF circulation and its effect on ventricular deformations. Of particular interest would also be model extension accounting for distortion of the brainstem, caused either by CSF occlusion along the brainstem or by tumour infiltration into the brainstem itself, which have been recently identified as characteristic features presented in final-stage glioblastoma patients .In the future the model can also be extended by incorporating various factors such as anisotropic tumour infiltration informed by patient-specific DTI ,78,101, To facilitate model calibration from patient data, the proposed model relies on a small number of parameters. The model calibration and accuracy of patient-specific predictions should be tested on a larger patient cohort in the following studies. The work presented here serves as a proof of concept that the proposed model holds the potential to capture glioma progression and accompanying tissue deformations and pressure dynamics in the patient's brain. These results encourage future studies of patient-specific model predictions aiming to assist clinical interventions by providing non-invasive estimates about the patient's state and the disease progression over time. Finally, to facilitate deployment of the proposed methodology, a highly parallel implementation of the model is publicly released.


An accurate tumour segmentation in brain images is a complicated task due to the complext structure and irregular shape of the tumour. In this letter, our contribution is twofold: (1) a lightweight brain tumour segmentation network (LBTS‐Net) is proposed for a fast yet accurate brain tumour segmentation; (2) transfer learning is integrated within the LBTS‐Net to fine‐tune the network and achieve a robust tumour segmentation. To the best of knowledge, this work is amongst the first in the literature which proposes a lightweight and tailored convolution neural network for brain tumour segmentation. The proposed model is based on the VGG architecture in which the number of convolution filters is cut to half in the first layer and the depth‐wise convolution is employed to lighten the VGG‐16 and VGG‐19 networks. Also, the original pixel‐labels in the LBTS‐Net are replaced by the new tumour labels in order to form the classification layer. Experimental results on the BRATS2015 database and comparisons with the state‐of‐the‐art methods confirmed the robustness of the proposed method achieving a global accuracy and a Dice score of 98.11% and 91%, respectively, while being much more computationally efficient due to containing almost half the number of parameters as in the standard VGG network. Brain tumours can vary from low grade glioma (LGG) to high grade glioma (HGG). HGG is more aggressive and has a poorer prognosis compared to LGG . Brain tTo this end, isolating the tumour from the healthy tissue is termed as tumour segmentation . In esseGenerally speaking, segmentation models can be universally classified as either generative models or discriminative models. While generative models segment objects by relying on the appearance, illumination and occlusion of the shape; they are difficult to design and their accuracy is generally low, especially for complex objects with inhomogeneous textures  such as Our contributions in this letter can be summarized as follows. (1) a lightweight brain tumour segmentation network (LBTS‐Net) is proposed for a robust yet fast tumour segmentation; 2) transfer learning is integrated within the LBTS‐Net to fine‐tune the base VGG network to achieve a robust tumour segmentation. To the best of our knowledge, this work is amongst the first in the literature which the VGG‐16 and VGG‐19 networks are lightened and tailored for brain tumour segmentation. This letter is organized as follows. Section  transfer2There has been an increasing amount of work related to brain tumour segmentation in the last years. This is imposed by the importance of this topic across the medical society . VariousDespite that the aforementioned methods improved the segmentation results; however, this improvement comes at the expense of increasing the computational complexity and storage requirement. Therefore, decreasing the complexity of CNN for tumour segmentation is essential and further work is required to develop an accurate and fast brain segmentation method.As far as we know, lightening a CNN has not been well studied for brain tumour segmentation. There are some attempts in the literature to lighten CNN for image recognition or semantic segmentation tasks. For example, Zhao et al.  proposed3The proposed method for tumour segmentation includes two parts: (1) a lightweight CNN for tumour brain segmentation which is specially designed to decrease the number of parameters and save storage requirements. (2) a transfer learning strategy including pre‐training and fine‐tuning to tailor the network and achieve an accurate brain tumour segmentation. The details of these two parts are given in the following sub‐sections.3.1Various CNNs architecture are available off‐the‐shelf such as Alex‐Net, Google‐Net, Inception‐Net and VGG‐Net. However, several works confirmed that the VGG models achieve a promising performance when dealing with medical imaging , 16, 17 In this letter, two models have been proposed, namely: LBTS‐Net‐16 and LBTS‐Net19, through lighting the VGG‐16 and VGG‐19 networks by reducing the number of convolution filters and adapting depth‐wise separable convolution. In this context, the proposed LBTS‐Net contains 32 convolution filters, which is half the number of filters in the original VGG‐16 or VGG‐19 networks. This is because the activations in this layer have redundant information with similar structures and patterns for brain images as can be seen in Figure 3.2The second part of the proposed method includes transfer learning. Transfer learning has recently been reported to achieve an outstanding image segmentation performance . In thismax. This is followed by sub‐sampling the output by a factor of 2 using a max pooling process with a 2 × 2 non‐overlapping window. As a result of the many sub‐sampling processes and max‐pooling layers in the encoder network, spatial resolution of the feature map will be affected. This will result in poor boundary details which will hinder the segmentation process. In order to mitigate this problem, the indices of the max‐pooling for each encoder feature map are stored and these indices are utilized later in the decoder stage to up‐sample the corresponding feature map and hence generate the sparse feature representation. Next, a trainable decoder filter bank is convolved with these feature sets to amplify the sparse feature sets. Later, these feature sets are forwarded to the soft‐max classification layer to classify the pixels in the tumour image into either a tumour or a brain pixel. To improve the network accuracy and avoid under‐fitting, image data augmentation is used. In this regard, different image manipulations have been used such as: rotation, translation and random reflection. Also, for the sake of improving the training process, the class weights have been balanced. Figure The architecture of the proposed network is shown in Table 1e−3, and 5e−4), respectively. A momentum term equal to 0.9 is used as an optimization procedure with the stochastic gradient descent with momentum (sgdm) and the cross‐entropy loss function. The batch‐size is set to 64 and the network converged after 30 epochs.The implementation details of the network are as follow. the initial learning rate and L2 regularization have been empirically set to  2015 database . The dat4.1All experiments are evaluated on a 2.6 GHz core i7 processor with 16 Gb of RAM and Nvidia GTX 1660 Ti GPU under the MATLAB environment. 70% of the MRI images are used for training while the rest are employed for testing. The results are generated based on the HGG images from the BRATS 2015 database considering the whole tumour region. The whole tumour regions are represented by the concatenation of all tumour labels namely: necrotic, non‐enhancing tumour, peritumoural edema and enhancing tumour. The confusion matrix for both the tumour and brain which provides a visualization of the semantic segmentation performance is generated as shown in Figure In order to illustrate the effect of reducing the number of filters and using the depth‐wise convolution in the first layers, we conducted comparisons with both the standard VGG‐16 and VGG‐19 networks which are trained on the same images under the same conditions. Table 5In this letter, two lightweight CNN models (LBTS‐Net16 and LBTS‐Net19) were proposed for brain tumour segmentation. The proposed models were based on lightening the VGG architecture by reducing the number of redundant convolution filters in the first layer and adopting the depth‐wise convolution in the initial layers of the network (layers 2–4). Transfer learning was also utlilised to fine‐tune the proposed method to achieve a robust segmentation. Experimental results demonstrated that the proposed method significantly reduced the computation complexity of the network while maintaining a similar performance compared to the base‐line VGG architecture. In addition, experimental results showed that the proposed model achieved promising performance which outperformed similar methods.The authors declare no conflict of interest.


The present article presents a novel idea regarding the implementation of Tiwari and Das model on Reiner-Philippoff fluid (RPF) model by considering blood as a base fluid. The Cattaneo-Christov model and thermal radiative flow have been employed to study heat transfer analysis. Tiwari and Das model consider nanoparticles volume fraction for heat transfer enhancement instead of the Buongiorno model which heavily relies on thermophoresis and Brownian diffusion effects for heat transfer analysis. Maxwell velocity and Temperature slip boundary conditions have been employed at the surface of the sheet. By utilizing the suitable transformations, the modeled PDEs  are renewed in ODEs  and treated these equations numerically with the aid of bvp4c technique in MATLAB software. To check the reliability of the proposed scheme a comparison with available literature has been made. Other than Buongiorno nanofluid model no attempt has been made in literature to study the impact of nanoparticles on Reiner-Philippoff fluid model past a stretchable surface. This article fills this gap available in the existing literature by considering novel ideas like the implementation of carbon nanotubes, CCHF, and thermal radiation effects on Reiner-Philippoff fluid past a slippery expandable sheet. Momentum, as well as temperature slip boundary conditions, are never studied and considered before for the case of Reiner-Philippoff fluid past a slippery expandable sheet. In the light of physical effects used in this model, it is observed that heat transfer rate escalates as a result of magnification in thermal radiation parameter which is 18.5% and skin friction coefficient diminishes by the virtue of amplification in the velocity slip parameter and maximum decrement is 67.9%. Cattaneo [Al2O3, TiO2 and copper Cu by considering H2O as a standard liquid through a nonlinearly expandable plate embedded with the CCHF. Shah et al. [Since 1991, this is the subject of the inquiry because of its synthetic and basic existence since the beginnings of the era of carbon nanotubes. In several technical and industrial applications such as electrochemical super-capacitors, transistors, sensors and field emitting machines, engine transmission oil, heat exhaust flue gas recovery, electrical cooling, nuclear cooling, nanofluid boiling, etc. special properties such as high surface radiation, carbon nanotubes (CNTs) were studied. These applications got the researcher’s attention to work on CNTs. Kundu et al.  inspecteCattaneo  modifiedCattaneo  introducCattaneo  discusseCattaneo  checked Cattaneo  researchCattaneo  scrutinih et al.  investigh et al.  studied Thermal radiation is one of three processes that permit energy exchange for bodies with different temperatures. The electro-magnetic wave emission from substances is characterized by thermal radiation (variation of its interior energy). It transmits radiation from ultraviolet to far-field infrasound depending on the material’s temperature. Thermal radioactivity is utilized where the high-temperature variance is essential having immense utilization in the industry like thermal furnaces, nuclear reactors, polymer production, combustion reactors, rubber production, etc. Sreedevi and Reddy  ponderedThe slip-free effect happens where the fluid and the wall are equal in velocity. On the other hand, the state in which the fluid and the wall velocity are different is called the slip velocity. In the case of temperature slip of the fluid and the sheet surface temperature is different. The liquid impact of boundary slip has distinguished utilizations like improving artificial interior cavities and valves of the heart. Shafiq et al. , under tThe reasons behind the organization of this research are given below:■ The Maxwell velocity and Smoluchowski temperature boundary slip constraints are considered to study a slip effect on RPF which is not explored yet in available literature. Before this investigation, no literature is available to study the effect of Maxwell velocity and Smoluchowski temperature jump boundary conditions on the Non-newtonian fluid past a stretching sheet.■ Other than Buongiorno nanofluid no literature is available to study the effect of nanoparticles on Reiner-Philippoff fluid past a stretching sheet. Attempt has been made in this article to implement Tiwari and Das nanofluid model for the case of heat transport analysis of Reiner-Philippoff model with blood as a standard fluid.■ Before this investigation, no literature on Reiner-Philippoff fluid is available to study heat flux of Cattaneo-Christov scheme along with thermal radiation is used to investigate the heat transfer analysis. Thermal radiation present in the fluid amplifies the heat transfer rate. The main purpose is to investigate the heat transfer rate with the inclusion of CCHF and thermal radiation.■ SWCNT/MWCNT are never used before for the case of Riner-Philippoff fluid.The expression Reiner-Philippoff  of stresτ, τs, μ0 and μ∞ indicates shear-stress, reference shear-stress, zero shear viscosity, and limited viscosity. Reiner-Philippoff model responds like shear thinning, Newtonian, and shear thickening subjected to a variation in fluid viscosity. Mathematical expression regarding RPF flow function is written asλ in fluid flow function represents Reiner-Philippoff fluid parameter. Reiner-Philippoff behaviour is Newtonian for λ = 1, shear thickening λ<0, and shear thinning λ>1.The symbols uw influential lengthways x−direction. The symbols T0 and T∞ depicts the fluid energy and concentration at the surface and ambient temperature outlying from the surface. The momentum equation has been scrutinized with the inclusion of carbon nanotubes. Momentum and thermal boundary layers occur when the velocity and temperature of the fluid is 0.99% of the free stream fluid velocity as well as temperature. Under these boundary conditions, the viscous, as well as velocity effects, hold. Heat transfer analysis has been carried out with the inclusion of solar thermal thermal and CCHF. Radiation is one of the best sources of heat and requires no medium for its propagation. Heat transfer rate in the case of the temperature equation is improved with the inclusion of carbon nanotubes, CCHF, and thermal radiation. Momentum and temperature slip boundary conditions have been employed at the boundary surface by the consideration of the assumption that the surface is rough, wet, and the effect of the adhesive forces is negligible. The fluid is incompressible and laminar. The density, as well as pressre, is constant. Human blood is considered as a base liquid flowing through a stretchable surface with the inclusion of SWCNT and MWCNT. The density ρnf, thermal diffusion αnf, nanofluid specific heat (ρCp)nf, thermal conductance knf are specified by the mathematical expressions mentioned below [ed below –3. Fig 2The models of the continuity, momentum, and energy equations are described below :∂u∂x+∂The physical boundary conditions (BCs) are :y=0:u(ere CCHF –22 is giThe expression of heat radiation flux  is speciThe function of a stream is defined as ormation  with velthe Eqs –6) are  are u=∂ψA1, A2 and A3 are given byThe associated non-dimensionless quantities are defined belowThe mathematical expression regarding skin friction coefficient  is givenqw indicates heat flux having expression mentioned belowThe expression regarding heat transfer Nusselt number  isNux=The dimensionless Nusselt number after utilization of similarity transformation is manifested byf = w1, f′ = w2, f′′ = w3, θ = w4, the system of ODEs are converted into first order, represented byThe MATLAB bvp4c which is the finite-difference scheme (collocation scheme) is executed to evaluate the non-dimensionless system of Eqs –14) sid sid14) s−6 and η∞ = 7. In the situation of the present problem, the tolerance rate and convergence value were set at 10λ and γ by holding other parameters fixed are given in The comparative analyses of the findings achieved with those stated by Reddy et al.  with theg(η) increases because of an increment in fluid factor λ but g(η) lessens as a result of enrichment in Bingham number γ and velocity slip γ1 but no alteration is detected for the case of radiation Rd, Prandtl number Pr, thermal relaxation time parameter δ, and temperature slip parameter γ2. The rate of heat transport implies result in an improvement in λ, Rd, δ but heat transfer depreciates as a result of an improvement in the remaining parameters like γ, γ1, γ2, Pr. For the case of MWCNT, shear stress field g(η) augments owing to amplification in λ but decreases in the case of γ and γ1 and no change is obvious in the status of the remaining parameters. The number of Nusselt amplifies by the virtue of enrichment in the amounts of Rd, λ and δ. The Nusselt number depreciates as a result of an improvement in the remaining parameters like γ, γ1, γ2, Pr.This sector is dedicated to studying the effect of sundry parameters that appear during the numerical simulation of the problem against shear stress field, velocity field, temperature field. Rd = 2.5 which is 18.5%. From Tables λ parameter on the profile of velocity f′(η). It is observed at an improvement in λ, the fluid behaves like shear thinning and the fluid flows more freely on the surface of the sheet which amplifies the velocity of the fluid and velocity profile. The Bingham number γ effect on the domain of velocity is represented in γ1 on f′(η). Slip phenomenon occurs when the velocity of the nanofluid and the surface is not the same. Physically, the slip phenomenon occurs due to roughness, wetness, and non-adhesives forces acting on the surface of the stretching sheet. That’s why they wander wall forces and adhesives forces are not acting on the fluid flow over the stretching sheet. As a result slip phenomenon occurs. In the presence of slip phenomenon, the nanofluid velocity flow over the surface declines which lessens the fluid velocity and f′(η). The portrayal of γ on shear stress field g(η) is shown in γ. Physically for the fewer values of γ and λ, the fluid behaviour is shear thickening. Both γ and λ are prominent factors of the Reiner-Philippoff fluid parameter and are somehow related to each other. The behaviour of the fluid is shear-thinning λ<1 which lessens the fluid velocity and amplifies the stress field. As a result g(η) augments. λ on g(η). Fluid parameter λ is the ratio of zero shear rate to the infinite sheat rate. Physically a positive variation in the infinite shear rate depreciates the fluid parameter λ. The viscosity of fluid abates by the virtue of an amplification in λ which lessens the shear-stress of the nanofluid that furthermore leads to a decrement in the domain of shear-stress. ϕ on the profile of velocity. Physically concentration is proportional to the diffusivity. Molecules diffuse more quickly by the virtue of an increment in the concentration of nanoparticles. Concentration of the fluid increases due to an augmentation in the nanoparticles concentration of nanoparticles which lessens the fluid flow that eventually diminishes the velocity of nanofluid.Pr impact on the distribution of temperature field θ(η) is illustrated. The number of Prandtl is the proportion of momentum diffusion and thermal diffusion. Physically Pr is one of the prominent factors of boundary layer analysis. In the case of Pr<1, the thermal boundary layer dominates the momentum boundary layer but the situation is quite opposite in the case of Pr>1 where the momentum boundary layer dominates the thermal boundary layer. It is well established, the thermal diffusion of the fluid diminishes result in an increase in Pr. The temperature of the fluid depreciates as a result of an abatement in the thermal diffusivity which furthermore guides to a decrement in θ(η). The characteristics of radiation parameter Rd on θ(η) are highlighted in Rd heat enter more easily into the system which improves the fluid temperature and temperature field θ(η). γ2 on the temperature profile θ(η). Physically temperature slip phenomenon occurs when the temperature of the sheet and fluid flow over the sheet is not in thermal equilibrium. With temperature slip condition, the temperature of the nanofluid declines which lessens the fluid temperature and θ(η). δ on the temperature field θ(η). Physically thermal relaxation time is the time in which fluid is allowed to relax to retain its original shape. During this time the fluid behaviour is shear thickening. As a result of a rise in δ, the nanofluid particles show nonconducting behaviour, which takes a long time to convey heat to their neighboring nearby particles. The temperature distribution diminishes as a consequence. ϕ on θ(η). Physically it is quite evident that the insertion of nanoparticles in the base fluid enhances the thermal conductivity of the fluid and ultimately amplifies the heat transfer rate. The thermal conductivity of nanoparticles increases owing to an amplification in ϕ which moreover augments the temperature of fluid and θ(η).In In the present research, a computational heat transfer of Reiner-Phillipoff nanofluids over a flat surface is investigated under the impact of Maxwell velocity slip and Smoluchowski temperature slip on CNTs with modified Fourier theory. The concluding remarks from this study are given belowλ escalates the velocity field but the fluid velocity depreciates by the virtue of amplification in the Bingham number γ.■ An improvement in the fluid parameter λ.■ The shear-stress domain depressed results in enrichment in the fluid factor ■ Velocity of the fluid lessens due to an increment in the concentration of nanoparticles.γ1 and temperature slip γ2 depreciates velocity and temperature profiles.■ An amplification in velocity slip δ brings about a decrement in the temperature distribution.■ A positive variation in a parameter of thermal relaxation Rd.■ Temperature field escalates by the virtue of amplification in the radiation parameter ■ Rate of heat transport augments owing to an augmentation in the volume fraction of nanoparticles.S1 Nomenclature(DOCX)Click here for additional data file.


Bone and joint infections (BJI) comprise a series of disorders, including septic arthritis, osteomyelitis, and prosthetic joint infections. Dalbavancin (DALBA) is a lipoglycopeptide with a very long half-life that allows the treatment of serious infections with once weekly or biweekly administration. We evaluated the activity of DALBA against pathogens isolated from BJI.S. aureus, 140 β-haemolytic streptococci (BHS), 71 coagulase-negative staphylococci (CoNS), 57 Enterococcus spp. (ESP), 22 viridans group streptococci (VGS), and 5 S. pneumoniae. Bacteria were identified by standard algorithms and MALDI-TOF-MS. Susceptibility testing was performed by the reference broth microdilution method in a central laboratory. A total of 798 organisms were collected from 62 US and 28 European (EU) hospitals in 2016-2020, including 503 S. aureus (63.0%) was the most common pathogen associated with BJI, followed by BHS (17.5%), CoNS (8.9%), and ESP (7.1%). All S. aureus isolates were susceptible (S) to DALBA , linezolid , teicoplanin , vancomycin , and daptomycin  rates among S. aureus (MRSA rates) were 35.5% and 15.4% in the US and EU, respectively. Ceftaroline (CPT) was active against 98.6% of S. aureus  and 94.7% of MRSA  isolates. Doxycycline and levofloxacin were active against 97.0% and 76.5% of S. aureus, respectively. Among CoNS, (54.9% OXA-R), DALBA  was the most potent agent, followed by DAPTO , CPT  and LNZ . The highest DALBA MIC value among BHS and VGS was 0.12 mg/L . VAN was active against 82.4% of ESP and DALBA inhibited all VAN-S ESP at ≤0.06 mg/L. in vitro activity against common gram-positive organisms (GP) causing BJI and appears to be a valuable option to treat BJI/osteomyelitis caused by GP.DALBA demonstrated potent Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Leonard R. Duncan, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services Shionogi (Research Grant or Support) Mariana Castanheira, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Bravos Biosciences (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Qpex Biopharma (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Mariana Castanheira, PhD, Affinity Biosensors  Involved: Self): Research Grant or Support; Allergan  Involved: Self): Research Grant or Support; Amicrobe, Inc  Involved: Self): Research Grant or Support; Amplyx Pharma  Involved: Self): Research Grant or Support; Artugen Therapeutics USA, Inc.  Involved: Self): Research Grant or Support; Astellas  Involved: Self): Research Grant or Support; Basilea  Involved: Self): Research Grant or Support; Beth Israel Deaconess Medical Center  Involved: Self): Research Grant or Support; BIDMC  Involved: Self): Research Grant or Support; bioMerieux Inc.  Involved: Self): Research Grant or Support; BioVersys Ag  Involved: Self): Research Grant or Support; Bugworks  Involved: Self): Research Grant or Support; Cidara  Involved: Self): Research Grant or Support; Cipla  Involved: Self): Research Grant or Support; Contrafect  Involved: Self): Research Grant or Support; Cormedix  Involved: Self): Research Grant or Support; Crestone, Inc.  Involved: Self): Research Grant or Support; Curza  Involved: Self): Research Grant or Support; CXC7  Involved: Self): Research Grant or Support; Entasis  Involved: Self): Research Grant or Support; Fedora Pharmaceutical  Involved: Self): Research Grant or Support; Fimbrion Therapeutics  Involved: Self): Research Grant or Support; Fox Chase  Involved: Self): Research Grant or Support; GlaxoSmithKline  Involved: Self): Research Grant or Support; Guardian Therapeutics  Involved: Self): Research Grant or Support; Hardy Diagnostics  Involved: Self): Research Grant or Support; IHMA  Involved: Self): Research Grant or Support; Janssen Research & Development  Involved: Self): Research Grant or Support; Johnson & Johnson  Involved: Self): Research Grant or Support; Kaleido Biosceinces  Involved: Self): Research Grant or Support; KBP Biosciences  Involved: Self): Research Grant or Support; Luminex  Involved: Self): Research Grant or Support; Matrivax  Involved: Self): Research Grant or Support; Mayo Clinic  Involved: Self): Research Grant or Support; Medpace  Involved: Self): Research Grant or Support; Meiji Seika Pharma Co., Ltd.  Involved: Self): Research Grant or Support; Melinta  Involved: Self): Research Grant or Support; Menarini  Involved: Self): Research Grant or Support; Merck  Involved: Self): Research Grant or Support; Meridian Bioscience Inc.  Involved: Self): Research Grant or Support; Micromyx  Involved: Self): Research Grant or Support; MicuRx  Involved: Self): Research Grant or Support; N8 Medical  Involved: Self): Research Grant or Support; Nabriva  Involved: Self): Research Grant or Support; National Institutes of Health  Involved: Self): Research Grant or Support; National University of Singapore  Involved: Self): Research Grant or Support; North Bristol NHS Trust  Involved: Self): Research Grant or Support; Novome Biotechnologies  Involved: Self): Research Grant or Support; Paratek  Involved: Self): Research Grant or Support; Pfizer  Involved: Self): Research Grant or Support; Prokaryotics Inc.  Involved: Self): Research Grant or Support; QPEX Biopharma  Involved: Self): Research Grant or Support; Rhode Island Hospital  Involved: Self): Research Grant or Support; RIHML  Involved: Self): Research Grant or Support; Roche  Involved: Self): Research Grant or Support; Roivant  Involved: Self): Research Grant or Support; Salvat  Involved: Self): Research Grant or Support; Scynexis  Involved: Self): Research Grant or Support; SeLux Diagnostics  Involved: Self): Research Grant or Support; Shionogi  Involved: Self): Research Grant or Support; Specific Diagnostics  Involved: Self): Research Grant or Support; Spero  Involved: Self): Research Grant or Support; SuperTrans Medical LT  Involved: Self): Research Grant or Support; T2 Biosystems  Involved: Self): Research Grant or Support; The University of Queensland  Involved: Self): Research Grant or Support; Thermo Fisher Scientific  Involved: Self): Research Grant or Support; Tufts Medical Center  Involved: Self): Research Grant or Support; Universite de Sherbrooke  Involved: Self): Research Grant or Support; University of Iowa  Involved: Self): Research Grant or Support; University of Iowa Hospitals and Clinics  Involved: Self): Research Grant or Support; University of Wisconsin  Involved: Self): Research Grant or Support; UNT System College of Pharmacy  Involved: Self): Research Grant or Support; URMC  Involved: Self): Research Grant or Support; UT Southwestern  Involved: Self): Research Grant or Support; VenatoRx  Involved: Self): Research Grant or Support; Viosera Therapeutics  Involved: Self): Research Grant or Support; Wayne State University  Involved: Self): Research Grant or Support Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)


We set out to explore the full burden of UTI hospitalizations in the US, including admissions both We conducted a cross-sectional multicenter study within the National Inpatient Sample (NIS) database, a 20% stratified sample of discharges from US hospitals, from 2018, to explore hospital resource utilization of patients discharged with a UTI diagnosis. We divided UTI into mutually exclusive categories of complicated (cUTI), uncomplicated (uUTI), and catheter-associated (CAUTI), in addition to healthcare-associated (HAUTI). We calculated unadjusted hospital charges, costs, average reimbursements, and length of stay (LOS) associated with these infections. Among 2,837,385 discharges with a UTI code, 77.9% were uUTI, 17.6% cUTI (80.2% HAUTI), and 4.4% CAUTI; UTI was principal diagnosis in only 17.0%. Median  LOS ranged from 4 [3-8] days in uUTI and cUTI to 5 [3-9] days in CAUTI. Overall median [IQR] hospital charges and costs were lowest in uUTI  and highest in cUTI , with the HAUTI subgroup being most costly . “Septicemia or Severe Sepsis without MV >96 Hours with MCC” was the most common DRG in uUTI (13.2%) and cUTI (14.2%), with the corresponding median [IQR] reimbursements of &11,057  and &12,226 , respectively. In contrast, CAUTI was most commonly (44.7%) reimbursed under “Kidney and Urinary Tract Infections without MCC” at &8,635 . The nearly 3 million hospital admissions with a UTI represent 8% of all annual admissions in the US. Though the majority are considered uncomplicated, all categories are nearly equally costly. Given that over 80% of all UTI-associated admissions are with UTI as a secondary diagnosis, annual estimates of primary UTI costs likely significantly underrepresent the true economic burden of UTI on the US healthcare system. Marya Zilberberg, MD, MPH, Cleveland Clinic (Consultant)J&J (Shareholder)Lungpacer Merck (Grant/Research Support)scPharma (Consultant)Sedana Spero (Grant/Research Support) Brian Nathanson, PhD, Lungpacer (Grant/Research Support)Merck (Grant/Research Support)Spero (Grant/Research Support) Kate Sulham, MPH, Spero Therapeutics (Consultant)


A 24-year-old man presented to our outpatient clinic with the left tinnitus and otalgia, which had awakened him early in the morning. Otoendoscopic examination revealed an earwig crawling in the external auditory canal. The earwig was carefully taken out with ear forceps. The tympanic membrane and external auditory canal were normal without traumatic lesions, and audiometric testing revealed normal hearing. Earwigs are insects of the order Dermaptera, and the name "earwig" originated from an ancient superstition that earwigs burrow through the external auditory canal and eat sleeping persons’ brains. Although this superstition turned out to be unfounded, the earwigs sometimes do enter the ear. There has been an old superstition that earwigs may crawl into the human ears and lay their eggs. The Merriam-Webster’s Dictionary defines an earwig as “any of numerous insects (order Dermaptera) having slender many-jointed antennae and a pair of cerci resembling forceps at the end of the body” . The EncA 24-year-old man presented to the outpatient clinic with the left tinnitus and severe otalgia, which had awakened him early in the morning. He was very agitated and reported that a bug seemed to enter into his left ear. Otoendoscopic examination revealed an earwig crawling in the external auditory canal Figure . A brillThe earwig is a nocturnal creature and generally herbivorous ,3. The eThere is no consensus on the etymology of the earwig. Due to a long-standing European superstition that earwigs burrow into human brains through the ear canals of sleeping people, the name, earwig, is derived from the Old English ēare, which means "ear," and wicga, which means "insect," or, literally, “beetle” . AlthougConsidering that clinicians meet many patients who have insects in their ears at the clinic, the present case may not be that of a rare case. However, the present study aimed to highlight the old superstition about earwigs, which is, to the best of our knowledge, the first study that shows video demonstration of an earwig crawling in the human ear. Although an ancient myth that earwigs burrow through the external auditory canal and eat sleeping persons’ brains is considered unfounded, these bugs sometimes do enter the ear, causing severe ear discomfort.


Fluid assisted Alpine fissure-vein and cleft formation starts at prograde, peak or retrograde metamorphic conditions of 450–550 °C and 0.3–0.6 GPa and below, commonly at conditions of ductile to brittle rock deformation. Early-formed fissures become overprinted by subsequent deformation, locally leading to a reorientation. Deformation that follows fissure formation initiates a cycle of dissolution, dissolution/reprecipitation or new growth of fissure minerals enclosing fluid inclusions. Although fissures in upper greenschist and amphibolite facies rocks predominantly form under retrograde metamorphic conditions, this work confirms that the carbon dioxide fluid zone correlates with regions of highest grade Alpine metamorphism, suggesting carbon dioxide production by prograde devolatilization reactions and rock-buffering of the fissure-filling fluid. For this reason, fluid composition zones systematically change in metamorphosed and exhumed nappe stacks from diagenetic to amphibolite facies metamorphic rocks from saline fluids dominated by higher hydrocarbons, methane, water and carbon dioxide. Open fissures are in most cases oriented roughly perpendicular to the foliation and lineation of the host rock. The type of fluid constrains the habit of the very frequently crystallizing quartz crystals. Open fissures also form in association with more localized strike-slip faults and are oriented perpendicular to the faults. The combination of fissure orientation, fissure quartz fluid inclusion and fissure monazite-(Ce) (hereafter monazite) Th–Pb ages shows that fissure formation occurred episodically (1) during the Cretaceous (eo-Alpine) deformation cycle in association with exhumation of the Austroalpine Koralpe-Saualpe region (~ 90 Ma) and subsequent extensional movements in association with the formation of the Gosau basins (~ 90–70 Ma), (2) during rapid exhumation of high-pressure overprinted Briançonnais and Piemontais units (36–30 Ma), (3) during unroofing of the Tauern and Lepontine metamorphic domes, during emplacement and reverse faulting of the external Massifs  and due to local dextral strike-slip faulting in association with the opening of the Ligurian sea, and (4) during the development of a young, widespread network of ductile to brittle strike-slip faults (12–5 Ma).The online version contains supplementary material available at 10.1186/s00015-021-00391-9. Fluid-assisted fissure-vein and cleft formation occurred in the Alps in metamorphic rocks due to fluid-assisted embrittlement under prograde, peak to retrograde metamorphic conditions at or below 450–550 °C and 0.3–0.6 GPa . Once formed, diffusion in monazite is negligible under prevailing P–T conditions 2(OH)6) growth. The latter has been reported from fissures in the Urals  fluid zones; Fig. A compilation of the oldest growth domains of dated fissure monazite is given in Fig. A compilation of best estimates for σ3 axes of paleostress orientations in the Alps, based on brittle deformation data obtained by many authors was provided in Bertrand and Sue . These dThe aim of this study is to combine published information from fissure monazite dating, quartz morphology and fissure orientation in order to attribute existing quartz fluid inclusion data to different tectono-metamorphic episodes of fissure formation.The European Alps, consisting of the E–W trending Eastern Alps and the arcuate Western Alps are the result of two orogenies. The first is Cretaceous in age, and the second Cenozoic   , freely grown quartz is short prismatic and is often overgrown by sceptre quartz. Bipyramidal quartz can also be observed. In oil rich fluids, fissure quartz tends to develop a steep rhombohedral habit Mullis, ; Fig. 3.4 zone, that covers the upper diagenetic and low-grade anchizone , fluids are hydrous, saline and contain < 10 mol% of dissolved CO2. Quartz crystallizing in such a fluid is prismatic in shape, shows complex macro-mosaic twinning , lamellar quartz of Dauphiné habit  oceanic and continental subduction followed by continental thickening  with Europe led to upward movements of the central part of the Alps in combination with strike slip movements along the Insubric Line  overgrowths on previously crystallized long prismatic or Tessin habit quartz  enrichment leading to formation of sceptre and ‘window-shaped’ quartz (amethyst overgrowth), and (3) Strong salt enrichment due to attribution of channelized fluids derived from evaporates.More generalized, with decreasing temperature different types of fluid evolution have been observed  fissure formation is associated with folding and exhumation of subducted material  open fissures provide important complementary information about the thermal-, fluid- and geodynamic evolution of the Alps and other orogens. Where fluid inclusion data are lacking, the quartz habit can be used to constrain the fluid type. Fissures are highly concentrated in areas where the brittle/ductile transition is preserved. Some areas with exhumed medium-grade amphibolite facies of higher-grade metamorphism contain either no fissures or completely overprinted fissures described as veins. In areas of missing competence contrast of the material, the brittle–ductile transition may never be reached and fissures are hence rare or completely missing.Additional file 1: Table S1. Th–U–Pb analyses of monazite by ion microprobe (SwissSIMS). Analyses resulting in unreliable dates  were not considered and are written in italic. Figure S1. Chemical, textural, and geochronological information for fissure monazite grains originally published in Ricchi et. al. ( et. al. . Colour-


A diagnosis of dementia in midlife can be challenging, causing losses or changes in aperson’s identity. Narrative provides a means of reconstructing identity and can becommunicated on social media. There has been initial evidence on the value of Twitter forpeople with dementia, but researchers have not yet directly engaged with users’perspectives. We employed a narrative model of identity to examine why people withdementia use Twitter and what challenges they face. Interviews were conducted with 11younger people with dementia and analysed thematically. Participants used Twitter tocounter a loss of identity through community membership and by regaining a sense ofpurpose. They sought to redefine dementia identities by challenging stigma and campaigningfor social change. The character limit of tweets facilitated narrative through whichparticipants preserved their identities. These findings suggest that Twitter could be animportant source of post-diagnostic support for people with young-onset dementia. However,there are some risks as Twitter was sometimes a hostile environment for individuals whodid not present in a ‘typical’ manner, or faced technical difficulties because of theirsymptoms. In the future, platform developers could work with people with dementia to makeTwitter more accessible for this group. There are an estimated 42,000 people in the United Kingdom (UK) living with a dementiadiagnosis made before the age of 65 years  Why do people with dementia use Twitter?(2) What challenges do people with dementia face when using Twitter?In this article, we address this gap in the literature and build on the earlier phases ofour study by engaging with people with dementia. We aimed to amplify the voices of peoplewith young-onset dementia and used a narrative model of identity to answer the followingresearch questions:This study was part of a larger multipart study that examined the use of Twitter bypeople with dementia over time , 2020b.Participants were sampled from a population of Twitter users with dementia who weidentified in the first phase of this study . All theM = 59.73;SD = 6.05). All participants had been diagnosed before the age of 65years, with age at diagnosis ranging from 45 to 63 years . Participants had been living with a diagnosis of dementiafor an average of 5.27 years . The mostfrequent diagnosis was mixed dementia (n = 4), followed by vasculardementia (n = 3), Alzheimer’s disease (n = 2) andposterior cortical atrophy . One participant was unsure ofher specific diagnosis. The sample comprised 11 people with dementia, with eight identifying as men and three aswomen. This included one participant who dropped out of the study after the initialinterview because his health deteriorated, but who consented to his data being used inthis analysis. Participants were aged between 48 and 66 years , participants took part ina series of interviews that explored their use of Twitter. After the initial interview,follow-up interviews took place six and 12 months later. All interviews were conducted inperson by the first author at participants’ homes or a place of their choosing.Each interview was split into two sections. In the first section, participants were askedabout their experiences of using Twitter, with the discussions guided by a semi-structuredinterview guide. Interview guides were developed for each time point. Each interview guidewas reviewed by two people with dementia to ensure relevant topics were being covered,questions were being asked in an appropriate and adaptable sequence and language wasaccessible. In the interviews, participants were encouraged to engage in reflectivestorytelling, in which they were asked to discuss their experiences of being diagnosedwith dementia and the role of Twitter during this time. They were also asked about thebenefits of Twitter, how they presented themselves on Twitter, interactions with otheraccount holders and barriers to using Twitter.The second section of each interview followed an adapted version of the scroll backmethod, which has previously been used with Facebook data . ParticiParticipants were asked to explain why they sent each tweet, what they hoped to achieveby posting the tweet, how they felt at the time they sent the tweet and what type ofreaction the tweet provoked. Interviews were recorded using a digital device, transcribedverbatim and anonymised. Pseudonyms are used in this article to protect participants’confidentiality. Interviews ranged in length from 35 to 80 min.Interviews were analysed using Firstly, the authors immersed themselves in the data by reading anonymised interviewtranscripts or listening to audio recordings of the interviews. The research team thendiscussed initial coding ideas. The first author subsequently coded the entire datasetusing QSR International’s NVivo 11 software. Following this, codes and relevant dataextracts were collated and examined to identify initial themes across the data. Thesethemes were then reviewed by the research team and revisions were made where appropriate.The next stage of the analysis was an iterative and reflective process, whereby theauthors repeatedly returned to the raw data and coding to refine the themes until allauthors agreed upon the finalised themes.We generated four themes from the data: (1) re-establishing identity; (2) communicating andpreserving identity; (3) redefining dementia identities; (4) threats to identity. We outlinethese themes below and use anonymised quotes to illustrate the findings.Participants reported losses and changes in their working, familial and social roles. Inresponse, participants used Twitter to re-establish their sense of identity. We generatedtwo related subthemes, showing how people with young-onset dementia re-established theiridentities through community membership and by regaining a sense of purpose.‘I went to work for the last time in September, then I was signed off work and Iretired in February. But there was nothing there…you’re just left...so I thought I’dhave a go on Twitter, and I found a lot of people in the same situation as me, andwe started learning from each other…so it’s helped me to start finding my way again’(Paul).Participants reported using Twitter to combat the loss of identity that accompaniedtheir diagnosis, by seeking out online communities of people with dementia. ‘You can tweet this has happened and then you get all these things. Either ‘ohsorry to hear that. You have a better night tonight’ or somebody will tweet ‘yesthis happens to me’. So, you know well that’s normal. It must be a regularoccurrence...and so you say oh yes, it’s the dementia. I’m not going mad’(Heather).Community membership was important to participants, with three people referring to itas a ‘lifeline’. Narrating lived experience on Twitter enabled participants to identifywith online communities of people with dementia. In turn, this created opportunities forsocial connection and peer support. Heather described her experience of receiving peersupport after tweeting about her symptoms:For Heather, community membership allowed her to see that others were facing similarchallenges, which normalised her own experiences. This suggests that membership ofcommunities on Twitter could help to counter some of the feelings of isolation and lossof identity that frequently accompany a diagnosis of dementia .‘If it wasn’t for Twitter nobody would have sent me a text message or knocked on mydoor or told me about anything. I wouldn’t have known about anything that I do nowwithout Twitter’ (Lewis).Membership of online communities also created opportunities for participants toincrease their number of offline social connections. This included attending DementiaEngagement and Empowerment Project (DEEP) group meetings, attending and speaking atconferences, going to dementia cafés, getting involved in research and being on advisoryboards. Participants explained that being active on Twitter opened ‘a new world’, andone participant said he would not have known about relevant information if he did notuse Twitter:These findings suggest that Twitter acted as a ‘springboard’ for some people withdementia, providing opportunities for meaningful offline activities and interaction.Other researchers have written about the ‘shrinking worlds’ of people with dementia,referri‘I’m not a do-it-yourself-er anymore, I’m far less a husband and father than I was,so this is concentrating on something I can do and that’s talking about dementia andknowing about dementia. It’s about giving yourself confidence, value, and a sense ofpurpose’ (Harry).Participants said they gained a sense of purpose from their use of Twitter, bysupporting others, educating themselves and others about dementia and engaging in onlineadvocacy. For example, one participant explained:By tweeting about dementia, Harry was able to establish himself as an authority figurewithin the dementia community, thus developing a positive identity with dementia as anexpert by experience. Participants likened these meaningful online activities to work;in fact, two participants referred to using Twitter as their ‘job’. Previous work hasshown that meaningful activity can preserve dignity and a sense of identity in peoplewith dementia , and tha‘Then having found some of those people and starting to receive links to documentsand meetings and things. I then, that, that lead to my first real involvement withother activists’ (Jack).Some participants reported being introduced to dementia advocacy on Twitter, which leadto them engaging in advocacy work (both online and offline) and, in turn, fostered asense of purpose. This reflects research showing that advocacy can provide people withdementia a way of regaining purpose and respect, and ‘fighting back’ against the effectsof the illness . Jack deIndeed, engaging with information on Twitter was an important first step for manyparticipants in developing an identity as an advocate. ‘When you’re using Twitter, you don’t have to think as much as when you’re having aface-to-face conversation with someone, because when you’re having a face-to-faceconversation with someone you’re frightened of making a mistake, whereas with Twitteryou can think about what you want to do’ (Robert).Participants said they used Twitter to narrate lived experience, which was ‘empowering’and ‘therapeutic’ for many reasons. Firstly, participants felt they could communicatebetter on Twitter than in offline settings because they could communicate at their ownpace, check the wording of tweets and not be interrupted:‘With Twitter, it’s more open and I don’t really need to be so careful because I cansay what I want. If I have a really crappy day I can be as open as I want to onTwitter, whereas on Facebook I have to be a bit cagey because my family don’t want tohear my bad days’ (Susan).Other participants felt that Twitter provided a safe space for self-expression becausetheir friends and family members did not use Twitter. This contrasted with participants’use of Facebook, which constrained self-expression due to family members using thisplatform. For example, Susan explained that she could be her ‘authentic self’ on Twitterand document her experiences of dementia without worrying about how this would affectfriends and family members:Participants also said the character limit of tweets facilitated self-expression. AsRobert stated: ‘I can’t do Facebook because there’s too many. You put too many sentencestogether, whereas Twitter it’s to the point’. This participant reported problems withconcentration and the character limit of tweets made it easier for him to communicate.These findings indicate that the short-text nature of tweets may provide an accessiblemeans of constructing narrative for some people with dementia, compared with other socialmedia platforms. This is important as the voices of these individuals might not otherwisebe heard.‘By the time next year comes I’ll have forgotten what I’ve done this year becausethat’s what’s happened, so it’s nice to read back’ (Susan).Participants said they narrated lived experiences on Twitter so they could look back atthem in the future. Susan described her experience of using Twitter for reminiscence:‘You’re creating a legacy for people to… I suppose a resource of information forpeople to access for long after I’m unable to carry on doing what I’m doing’(Fred).Others likened tweets to a resource of information, which they hoped people would accessafter they were no longer able to use social media:We interpret this as evidence of participants preserving aspects of themselves in theirtweets, which may serve as a valuable source of information about lived experience and bea useful tool for prompting memories. This has important implications for reminiscencetherapy, whereby social media posts could be integrated into therapy to evoke memories andstimulate mental activity.‘I sent a tweet this morning, the other day, and it was all gobbledegook because mybrain wasn’t working very well, and I think ‘oh’ so I’ll have to delete the wholetweet’ (Susan).Despite participants generally reporting that Twitter facilitated self-expression, theyalso described challenges related to their symptoms. For example, participants said theyoften made mistakes in their tweets, and would reread their tweets before posting them.One participant described her experience of making mistakes in tweets when she wasstruggling with her symptoms:Indeed, on days when participants faced increased difficulties with their dementia, usingTwitter was an effortful process requiring considerable concentration. It is likely thatif tweeting becomes too much effort for people with dementia, they will stop usingTwitter, which some participants said would leave them feeling ‘lonely’ and‘disconnected’. While it might be a relief for some people to stop using Twitter when itbecomes too challenging, it could impact their social connectedness and sense of identityby removing one of their outlets for expression.Participants reported using Twitter to redefine what it means to be a person withdementia, by challenging stigma and misconceptions about the diagnosis. In fact,participants recognised that they were already challenging dementia stereotypes by simplybeing active on Twitter. For example, Robert explained: ‘People are surprised that you’reactually on social media’.‘People don’t realise the positive side, that you can still live, and you can livefor quite a long time, depending on the dementia. So, I use it to educate and tochange minds about things’ (Harry).By showing that it is possible to live with dementia on Twitter and publicly identifyingas a person with dementia in their profiles, participants sought to represent dementia ina more positive way:‘Having a Twitter account is one way of actually saying look, I’m not ashamed ofhaving a diagnosis, and all the stigma around it is wrong’ (Judith).‘The more people that come out, the more we’ll normalise it’ (Harry).In turn, participants hoped this would change public perceptions, combat the shame thatoften accompanies dementia  and give‘Making people aware that there are young people with dementia that need help andsupport, and access to the right help and support, and not just when you reach 65.Life doesn’t just start at 65 for people with dementia’ (Robert).Another way in which participants sought to redefine dementia identities was throughusing Twitter to raise awareness and campaign for changes that would improve the lives ofpeople with dementia. These individuals aimed to get others to view dementia and the needsof those living with the diagnosis differently, thereby changing perceptions. For example,participants often commented on a lack of support for people with young-onset dementia, sothey used Twitter to challenge the idea that only those over the age of 65 years developdementia and campaign for tailored support services:Participants explained that Twitter allowed them to reach a wider audience and connectwith politicians, clinicians, researchers, organisations, local NHS trusts and localpolice forces. Indeed, participants often referred to the potential of tweets to reach avast audience, with one participant (Robert) stating: ‘if they’re telling one other personthen that person tells someone, it’s just like a snowball effect you know, if you send outpositive messages’. Thus, these participants not only used Twitter to alert others totheir needs but also used the platform as a vehicle for social change through which theypresented dementia in a more positive light.‘He said you’re all mad…but it was terrible to call us mad. I just thought ah. Youknow, ‘can tell you’re all demented’. Because some people just they come on and sayall people with dementia are lunatics’ (Robert).Whilst participants’ experiences of using Twitter were mainly positive, they did describesome negative interactions that they had online. As a result of tweeting about their livedexperiences, some participants attracted attention from trolls .Some participants said they received backlash from other account holders as a result ofpresenting themselves as people ‘It has a negative effect on you because then you can start questioning. Have I gotdementia? Am I being a fraud? It sends those questions through your mind’ (Paul).These threats to identity caused participants to feel angry, frustrated and upset. As aresult, some participants questioned the legitimacy of their diagnosis, with oneparticipant stating that he felt like a ‘fraud’:Unfortunately, almost all participants reported being exposed to tweets that questionedtheir diagnosis. These findings indicate that while Twitter was generally a positive spacefor participants, it might sometimes be a hostile environment for people with young-onsetdementia whose presentation is not consistent with more typical (late-onset) dementia.‘I started writing about that course to try and encourage [city] council and that totake it up, which has fallen on deaf ears’ (Paul).While Twitter has potential to give voice to those who have been marginalised or ignoredoffline , thiswaUnfortunately, not feeling heard by other account holders was a common experience amongparticipants, leaving them feeling discouraged, frustrated and ignored. Twitter mightprovide a platform for people with dementia to broadcast their perspectives; however, itdoes not necessarily mean that others are listening. Thus, online advocacy by itself mightnot be enough to change the lived experiences of people with dementia.We used a narrative model of identity to examine why people with young-onset dementia useTwitter and what challenges they face when using the platform. Our findings suggest thatTwitter provides opportunities for people with dementia to re-establish, redefine,communicate and preserve their identities. Despite these benefits, we also found thatTwitter can be a hostile environment for people who live with young-onset dementia, whooften experience threats to their identity from trolls and dementia doubters.Importantly, our findings highlight the value of Twitter for promoting a sense of identityamong people with dementia through community membership, instilling a sense of purpose andfacilitating self-expression. Given a growing focus on non-medical interventions to helppatients manage long-term conditions (e.g. social prescribing; We found that people with dementia experienced difficulties when using Twitter because oftheir symptoms, indicating that there is scope for it to be made more accessible for peoplewith dementia. Everyday technologies, including Twitter, have been developed in a‘hypercognitive society’  that empOur findings raise questions about what constitutes narrative. Tweet narratives differ fromother forms of narratives, such as books e.g. , as theyOur research focused on people with young-onset dementia; therefore, these individuals arenot representative of people diagnosed later in life, nor do they claim to be. The findingsof the first phase of this study, however, suggest that the population of Twitter users withdementia is small and comparatively young , so the The sample lacked diversity as participants were all White British and tended to havereasonably high socioeconomic status. It is likely that minority and vulnerable groups ofpeople with dementia, who experience intersectional oppression and face additional stigma, will haAn adapted version of the scroll back method  was usedThe focus of this analysis was cross-sectional rather than longitudinal. Given theprogressive nature of dementia, it is likely that the use of Twitter by people with dementiawill change across the disease trajectory. For example, people with dementia might useTwitter more for advocacy in the early stages and more for peer support in the later stages.In the future, researchers could conduct longitudinal research with people living withdementia to elucidate this process.In conclusion, the findings of this research suggest that people with young-onset dementiaused Twitter to re-establish, redefine, communicate and preserve their identities. Thesefindings suggest that Twitter could be an important source of post-diagnostic support forpeople with dementia. Clinicians, non-profit organisations, carers, friends and familymembers could, therefore, consider introducing people with young-onset dementia to Twitterto help them cope with the diagnosis. However, there are some risks as Twitter was sometimesa hostile environment for people with young-onset dementia who did not present in a‘typical’ manner, and their symptoms created technical difficulties when using the platform.In future, platform developers could work with people with dementia to make Twitter moreaccessible for this group.