Only a few earlier publications on intrasellar pressure (ISP) have not been able to fully clarify any association between ISP and pituitary adenoma size and growth pattern. The aim of the study was to determine if intrasellar pressure (ISP) is elevated in patients with pituitary adenoma, and if the pressure is associated with tumour size and growth pattern.The study included 100 patients operated for suspected pituitary adenoma, who have had their ISP measured intraoperatively. All adenomas were classified on the basis of Knosp and SIPAP, from which further classification of invasiveness was performed. MRT examinations were used to calculate the tumour volume and diameter in three axes.After exclusions, 93 cases were analysed. The mean ISP was 23.0 ± 8.4 mmHg. There were positive correlations between ISP and tumour volume and tumour diameters along all three axes. Coronal tumour diameter showed the strongest correlation with ISP elevation in a multivariate effect test. Adenomas classified as parasellar invasive (Knosp grade 3–4) showed higher mean ISP than adenomas considered as non-invasive (Knosp 0–2).ISP is affected by tumour anatomy and correlates positively with tumour volume. Tumour width, i.e. diameter in the coronal plane, appears to be the measure that most strongly affects the ISP. This is confirmed by the association between ISP elevation and parasellar growth. Pituitary adenoma is one of the most prevalent of all tumours affecting the central nervous system. These tumours are benign, and often cause symptoms mainly associated with compression of surrounding structures. The role of intrasellar pressure (ISP) in patients with pituitary adenoma has been the subject of investigation in a few earlier publications, in which the ISP has been measured perioperatively to elucidate the role of ISP in relation to tumour size and symptoms of the patient. Although ISP has never been measured in healthy pituitaries, normal ISP is suggested to be similar to normal intracranial pressure (ICP). It is likely that a growing pituitary adenoma will cause an elevation of the ISP, and some publications have strengthened this hypothesis –3. EarliWe assumed ISP to be elevated over suspected normal levels in patients with adenoma. We also hypothesized a correlation between ISP elevation and tumour size. At our clinic, ISP was measured during transphenoidal pituitary surgery between 2009–2015. The aim of the study was to evaluate ISP levels in patients with pituitary adenoma, and to determine if any association could be found between ISP and tumour size and/or growth pattern.Preliminary results have previously been reported at the Scandinavian Society of Neurosurgery Congress 2013, Reykjavik, Iceland and at International Congress of Endocrinology 2018, Cape Town, Republic of South Africa.This study was a single-center, consecutive, retrospective, observational study with prospectively collected ISP data. Included in the study were patients with suspected pituitary adenoma who were operated at the Neurosurgical Department, Umeå University Hospital, Sweden between 2009–2015. All of these have had their ISP measured intraoperatively. This constituted a consecutively collected study population of 100 patients between 16–85 years old.All patients were preoperatively investigated according to the standardized procedure at our clinic. This included preoperative CT of the brain and sella, and MRI examination with and without gadolinium contrast enhancement. Endocrinologists and ophthalmologists evaluated each patient before and after surgery. Data were collected from patient records. On the basis of the preoperative radiological images, tumour characteristics including tumour diameter and growth pattern were acquired. Calculations of tumour measures in 3 axes  were performed. For tumour volume estimation, Automatic Sectra Volume Tool  was used. All volume measurements were also manually checked.Tumours were classified on the basis of Knosp  and SIPAThe surgical approach was transsphenoidal tumour extirpation, either microscope assisted through lateral rhinotomy, or by endoscopic assisted transnasal approach. All procedures during these years (2009–2015) were executed with one neuro-surgeon as the responsible main surgeon, and ISP measurements were performed as a part of the standardized surgical procedure at the clinic. Surgery was performed under standard neuro-anesthesia with oral intubation. Patients were normoventilated with pCO2-levels between 4.6–5.5 kPa. The ISP was measured before start of tumour resection using an intracranial pressure monitoring device (Codman® MicroSensor™ (CMS) Codman & Shurtleff Inc, Raynham, MA USA), which has been shown to accurately measure parenchymal pressure. This devices accuracy is well documented, and it is used clinically as a standard method for intracranial pressure monitoring –12. A smHistological diagnoses were defined according to the the routine histopatholocigal assessment at our hospital. Three adenomas had not a fully conclusive histochemical assessment and therefore classified as “histochemically unclear”, and was separated from the functioning and non-functioning adenoma group.Seven cases were excluded from the whole analysis, 6 of those because they had histological diagnoses other than pituitary adenoma. One subject was excluded because the anatomy of the sellar region had been completely destroyed by the pituitary adenoma, making it impossible to monitor the pressure accurately and draw any conclusion from the measurement. Thus, the final population consisted of 93 subjects. Of those, two cases were not included in tumour volume calculations, since their radiological images did not show enough quality for the software to performe acceptable and comparable volume estimations. A few cases , malignant sarcoma, and pituitary metastasis. After exclusions, the total study population constisted of 93 patients, all with pituitary adenoma diagnosis. The distribution of biochemical diagnoses are listed in Table 3. The mean coronal tumour diameter was 18.9 ± 5.1 mm, anteroposterior diameter 17.2 ± 5.7 mm, and craniocaudal diameter 21.9 ± 7.6 mm. The distribution based on the classifications is presented in Table 4. Thirty-six tumours showed parasellar growth in either or both directions classified as Knosp grade 3 or 4, and therefore defined as parasellar invasive. No differences in tumour volume, tumour measures or invasiveness were seen between men and women (Table The population consisted of 52 men and 41 women. The mean age was 61 ± 14 years (Table n = 93) was 21 mmHg, with a mean of 23.0 ± 8.4 mmHg. Men had higher mean ISP than women    , and the craniocaudal tumour diameter . In the multivariate effect test including all diameters the coronal tumour diameter showed the strongest effect in the model (p = 0.0007). Tumours classified as parasellar invasive  had higher mean ISP (26.3 ± 9.4 mmHg) than tumours classified as Knosp grade 0–2  (p = 0.0022)  compared to patients without  (p > 0.05).ISP showed no correlation to age. Neither were there any difference in ISP between the different surgical approaches. No difference in mean ISP was found in patients with acute apoplexy , tumour volume (p = 0.0140), and parasellar invasiveness (p = 0.0249) still showed significant effect on ISP.The results from univariate analyses were confirmed by an additional multivariate regression analysis exploring ISP in correlation to the basic characteristics . In this model sex , by performing ISP measurements on patients with empty sella and patients with bromocriptine treated microadenoma, acquiring ISP levels below 15 mmHg –5, 13, aThe relationship between tumour volume and ISP was investigated by Gondim et al. 2006, who found the highest ISP levels in large tumours which still had not grown through the sellar wall . In a neTo further discuss how tumour growth pattern affects ISP, we found higher ISP levels in tumours with an invasive parasellar growth into the cavernous sinus, in this study defined as Knosp grade 3–4. This result is in line with the conclusion of the tumour width being the measure that most strongly influences the ISP. Knosp’s classification is today the widely used system for classification of parasellar growth. However, definition of invasiveness from MRI is not unproblematic since there are reports showing that invasiveness can not be excluded in tumours graded as Knosp < 3 , 19, 20 One possible explanation for these findings, firstly postulated by Lee et al., is thatA finding of interest is that this study demonstrates higher mean ISP in men compared to women. Similar findings are not reported in previous publications where ISP have been explored. There have, though, been reported gender differences in some parts of the clinical course of pituitary adenoma disease , for exaThis study presents one of the largest study populations presented so far in this field. ISP measurements have been performed in a standardized manner at one centre, by one responsible neuro-surgeon. The method chosen for the ISP measurements is similar to that used in the majority of previous studies, and the accuracy of the device used is satisfactorily documented. Is there a risk of pressure decrease following durotomy? We do not think so because the actual dural opening in our study was initially only big enough for the insertion of the monitoring device. Special attention was taken toward ensuring that no leakage of intrasellar content followed the insertion. As in every case concerning this type of invasive pressure monitoring, it is not possible to exclude a small pressure decrease, but as long as studies are performed according to similar methodology, results are still comparable.Our results further explore the significance of tumour anatomy in terms of ISP, and may serve as a ground for understanding the pathophysiological mechanisms of pituitary tumourous disease. Further clinically relevant questions that are raised with these results is how ISP corresponds to preoperative symptoms and postoperative outcome. Sella constitutes a confined space with crucial structures in the close surrounding, including cranial nerves and the low-pressure venous portal system that regulates the important functions of the pituitary. One may speculate that increased ISP leads to a microcirculatory deterioration affecting the pituitary function and surrounding tissues, that in turn may be associated to hormonal imbalances, endocrine recovery potential and postoperative complications.ISP seems to elevated above suspected normal levels in patients with pituitary adenoma. ISP is positively correlated with tumour volume and tumour width. We could not confirm an earlier study that found the highest ISP levels in adenomas confined in the sella. Coronal tumour diameter seems to have a greater impact on ISP than growth in the other directions.LOK contributed to the study conceptualization and design. LOK, POE and PL contributed to data collection. Data analysis was performed by GS and LOK. The manuscript was written by GS and LOK. All authors have read, commented on, and approved the final manuscript.


S. maltophilia should enable early optimization of antimicrobial therapy.The GenMark Dx ePlex BCID Gram-Negative (GN) panel utilizes electrowetting technology to detect the most common causes of GN bacteremia (21 targets) and 6 antimicrobial resistance (AMR) genes from positive blood culture (BC) bottles. Rapid detection of extended spectrum β-lactamases , and highly resistant bacteria such as In this prospective study, aliquots of positive BC bottles with GN bacteria detected on Gram stain (GS) (n=108) received standard of care (SOC) culture and antimicrobial susceptibility testing (AST). Additionally, samples were evaluated with the BCID-GN panel but only SOC results were reported in the EMR and available to inform clinical decisions. Chart reviews were performed to evaluate the impact of the BCID-GN panel on the time to organism identification, AST results, and optimization of antimicrobial therapy. Escherichia coli was the most common bacteria identified followed by Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter species (Table 2). There were 11 (10.2%) polymicrobial bacteremias. Repeat BCs were obtained in 68 (63%) patients of which 13 (19%) were persistently positive. Eight (7%) patients had evidence of additional gram-positive (GP) pathogens. Organism identification occurred 26.7 hours faster than culture. In conjunction with GS, negative pan-GP marker data could have helped providers make the decision to remove GP antibiotic coverage in 63 (58%) patients. Narrowing from empiric meropenem could have occurred in 5 patients. Of 10 individuals infected with resistant isolates  empiric therapy was ineffective in 4 (40%) cases. Optimization of antimicrobial therapy for 9 (8.3%) patients could have occurred an average of 52.4 hours earlier than standard methods. A total of 108 patients are included in the analysis (Table 1). Table 1. Patient demographics and co-morbidities.Table 2. Gram-negative bacteria frequency.The BCID-GN panel enabled earlier time to optimal treatment of highly resistant bacteria as well as multiple opportunities for narrowing gram negative spectrum and a higher degree of certainty in cessation of broad-spectrum gram-positive antibioticsTodd P. McCarty, MD, Cidara (Grant/Research Support)GenMark T2 Biosystems (Consultant) Sixto M. Leal, Jr., MD, PhD, Abnova (Grant/Research Support)AltImmune (Grant/Research Support)Amplyx Pharmaceuticals (Grant/Research Support)Astellas Pharmaceuticals (Grant/Research Support)CNINE Dx (Grant/Research Support)GenMark Diagnostics IHMA (Grant/Research Support)IMMY Dx (Grant/Research Support)JMI/Sentry (Grant/Research Support)mFluiDx Dx (Grant/Research Support)SpeeDx Dx (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)


The characteristics features of thermal energy transfer of hybrid nanofluid are investigated by varying the pitch ratio (P) of the helical turbulator and Reynolds number (Re) of the fluid. The outputs of the study are depicted in terms of contour plots of temperature, velocity, frictional irreversibility Sgen,f, and thermal irreversibility Sgen,th. The variation of Sgen,f, and Sgen,th with changing P and Re are also displayed by 3D plots. It is found that making the fluid more turbulent by increasing Re, the temperature of the fluid drops whereas the fluid velocity augments. The frictional irreversibility enhances, whereas the thermal irreversibility drops with the increasing turbulent motion. The decreasing P causes to drop the temperature of the higher turbulent fluid flow, while opposite effect is observed for smaller Re. The decreasing P causes to enhance the fluid mixing and thus augments the fluid velocity. Sgen,f and Sgen,th both augment with decreasing P. The comparison of current outputs with the older article shows an acceptable accuracy. The results of the present investigation will be useful in modelling of efficient thermal energy transfer systems.The thermal features of hybrid nano-powder turbulent motion through a pipe employing helical turbulator is numerically simulated via Finite Volume Method (FVM). The hybrid nanofluid (MWCNTs + Fe These methods are actually the augmenting techniques which can enhance the performance rate, reduce the system size and also minimize the working cost. The heat transfer enhancing approaches can be mainly characterized as active and passive methods. The passive technique uses turbulator such as twisted tape, spiral fins, etc. whereas active technique uses power from external source. Due to small size, simple manufacturing, high strength and low occupancy, pipes are used widely as thermal exchanger in different commercial and industrial sectors. The common widely used heat transfer ordinary single-phase fluids are oils, water, ethylene glycol, etc. The issue with using single-phase fluid is its low thermal conductivity. In the recent past, nanofluids have been developed to be used instead of ordinary single-phase fluids due to their high thermal conductivities7. Nanofluids are obtained by intermixing nanoparticles in the host fluids. The size of the nanoparticles lies in 1 to 100 nm range. Nanoparticles are made usually from metals and their oxides. Nanofluids can have tremendous thermal conductivities, which find applications for heat transfer processes in different sectors of engineering and technology10. Choi11 scrutinized the idea of nanomaterial as carrier fluid. Researchers have investigated different features such as shape, size, and concentration of nanomaterials for augmenting the nanofluid thermal energy transfer rate. Nowadays, hybrid nanofluids which consist of nanoparticles of more than one kind are also used for augmenting the thermal features of ordinary fluids. Khedkar et al.12 studied the Al2O3-H2O nanofluid thermal characteristics by using 3% volume concentration of Al2O3 nanomaterial in H2O. They obtained an increase of 16% Nu. Hilo et al.13 reviewed the different features of graphene nanomaterial, and described its applications in cooling phenomena. Wu et al.14 examined the heat transportation features of H2O-Al2O3 nanomaterial moving through a helical shape heat exchanger. They showed that the nanoparticles impact can be neglected on various critical Reynold numbers. They also found that nanomaterial can grow Nu up to 3.43%. Sun et al.15 experimentally scrutinized the performance of different nano-powders flowing through pipes having twisted tapes. They found that the system efficiency enhances with the increasing nanoparticles concentration. Chougule and Sahu16 performed an investigation of Al2O3 + H2O and CNT + H2O nanofluids moving through a tube containing complex tape. They found that for the twist ratio 1.5, highest heat energy transfer occurs. Mohamad et al.17 used FVM to examine the heat energy transfer capability of different nanomaterials types, such as ZnO, Alumina, CuO, and SiO2 using various volume concentrations maximum up to 4%. Their results show that SiO2 has the highest Nu. Labib et al.18 analyzed the thermal features of H2O-CNTs nanofluid containing Al2O3 nanoparticles. The authors reported a tremendous augment in the convection for such type of nanofluid. They found that h increases by 22.8% and 59.86% when 0.6 and 1.6 vol% of Al2O3 are added with 0.05 vol% of H2O-CNT. The thermal efficiency of radiator was examined by Prayogo et al.19. They investigated the cooling rate for different conditions. Garcia et al.20 defined the basics of helical device and used it for homogenous fluid motion in the transitional area of a pipe. They found high Nusselt number for the investigated system. Sajid and Ali21 presented different applications of nanomaterials in their review article. For intensification of swirl flow, Qi et al.22 used rotating twisted tape during nanofluid flow through a system.To augment heat transfer in different process like heat exchangers, refrigeration, chemical process and automotive cooling, varieties of methods have been developed26. Entropy analysis becomes important to investigate the thermal features of the considered system. Bejan27 introduced the irreversibility optimization concept during convective thermal energy transformation processes. Finding innovative kind of operating fluid was main aim of various scientists30. Ellahi et al.31 scrutinized the impacts of various shapes nanomaterial using irreversibility optimization. Miroshnichenko et al.32 analyzed the nanofluid convective magnetized motion from a trapezoidal cavity. Their study displays that the value of Nu drops with the increasing MHD, while grows with the enhancing concentration of nano-powders. Shafee et al.33 performed numerical simulation study of nanofluid turbulent motion through entropy analysis. During their investigations, they depicted that the thermal energy transfer improves with the augmenting turbulator height and exergy loss is related inversely with input power. Feroz et al.34 employed the effective conductivity model to investigate the CNTs nanofluid motion in a rotating channel by considering Ion slip and Hall effects. They applied entropy optimization principle to model the thermal characteristics of the nanofluid motion. Elahi et al.35 examined the nanofluid peristaltic motion through permeable enclosure using entropy optimization principle.The efficiency of heat transfer system deteriorates with the enhancing use of free energy available for doing useful work in the systemMotivated from the above studies, it is planned to investigate the thermal energy transfer features of hybrid nanofluid turbulent motion using entropy optimization. The innovation of the current article is the second law investigation of the hybrid nanomaterial migration by inserting a helical turbulator in tube. The helical turbulator is used to make the flow more swirling and generating secondary flow. Among different geometric parameters of the helical turbulator, the impact of varying pitch ratio (P) over the heat transfer characteristics is investigated in the current work. The model relations are numerically solved through FVM. The outputs of the study are explained through contour and 3D plots. This research work has potential applications in heat exchangers, refrigeration, automotive cooling, and different physical and chemical processes. This article is organized in the following way. The physical model of the study is explained in “3O4 + H2O) hybrid nanofluid. A helical turbulator is used to make the nanofluid motion turbulent and more swirling inside the tube. The sample mesh is also shown in Fig. 36.Figure 38Forced convection turbulent hybrid nanofluid motion through a heat exchanger can be mathematically formulated as38:37:Turbulent model has been added two scalars3O4 + H2O) properties as illustrated in Table 136. The nanofluid properties are described by the relations36:This study uses the empirical data of the mixture of  is chosen as working substance considering single phase model to estimate its properties. The different aspects of the turbulent fluid motion are studied by depicting contour graphs of temperature, frictional and thermal irreversibilities  as function of varying pitch ratio (P) of the helical turbulator and enhancing Reynolds number (Re) of the hybrid nanofluid motion. The 3D plots are plotted which display the functional dependence of Sgen,f and Sgen,th with augmenting pitch ratio (P) and enhancing Re associated with higher values of the input power.In current research the hybrid nano-powder migration through a pipe having a helical turbulator is simulated numerically via FVM. The helical turbulator causes to make the fluid motion more turbulent and also causes secondary fluid flow. The tube is under effect of constant heat flux. The entropy analysis is applied to examine the hydrothermal features of the fluid motion. The hybrid nanofluid , and thermal irreversibility  at varying values of Reynold number (Re) and pitch ratio (P). In Figs. gen,f enhances due to enhanced swirling flow as a result of the insertion of helical turbulator. The increase in Reynolds number due to the enhancing input power causes to augment the entropy creation tremendously due to higher frictional motion. The enhancing swirling flow also results a decrease in Sgen,th owing to decrement of ∇T between the fluid and wall of the tube. The enhancement in Reynolds number due to increase in the input power also drops the entropy generation as an output of decrease in the ∇T that exists among the fluid and tube wall.The outputs of the current study were explained by depicting the contour and 3D plots showing the variation of hybrid nanofluid characteristics with changing pitch ratio of the helical turbulator and enhancing turbulent motion associated with higher values of Reynolds number. Figures P = 0.1) as compared to the previous value for P in Figs. P also drops the temperature of the fluid. Thus the augmenting swirling flow due to smaller pitch ratio and the generation of secondary flow result in the reduction of the fluid temperature. The contour plots for the velocity shows an enhancement in the velocity with the increasing Re. This is obvious that fluid velocity shall be larger at higher input power (larger Re). Furthermore, the turbulator with smaller P also enhances the fluid velocity due to high swirling motion. The distributions of Sgen,f display that the entropy development linked with resistance of fluid because nanomaterial motion augments with the increasing Re as a result of enhancing friction associated with the higher fluid velocities. Furthermore, Sgen,f augments with the decreasing P except at Re = 5000. The entropy generation related with ∇T exists among the fluid and walls of the container decreases with the augmenting input power (higher Re). This displays that the temperature gradient exists between fluid and wall of the tube drops with the enhancing turbulent motion.Figures The following formulae are used for computing It is evident from Eqs.  and 14)14) that gen,f and Sgen,th with varying values of Reynolds number (Re*) and pitch ratio (P) of the helical turbulator. The figure displays that Sgen,f augments with enhancing Re*, while drops with increasing P. We see that the rate of enhancement of Sgen,f with rising Re* is much larger than its rate of drop with increasing P. This shows that the higher the hybrid nanofluid turbulent motion, the larger Sgen,f will be achieved. The 3D plots for Sgen,th display that the entropy generation variation owing to the temperature difference. It drops with the increasing input power (augmenting Re*). We also observed that Sgen,th drops with the enhancing P. But this rate of drop of Sgen,th with rising P is much smaller than the drop with rising Re*.Figure gen,th associated with the temperature gradient among the working fluid and wall drops, while the frictional irreversibility Sgen,f enhances with the increasing turbulence (higher Re) of the hybrid nanofluid. The decreasing pitch ratio (P) of the helical turbulator enhances the fluid velocity for the entire turbulent flow and drops the fluid temperature at higher Re. The entropy generation augments with the decreasing values of P.The hybrid nanofluid turbulent motion through a pipe in the presence of constant heat flux is numerically simulated in this study. A helical turbulator is employed to make the fluid motion a swirling one and to generate secondary flow. The modeled formulation consisting of flow and temperature equations are solved using FVM. The forced convective features of the flow are analyzed through entropy optimization. The impacts of varying pitch ratio of the helical turbulator (P) and Reynolds number (Re) of the fluid are investigated over the forced convective characteristics of the hybrid nanofluid motion through the heat exchanger. The results are displayed through contour and 3D plots. The comparison with the published work ascertains an acceptable accuracy. It is perceived that the fluid temperature drops while velocity enhances with increasing Re. The thermal irreversibility S


Primary tumours, particularly from major solid organs, are able to disseminate into the blood and lymphatic system and spread to distant sites. These secondary metastases to other major organs are the most lethal aspect of cancer, accounting for the majority of cancer deaths. The brain is a frequent site of metastasis, and brain metastases are often fatal due to the critical role of the nervous system and the limited options for treatment, including surgery. This creates a need to further understand the complex cell and molecular biology associated with the establishment of brain metastasis, including the changes to the environment of the brain to enable the arrival and growth of tumour cells. Local changes in the vascular network, immune system and stromal components all have the potential to recruit and foster metastatic tumour cells. This review summarises our current understanding of brain vascular microenvironments, fluid circulation and drainage in the context of brain metastases, as well as commenting on current cutting-edge experimental approaches used to investigate changes in vascular environments and alterations in specialised subsets of blood and lymphatic vessel cells during cancer spread to the brain. Cancer arises when acquired or inherited mutations in the cells of the body result in uncontrolled cellular proliferation. In the case of solid tumours, the most lethal attribute of cancer is the ability of tumour cells to escape the primary tumour and metastasise via blood and lymphatic vessels to distant organs. Assessment of the number and location of metastatic lesions in a patient forms a critical part of disease staging and dictates both prognosis and treatment options . MetastaThe brain is a vital, complex, and intricately compartmentalised organ, containing equally complex and specialised vascular microenvironments in each of its distinct anatomical regions. Perhaps the most specialised and fundamental component of the brain vasculature is the blood–brain barrier (BBB). The BBB, a key feature of the vessels penetrating into the parenchymal tissue, refers to the tightly regulated assembly of cells including the endothelial cells, pericytes, vascular smooth muscles cells, and astrocytes that are collectively known as the neurovascular unit (NVU) . EndotheEarly tumour cell seeding as well as tumour-derived extracellular vesicles or circulating factors from distant primary tumours will often shape the microenvironment in secondary sites such as the brain before tumour cell colonisation, creating a favourable environment for secondary tumour establishment termed the pre-metastatic niche ,9,10,11.In this review, we discuss the current understanding of brain vascular microenvironments, fluid circulation and drainage in the context of brain metastases. We describe the current understanding of the cellular components of the metastatic tumour microenvironment in the brain, with a specific emphasis on tumour–vasculature interactions during the early events of tumour cell seeding in the brain and the formation of established metastatic lesions. In addition, we comment on current cutting-edge experimental approaches used to support our understanding of the tumour–vascular interactions in brain metastasis.The brain is anatomically complex, containing several distinct compartments including the parenchyma, ventricles, brainstem, and meningeal layers at the cortical surface. Each of these compartments houses phenotypically unique vascular environments, and all depend on a continuous supply of blood from a highly integrated network of penetrating blood vessels arising from the neck region A,B. The The major arteries and penetrating blood vessels of the brain parenchyma contain specialized BBB endothelial cells that create a highly selective semipermeable border due to the abundance of tight junctions that adhere neighbouring cells to each other, forming a tight barrier  Figure C. This iThe meninges, which encapsulate the brain, are composed of three membranous layers known as the dura, arachnoid and pia mater, each unique in its contributions to the vasculature present at the cortical surface C 17]. T. T17]. TThe vasculature of the brain, as with other organs, branches hierarchically from larger vessels down to the smaller capillaries where most of the molecular and cellular exchange occurs between circulation and the brain parenchyma. Anatomically, larger arteries at the cortical–meningeal surface will branch into arterioles that penetrate into the brain parenchyma, maintaining the characteristic phenotypical features of the blood–brain barrier B. ArteriBmx, Efnb2, Vegfc and Sema3g, and venous markers included Nrf2. Gradual changes in expression of genes such as Tfrc and Slc16a1 were seen, with expression levels peaking toward the capillary–venous end of the spectrum, corresponding to protein expression detected in capillaries and venules but not arteries. Other genes such as Vwf and Vcam1 peaked in arterial and venous clusters, with a loss of expression within the capillary population, whereas Mfsd2a, the gene encoding a BBB-specific lipid transporter, was seen to peak in the capillaries, again matching peaks seen in the distribution of protein staining of the marker across different vessel types . SMC populations were further subcategorised as arterial SMC (aSMC), arteriole SMC (aaSMC), and venous SMC (vSMC). One stark contrast to endothelial cell arteriovenous zonation was that the order of transcriptional relatedness of mural cell types (Pericyte → vSMC → aaSMC → aSMC) did not match the anatomical organization along the arteriovenous axis. In fact, two predominant gene expression patterns were found in the mural cell analysis that identified two distinct subclasses of mural cells—one group consisting of pericytes occurring in continuum with vSMCs through gradual loss of pericyte markers and gain of SMC markers, and the other consisting of aaSMCs in continuum with aSMCs through the progressive gain of aSMC markers. High resolution imaging of the SMC marker smooth muscle α-2 actin (ACTA2), and the pericyte marker platelet-derived growth factor receptor beta (PDGFRβ) expression further indicated the abrupt transition between the two major subclasses of mural cells at the arteriole–capillary boundary where arterioles predominant in aaSMC transition to pericytes surrounding the capillaries.Plvap and low expression of tight junction-encoding genes such as Cldn5  are key sites of fluid exchange between the brain parenchyma and the CSF space. These consist of a network of perivascular spaces or channels formed via separation between the layer of astrocytic foot processes  and endothelial basement membranes ,35. HereThe dura is also a major site of venous drainage in the brain, where the superior sagittal sinus, running along the midline of the cortical surface, drains cerebral veins by providing a low-pressure system for blood flow back into systemic circulation A,B 37,3,337,38. For some time within the field of metastasis, a key area of interest has related to a concept that was first theorized in 1889 termed the “seed and soil” hypothesis, which highlights the intrinsic properties certain sites (“soil”) possess that make them a preferential site for establishment of secondary tumours (“seed”) . This coThe ability to detect brain metastases in patients is improving with advances in technology, nevertheless a stark number of brain metastases remain undetected until autopsy analysis in otherwise asymptomatic patients, occurring at rates of up to 75% . This inExtensive reviews have already been undertaken on the current treatment modalities and their efficacy for brain metastases from different primary tumour sources ,56,57,58Immune therapies, such as checkpoint inhibitors, are possibly the most promising treatment modality for advanced metastases. It has recently been shown that anti-CTLA-4 in combination with anti-PD-1 therapy has resulted in response rates of 45–60% in patients with melanoma brain metastases ,67. CTLAThe meninges, parenchymal penetrating blood vessels, ventricles, and CSF are all sites of metastatic lesion formation or circulating tumour cell accumulation, each presenting their own challenges regarding treatment ,74,75,76In order for circulating tumour cells to successfully seed into distant tissues, they require a favourable environment (“soil”) in which to do so, containing the necessary nutrients, extracellular matrix proteins, and supporting cells to sustain the ongoing growth and proliferation of a metastatic lesion after initial dissemination . It contEPB41L5 mRNA, the encoded protein of which has known oncogenic effects . C. C96]. CHematogenous spread of disseminated tumour cells from a distant primary tumour toward the brain and subsequent micro-metastasis formation is an extremely inefficient process. It has been shown in mouse experimental models of brain metastasis that upon vascular arrest of tumour cells in the brain, approximately 1–5% of cells will actually go on to form a macrometastasis ,99. In lAfter tumour cell arrest and successful extravasation, tumour cells attempting to colonise the brain require close physical contact to the abluminal surface of blood vessel walls in a pericyte-like position in the perivascular space A 98]. M. M98]. MIt is becoming increasingly evident that to fully understand how metastases colonise the brain, one must take into account the dynamic mechanical and molecular processes governing early tumour establishment, as the location of larger established secondary tumours in the brain may not be representative of the infiltration and early seeding sites. An example has been illustrated in a recent study where it was found that in the majority (up to 90%) of small intracranial melanoma metastases (2–9 mm) in a cohort of patients developed in close relationship to the leptomeninges, commonly at the cortical-pial surface, as well as in the ventricular system and perivascular spaces . It was Leptomeningeal disease, although less common, is also another significant form of cerebral metastasis that confers poor prognosis, diagnosed by the identification of tumour cells circulating within the CSF. Leptomeningeal disease has been found often in close association with leptomeningeal metastases and is thought to be characterised by a change from an adherent phenotype  to a floating, more aggressive phenotype that circulates in the CSF . ThroughRecent advances in characterising the meningeal lymphatic system have illustrated an avenue for soluble factors and immune cells to drain from CSF within the subarachnoid space into the cervical lymph nodes ,43. It wUnderstanding tumour–vasculature interactions at the early stages of tumour formation as well as before tumour cells have established is key for progressing our understanding of organotropic tumour cell spread. The pre-metastatic niche is becoming a critical point of interest in cancer metastasis research and understanding the mechanisms regulating its formation could play a vital role in the future for creating preventative treatments. Extracellular vesicles have been shown to play a major role in shaping pre-metastatic environments, and influencing endothelial cell behaviour ,95,96,97ScRNA-seq has recently come to the forefront of cancer biology research, providing a platform to run large discovery studies on gene expression changes within different disease models at single-cell resolution . This hiSpatial transcriptomics is another related technique that is beginning to approach the forefront of research into the tumour microenvironment. This technology allows investigators to map transcriptomic expression spatially across a tissue sample, which is extremely useful for visualising tumour–microenvironment interactions. Using a zebrafish model of melanoma, one study uncovered a distinct interface cell state between the tumour boundary and microenvironment cells, where cilia genes were upregulated. Whilst recent studies have implicated cilia in different aspects of melanoma biology, including the deconstruction of cilia driving metastasis, this study was the first to show spatial specificity to the upregulation of cilia genes. More importantly, only cells at the tumour boundary had this high expression, illustrating the power of spatial transcriptomics in coupling spatial and molecular alterations in disease models .It is also important to understand the route of cancer cell spread towards the brain. Particularly the alterations to blood and lymphatic vessels associated with the primary tumours and tumour-draining lymph nodes that allow a cancer to metastasise more readily and promote aggressive phenotypes. It has already been shown that melanoma tumour cells isolated from human lymph nodes will metastasise more readily to the leptomeninges in mouse models, as opposed to tumour cells isolated from the brain parenchyma which produce parenchymal metastases ,107. StuIt is important to factor in the complexity and heterogeneity of the vascular environments within the brain when designing experimental approaches to understanding tumour–vascular interactions and the brain tumour microenvironment in general. Taking the aforementioned principles into account may lead to interesting experimental designs that seek to characterise the differences in tumour cell colonisation of the brain in different experimental models of metastasis in order to better understand the site-specific spread of cancer to the brain from solid primary tumours. By using new discovery techniques such as scRNA-seq and spatial transcriptomics, more drivers of cancer cell spread to key organs such as the brain will be uncovered. These discoveries will lead to better understanding of cancer cell biology, thereby informing the generation of new therapeutics, more effective use of existing treatments and, ultimately, better outcomes for cancer patients.


Managing burn fluid resuscitation for large burns is challenging and relies heavily on accurate nursing documentation. The Burn Navigator (BN) is a clinical decision-support system designed to guide clinicians in burn fluid resuscitation. However, data entered into the BN do not auto-populate into the electronic medical record (EMR), thus requiring nurses to document in two systems. We sought to compare differences in nursing documentation of data entries between the EMR and the BN on burn patients with ≥ 20% total body surface area (TBSA) undergoing intravenous (IV) fluid resuscitation.Institutional Review Board approval was obtained for a multi-center observational study of burn patients undergoing fluid resuscitation using the BN. Data were collected and analyzed between the EMR and BN entries entered into the REDCap database from 5 American Burn Association (ABA)-verified burn centers. The following variables were analyzed: time of burn injury, weight, TBSA burned, urine output (UOP), and hourly IV crystalloid fluid volume.Analysis included 296 subjects (of 300 enrolled). Results show no significant difference between burn centers for mean weight (BN 87.02 ± 22.9 kg vs. EMR 87.1 ± 23.3 kg), TBSA (BN 40.71 ± 19.24% vs. EMR 40.97 ± 19.29%), or time of burn injury (< 1 hour). The time of injury recorded in the BN versus EMR was later in 44.6% (n=132) of patients and earlier in 46.4%, (n=138) and the same in 8.8% (n=26) of records. Additionally, in 293 records, there was no significant difference between centers in patient UOP (BN 0.91 ± 0.52 ml/kg/hr vs. EMR 0.91 ± 0.63 ml/kg/hr). One site had a significant difference in hourly fluid rates  due to a lack of inclusion of pre-hospital fluids.When comparing the data between the EMR to BN, it was observed that pre-hospital fluids tended not to be documented in the EMR, causing a statistically significant difference in total fluids administered in one burn center. Overall, the nursing documentation variability was minimal across all sites even though the nurses had to document the data in two different systems, while simultaneously caring for critically ill patients with large burn injuries. Close monitoring of the nursing documentation during burn fluid resuscitation should always be a priority.


Background: A key issue in abdominal US is the assessment of fluid, which is usually anechoic, thus appearing “black”. Our approach focuses on searching for fluid in non-traumatic patients, providing a new, simplified method for point-of-care US (POCUS). Objective: Fluid assessment is based on a three-step analysis that we can thus summarize. 1. Look for black where it should not be. This means searching for effusions or collections. 2. Check if black is too much. This means evaluating anatomical landmarks where fluid should normally be present but may be abnormally abundant. 3. Look for black that is not clearly black. This means evaluating fluid aspects, whether wholly anechoic or not (suggesting heterogeneous or corpusculated fluid). Discussion: Using this simple method focused on US fluid presence and appearance should help clinicians to make a timely diagnosis. Although our simplified, systematic algorithm of POCUS may identify abnormalities; this usually entails a second-level imaging. An accurate knowledge of the physio–pathological and anatomical ultrasound bases remains essential in applying this algorithm. Conclusion: The black pattern approach in non -traumatic emergencies may be applied to a broad spectrum of abnormalities. It may represent a valuable aid for emergency physicians, especially if inexperienced, involved in a variety of non-traumatic scenarios. It may also be a simple and effective teaching aid for US beginners. Ultrasound (US) is rightly regarded as the initial imaging tool for the evaluation of patients with abdominal pain. It is crucial in the management of both trauma ,2 and noPOCUS is primarily used to answer focused clinical questions at the bedside, to narrow the differential diagnosis and direct early appropriate therapy. This approach has many advantages over traditional imaging modalities: it is rapid, portable, non-invasive, repeatable, less expensive, and does not entail ionizing radiation exposure. POCUS has several applications, including diagnostic, screening, and procedural, as already recognized by leading scientific societies ,3,5. ScaDespite the high accuracy reported for POCUS protocols among radiologists and non-radiologists alike, these diagnostic tools are usually limited to confirming or excluding a single clinical hypothesis on which the exam is focused. In such a mindset, the abdomen would not be considered as a whole with each organ or structure representing an independent topic and thus a separate exam. As has already been done for POCUS in traumatic cases, where focus is on free-fluid detection, the purpose of our pattern approach is to apply the search for abdominal fluid in non-traumatic emergencies, considering the abdomen as a whole. Our re-reading of the POCUS approach consists of a three-step analysis. 1. Looking for black where it should not be, 2. looking to see if there is too much black, i.e., if it is overabundant where normally present, 3. looking for black that is not clearly black. On the basis of this simplified US analysis, a first diagnostic hypothesis can thus be proposed, and patients quickly stratified. It can be considered as a first diagnostic approach to acute, non-traumatic abdominal pain, easily performed by all physicians involved in acute care settings. US is widely available nowadays and fluid semeiotics is the first teaching point in the US learning process . ProvidiFluids, especially if poor in cells, appear as black, hypoechoic to anechoic in US, because most of the US’ beam goes through them and only a small part of the waves is reflected and returns to the transducer. The search for black fluid and its possible shades of gray is the basic principle of our POCUS protocol ,4,7. ThiFAST has become the common initial screening modality in most traumas. The goal of FAST examination is the detection of free fluid in the peritoneal cavity, pericardium, and pleural spaces. The volume of fluid accumulation required for visualization by US ranges between 250 and 620 mL ,2. SimilThe presence of free fluid in non-traumatic patients is highly indicative of a broad spectrum of abnormalities that require prompt diagnosis and management. Patient management often requires a second level of imaging  in many cases to identify and stage the pathology and then choose optimal treatment, including medical therapy, intervention, or surgery .Here, we summarize the main etiologies underlying those conditions in which there is black where it should not be.Identifying the cause of intra-abdominal bleeding in non-traumatic patients is a challenging diagnosis. Causes of non-traumatic hemoperitoneum have been grouped into etiologies such as iatrogenic , tumor-related, gynecological, and vascular. The three most common causes among women and in order of decreasing frequency are a ruptured ovarian cyst (women < 35 years old), recent procedure, and unknown mass .In patients with abdominal distension, US can quickly determine whether abdominal ascites is the cause. The technique is similar to that used in the FAST protocol. The fluid is usually anechoic; however, the presence of free-floating echogenic particles may be telling of exudate or blood ,4,7,8.The identification of post-surgical intra-abdominal fluid collections is a challenging task. In post-surgical patients, free fluid or organized loculated fluid collections may be a sign of complications such as ascites, seroma, hematoma, biloma, lymphocele, anastomotic leaks, or abscesses  9]..9].Instead, if we focus on the anatomical site where we find anechoic liquid not normally present, we can encounter the following US scenarios:US cannot determine the presence of visceral perforation directly . Bowel pPerforation of the collecting system may be spontaneous or due to pathology or intervention . Urine lUterine rupture is a possible complication in all intrauterine procedures and may be associated with injury to surrounding blood vessels or viscera  . One of Gallbladder perforation diagnosis with US is tricky. The wall rupture is rarely seen, but indirect signs, such as pericholecystic fluid and focal areas of increased fat echogenicity, may help in the diagnosis ,24.Abdominal fluid in non-traumatic patients may be the expression of inflammatory diseases and infection and can be either free or organized. Free fluid around parenchymas and viscera is the expression of a complicated pathology or an extra-visceral extension of the disease where free fluid can stand next to the affected organ or organize into infected collections ,26 Figu.Apart from the presence of clearly benign uncomplicated anechoic cystic lesions, which may be due to infected cysts, either pre-existing or caused by infection, hematomas, and abscesses ,27,28 F, pseudoaSuperficial and intramuscular non-traumatic hematomas can occur secondary to invasive procedures or spontaneously, particularly in anticoagulated patients. Soft-tissue hematomas may be regular or irregular in shape with variable echogenicity, usually hyperechoic in the acute phase, and generally heterogeneous and hypoechoic later. An internal Doppler signal should be considered a sign of active bleeding ,32. RectSoft tissue infections include cellulitis and abscesses. Cellulitis is characterized by non-compressible hyperechoic adipose tissue with non-loculated perifascial fluid effusion, usually defined as “cobblestoning”. An abscess can be organized/capsulated or ill-defined with inhomogeneous internal findings, ranging from anechoic to hyperechoic. The purulent material inside the abscess, when compressed by the US transducer, produces the typical “swirl sign” Clinical symptoms in addition to US findings and the patient’s history help in the differential diagnosis of hematoma, although at some stage even hematomas can become infected. The presence of air in soft tissues is highly suspicious for necrotizing fasciitis ,34 Figu.Fluids are normally present in vessels, in the urinary tract, in the biliary system, and in the bowel. The presence of “too much fluid” suggests quite a wide range of pathologies , which wA focal dilatation in an artery, with at least a 50% increase compared to its normal diameter, is defined as an aneurysm. Abdominal aortic aneurysms are defined as focal dilatations of the abdominal aorta that are 50% greater than the proximal normal segment or more than 3 cm in maximum diameter. Aortic CT and MRI are superior to US in the imaging of aortic disease location, morphology, extension, and complications ,36; howeUS is the first imaging modality in non-complicated renal colic. It may help guide clinical suspicion and the need for further imaging in patients with less typical signs and symptoms ,41,42. TUS is the best non-invasive method to evaluate patients with suspected biliary abnormalities ,45. BileUS is highly accurate in confirming or excluding the presence of small bowel obstructions (sensitivity 92% and a specificity of 94%). US diagnostic criteria include the presence of dilated loops and abnormal peristalsis. Small bowel dilatation is defined as bowel diameter ≥ 2.5 cm measured from outer wall to outer wall ,50,51 F.The diagnostic capability of US in characterizing fluid components is comparable to MR imaging. US can differentiate transudative, exudative, and complex fluid components such as debris and fluid/fluid levels ,25,52. TThe presence of arterial intraluminal hypoechoic and heterogeneous material is highly suggestive of thrombus . On the The presence of hyperechoic spots within the urinary system is usually referred to calculi, although the presence of gas can mimic renal calculi. In a dilated calico–pelvic system and a distended bladder, the presence of intraluminal mass or material is easily appreciable. US findings include hydronephrosis with echogenic material in the collecting system, with a shifting urine debris. This finding has a 100% positive predictive value for suspected pyonephrosis and can thus ascertain the presence of urosepsis ,57,58 F.As in the case of the urinary tract, the presence of hyperechoic spots is also indicative of calculi in the biliary one ,59. BedsFamiliarity with the typical US appearance of fluid helps emergency clinicians to provide a timely diagnosis. The goal of our approach is not to introduce new data or protocols but to help clinicians to focus on fluid presence, easing the early identification of a large spectrum of abnormalities. This approach, starting from the three search-for-black levels, makes it possible to stratify the severity of the disease, improving the correct management, further imaging, and speeding up of an operative procedure. Based on what was previously described, we thus propose a targeted and methodical search for US black patterns in well-defined anatomical sites as a standard method, bearing in mind that, despite the high yield of such an approach, a secondary imaging is often mandatory. One of the limits of this paper is that it represents a teaching–reasoning concept, and the black approach needs to be verified prospectively. The list of clinical indications for abdominal ultrasound in non-traumatic abdominal emergencies is extremely wide and although the black approach can identify a wide spectrum of pathologies, it has to be focused on the patient’s symptoms and clinical suspects.It is essential to guarantee an adequate US support in every emergency setting by ensuring training courses for the entire medical team.


Background: It was speculated that the alteration of the geometry of the artery might lead to hemodynamic changes of distal arteries. This study was to investigate the hemodynamic changes of distal arterial trees, and to identify the factors accounting for hyperperfusion after the obliteration of large intracranial aneurysms.Methods: We retrospectively reviewed data of 12 patients with intracranial carotid aneurysms. Parametric models with intracranial carotid aneurysm were created. Patient-specific geometries were generated by three-dimensional rotational angiography. To mimic the arterial geometries after complete obliteration of the aneurysms, the aneurysms were virtually removed. The Navier–Stokes equations were solved using ANSYS CFX 14. The average wall shear stress, pressure and flow velocity were measured.Results: Pressure ratio values were significantly higher in A1 segments, M1 segments, and M2 + M3 segments after obliteration of the aneurysms . Velocity ratio values were significantly higher in M1 segments and M2 + M3 segments after obliteration of the aneurysms . The percentage of pressure ratio increase after obliteration of aneurysms was significantly correlated with aneurysmal angle .Conclusions: The pressure and flow velocity of distal arterial trees became higher after obliteration of aneurysms. The angle between the aneurysm and the parent artery was the factor accounting for pressure increase after treatment. Intracranial aneurysm is a common disease in the general population . CerebraWith the development of computational fluid dynamics (CFD) and three-dimensional imaging technology, patient-specific hemodynamic analysis has become feasible. However, quantitative study of the hemodynamic changes that occur in the region distal to the aneurysms after the obliteration of large intracranial aneurysms is relatively rare .The aim of our study was to investigate the hemodynamic changes of distal arterial trees after the obliteration of large intracranial carotid aneurysms and to identify the factors accounting for hyperperfusion after the obliteration of large intracranial carotid aneurysms.We retrospectively reviewed data of 12 patients with large intracranial aneurysms of internal carotid artery (ICA) between August 2018 and August 2019 in our institution.Inclusion criteria were unilateral intracranial aneurysms of ICA and the maximum diameter of aneurysm ≥10 mm. Exclusion criteria were stenosis of ICA and multiple cerebral aneurysms.The angles between parent artery and the aneurysm were measured.Parametric models with an aneurysm of ICA (15–10–10 mm) derived from patient 11 were created using SolidWorks software . Three models were created with aneurysmal angles of 45°, 90°, and 135° .Patient-specific geometries were generated by three-dimensional rotational angiography. The surface images were reconstructed using Mimics software . To mimic the arterial geometries after complete obliteration of the aneurysms, the aneurysms were virtually removed.After segmenting and surface smoothing by Geomagic Studio 9.0 software (Geomagic USA), the geometries in stereolithography (STL) format were then exported to ICEM CFD 14.0  for meshing. The vessels were assumed to be rigid with no-slip boundary conditions.3 and a viscosity of 0.0035 Pa s. The walls of the patient geometry were assumed as rigid , pressure, and flow velocity were measured. We therefore normalized them to achieve the relative indices such as WSS ratio, velocity ratio and pressure ratio, divided by the values of the corresponding origin plane .Comparisons of hemodynamic parameters of the middle cerebral arteries (MCAs) and anterior cerebral arteries (ACAs) between the pre-obliteration group and post-obliteration group were performed.t-tests comparing the hemodynamics between the pre-obliteration group and post-obliteration group. The association between the percentage of pressure ratio increase after obliteration of aneurysms and aneurysmal angles was quantified using Pearson's correlation coefficients. All tests used a significance level of p < 0.05.SPSS 19.0 software  was used for statistical analyses. Statistical significance was assessed by the application of paired The study population comprised 12 patients, including nine females (75%) and three males (25%). The patient characteristics and the aneurysm features are summarized in p = 0.048 in A1 segments, p = 0.017 in M1 segments, p = 0.001 in M2 + M3 segments). Velocity ratio values were significantly higher in M1 segments and M2 + M3 segments after obliteration of the aneurysms . The WSS ratio values were similar in MCAs and ACAs for both groups  . The percentage of the pressure ratio increase in A1 and M1 segments after obliteration of aneurysms was not significantly correlated with aneurysmal angle . The percentage of the pressure velocity increase after obliteration of the aneurysms was not significantly correlated with the aneurysm angle .The percentage of the pressure ratio increase after obliteration of aneurysms was significantly correlated with aneurysm angle (M2 + M3) . The perCerebral HPS and remote ICH are unpredictable and potentially severe complications after treatment of the large intracranial aneurysm. Among all the possible etiologies , 12–14, The relationship of geometry and hemodynamics is mutually causal. The hemodynamics of arteries distal to the aneurysms may be changed after obliteration of aneurysms. Many studies have concentrated on the hemodynamic changes within the aneurysms after treatment of intracranial aneurysms. However, hemodynamic changes within distal arterial trees after aneurysm treatment are much less understood.The incidence of remote ICH appears to be higher for large aneurysms than for small aneurysms , 14–16. After obliteration of aneurysms, blood flow through the vessels distal to the aneurysms may suddenly increase. Increased flow rate and pressure distal to the aneurysms after clipping or endovascular treatment have been demonstrated in several studies. Brunozzi et al. reported that the ratio of ipsilateral MCA to systemic systolic and mean blood pressure increased after flow diverter device deployment . In our There are few findings regarding risk factors of the appearance of hyperperfusion after obliteration of aneurysms . BrunozzAccording to the results of our study, the percentage of the pressure ratio increase after obliteration of aneurysms was not correlated with aneurysm volume. Our study suggested that the angle between the aneurysm and the parent artery was the factor accounting for the pressure increase after obliteration of aneurysms. It was only a preliminary finding based on the results of our study. Further studies are required to identify which patients are at a higher risk of hyperperfusion after obliteration of aneurysms.Brunozzi et al. demonstrated that the mean flow velocity of MCA increased especially in patients with delayed ipsilateral ICH after flow diverter device deployment . Chiu etPrevention of HPS is critical. Several investigators have found that careful monitoring and comprehensive management of blood pressure can lower the incidence of HPS after carotid artery stenting , 18. BloWSS can be viewed as the frictional force applied against the vascular wall by the movement of blood. Study of the WSS of the arteries distal to the aneurysms after the obliteration of large intracranial aneurysms is sparse. In a study by Shakur et al., the WSS values were higher in the ipsilateral MCA among patients with hemorrhage after flow diverter device placement . Our stuLimitations to this study include its retrospective nature, a small sample size, and single institution design. Further study with a larger number of patients would be necessary to validate our findings. Patient-specific flow-boundary information was unavailable, which might affect the results. Virtual aneurysm removal might underestimate or overestimate the size of the healthy lumen. This study only involved large intracranial aneurysms of ICAs, which limited the generalization of the study results.Pressure ratio values became higher in MCAs and A1 segments after obliteration of large intracranial carotid aneurysms. The angle between the aneurysm and the parent artery was the factor accounting for the pressure increase after treatment. Velocity ratio values became higher in M2 + M3 segments after obliteration of aneurysms.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of First Affiliatted Hospital of Dalian Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.YL and GJ carried out the simulation study and drafted the manuscript. GJ and XA performed the data collection and data analysis. YL and FW participated in the design of this study. XA helped to check the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ex vivo and in vivo detection and imaging of adenosine triphosphate (ATP) is critically important for the diagnosis and treatment of diseases, which still remains challenges up to present.We herein demonstrate that ATP could be fluorescently detected and imaged ex vivo and in vivo. In particular, we fabricate a kind of fluorescent ATP probes, which are made of titanium carbide (TC) nanosheets modified with the ROX-tagged ATP-aptamer (TC/Apt). In the constructed TC/Apt, TC shows superior quenching efficiency against ROX . While in the presence of ATP, ROX-tagged aptamer is released from TC surface, leading to the recovery of fluorescence of ROX under the 545-nm excitation. Consequently, a wide dynamic range from 1 μM to 1.5 mM ATP and a high sensitivity with a limit of detection (LOD) down to 0.2 μM ATP can be readily achieved by the prepared TC/Apt. We further demonstrate that the as-prepared TC/Apt probe is feasible for accurate discrimination of ATP in different samples including living cells, body fluids  and mouse tumor models.Fluorescence detection and imaging of ATP could be readily achieved in living cells, body fluids , as well as mouse tumor model through a new kind of fluorescent ATP nanoprobes, offering new powerful tools for the treatment of diseases related to abnormal fluctuation of ATP concentration.The online version contains supplementary material available at 10.1186/s12951-021-00930-4. Adenosine triphosphate (ATP), known as a primary energy storage molecule, plays a critical role in the regulation of cellular metabolism and biochemical pathways in a varied cell physiology , 2. SeveTo this end, numerous approaches have been developed for ATP detection, including surface-enhanced Raman scattering, electrochemistry, chemiluminescence, colorimetry, fluorescence and so on –16. AmonHerein, we intend to present a kind of transition metal carbides and carbonitrides (MXenes)-based fluorescent probes, which is high-efficacy for in vitro and in vivo detection of ATP  and ROX-labelled ATP-aptamer  was transferred to a 1.5 mL centrifuge tube at room temperature, and then standing in the dark for 15 min. The aptamer sequence is listed as follows: ACCTGGGGGAGTATTGCGGAGGAAGGT-ROX. Then, these ATP-aptamer modified TC sheets (TC/Apt) were obtained via centrifugation at 12,000 rpm for 10 min. The unabsorbed aptamers were removed by the centrifugation  for three times. Finally, the collected TC/Apt stored in the dark for the following experiments. The mass extinction coefficient of 29.1 Lg−1 cm−1 is used for the determination of TC/Apt concentrations [The established MXenes were prepared via organic-base-driven intercalation and delamination method reported previously . Firstlytrations .2+ or 0.1 mM etoposide at 37 °C for another 2 h, respectively [Human cervical cells (HeLa cells), mouse 4T1 mammary carcinoma (4T1 cells), Human breast adenocarcinoma cells (MCF-7 cells), and Human retinal epithelial cells (ARPE-19 cells) were respectively incubated with 100 μg/mL of TC/Apt for 12 h at 37 °C. The excess TC/Apt was eliminated by using PBS buffer (pH 7.4) to rinse cells for several times. Next, the TC/Apt-treated cells were further incubated with 5 mM Caectively . The livThe serum and urine samples were extracted from mouse or human. ATP solutions covering from 0.0 to 1.0 mM were separately spiked into the 0.1% diluted three different body fluid samples , respectively . Finally6 cells) or MCF-7 cells (containing 5 × 107 cells) were subcutaneously injected into the right back region of Balb/c nude mice . After that, the PBS buffer were subcutaneously injected into the left back region of Balb/c nude mice. The mice whose tumour size was up to ~ 100 mm3 were randomly divided into two groups. Each group was intratumorally administered with TC/Apt probes with the concentration at 200 μg/mL (V = 0.1 mL). The TC/Apt probes-treated mice were euthanized after the 1-day period post-administration, and imaged by the Maestro EX in vivo fluorescence imaging systems . All above animal experimental procedures were performed according to the Guideline for Animal Experimentation with the approval of the animal care committee of Soochow University.These 4T1 or MCF-7 tumour-bearing mice were used as in vivo models in our experiments. For the in vivo imaging, the 0.1 mL cell suspensions of 4T1 (containing 5 × 10http://rsbweb.nih.gov/ij/). Error bars represent the standard deviation obtained from three independent measurements. All statistical analyses were performed using the Origin and GraphPad Prism 7 software. The statistical significance of differences was determined by a one-way ANOVA analysis. p < 0.05 (*), p < 0.01 (**) and p < 0.001 (***) were used to indicate statistical difference.The confocal images were processed by the commercial image analysis software  and common software of ImageJ  ring-stretch of ROX [The ROX-labelled ATP-aptamer (Apt-ROX) can be facilely and selectively adsorbed onto the prepared TC nanosheets by hydrogen bond and metal chelate interaction between the aptamer and TC nanosheets, guaranteeing the proximity of ROX to TC nanosheets surface Fig. a. As thuh of ROX , 27. The−1 cm−1 based on the Lambert–Beer law, which is much higher than that of 3.6 Lg−1 cm−1 for GO and 24.6 Lg−1 cm−1 for the reduced GO [−1, which is covered by the TC nanosheets; and the TC/Apt probes show a shoulder peak of the carbonyl (C=O) stretching band at ~ 1640 cm−1 with a slight peak shift to short wavenumber  of TC nanosheets against ROX, graphene oxide (GO) with the same concentration of 200 μg/mL is selected for a comparison. Typically, GO as well as MXenes belong to 2D nanosheets, featuring similar physical/chemical properties such as electron confinement in ultrathin two dimensions, large cargo loadings, high aspect ratios and so forth . Of noteduced GO –31. Ther0)/F0) at the 610 nm versus ATP concentration  or without ATP (F0), respectively. As revealed, the whole process from signal-off to signal-on state shows an ATP concentration-dependent manner. Notably, when the ATP concentration reaches 1.5 mM, the maximal (F − F0)/F0 value is achieved. While when ATP concentration further increases, no further significant enhancement is observed, indicating no more Apt is dissociated from TC nanosheets triggered by ATP. In addition, a good linearity is presented between the relative (F − F0)/F0 and ATP concentration in the range of 1 μΜ to 1.5 mM /F0 value and X means ATP concentration. The corresponding limit of detection (LOD) is calculated to be ~ 0.2 μΜ by setting the signal-to-noise ratio of 3:1  and etoposide are used to promote the ATP production of the cancer cells. In previous reports, Ca2+ and etoposide as apoptotic stimuli are widely employed for the elevation of cytosolic ATP level [2+ or etoposide (untreated groups), relatively strong fluorescence is measured in cells incubated with Ca2+ or etoposide  [5 to ~ 34 × 105, indicating that the prepared TC/Apt probes offer the ability to detect the ATP content in different body fluid samples. As further shown in Fig. .). Furthermore, the 4T1 or MCF-7 tumor-bearing mouse model is employed for verify the feasibility of TC/Apt probes for imaging ATP in vivo  belong to autofluorescence of mice, which cannot obviously affect the analysis and discussion of in vivo imaging analysis. However, high-performance probes  need to be designed and developed for the higher-quality imaging and diagnosis of different diseases in clinical researches [To evaluate the feasibility of the developed probes for imaging and sensing ATP in real complex samples, the fluorescent TC/Apt probes are utilized to detecting ATP with various concentrations in the different body fluid Fig. a. In detsearches –39. For 2+ or etoposide. Furthermore, the TC/Apt probes are capable for detecting the content of ATP in body fluids  and imaging the intracellular ATP in mouse tumor model. Taken together, our findings suggest new opportunities for the treatment of diseases related to abnormal fluctuation of ATP concentration.In summary, we herein develop a novel kind of fluorescent nanoprobes for ex vivo and in vivo detection and imaging of ATP based on FRET sensing strategy. Specifically, the probes are composed of TC nanosheets linked with ROX-tagged ATP-aptamer through the hydrogen bond and metal chelate interaction between the aptamer and MXenes. Of note, the quenching efficiency of TC sheets against ROX is up to ~ 97%, which is much higher than that of GO nanosheets (~ 90%), leading to a wide dynamic range from 1 μM to 1.5 mM and a low limit of detection (LOD) down to 0.2 μM. Moreover, the as-prepared TC/Apt can be utilized as fluorescent probes for the imaging and sensing of intracellular ATP in living cancer cells treated by CaAdditional file 1: Table S1. Comparison of analytical performances of current two-dimensional fluorescent probes. Figure S1. TEM images, SEM images, size distribution and DLS of TC and TC/Apt. Figure S2. The fluorescence stability of TC/Apt at different storage temperature. Figure S3. The pH stability of TC/Apt. Figure S4. Hydrogen bond analysis of TC/Apt probes. Figure S5. Zeta potential of TC/Apt. Figure S6. Thermogravimetric analysis of TC/Apt. Figure S7. Agarose gel electrophoresis analysis of free Apt-ROX, TC/Apt without treatment and TC/Apt treated with ATP of different concentrations . Figure S8. The fluorescence stability of TC/Apt treated by different bases. Figure S9. The fluorescence stability of TC/Apt treated by different ions. Figure S10. The fluorescence stability of TC/Apt treated by different amines. Figure S11. Cytotoxicity evaluation of the resultant TC/Apt-based probes. Figure S12. Energy-dependent endocytosis of TC/Apt. Figure S13. Intracellular localization of TC/Apt with different incubation time. Figure S14. Intracellular distribution of TC/Apt. Figure S15. Confocal images and reconstitution of HeLa and MCF-7 cells treated with TC/Apt. Figure S16. Fluorescence cellular imaging of ATP in 4T1 cells with different treatments.


Escherichia coli makes this an increasingly unsuitable option. Tebipenem (TBP) is an orally bioavailable carbapenem administered as a pro-drug (tebipenem pivoxil hydrobromide) with broad-spectrum activity that is currently in development for the treatment of patients with complicated UTI. Herein we describe a series of 7-day hollow-fiber in vitro infection model (HFIM) assays designed to evaluate the potential of PO TBP as step-down therapy from IV ertapenem (ETP).Intravenous (IV) to oral (PO) antibiotic step-down therapy has many benefits including reducing the length of hospital stay and lowering the risk of nosocomial infections and overall cost. While fluoroquinolones have been utilized as a step-down therapy for urinary tract infections (UTI) for some time, increases in fluoroquinolone-resistant E. coli isolates, selected based upon ETP and TBP MIC values and known resistance profiles, were evaluated at an initial burden of 107 CFU/mL. HFIM, ETP and TBP free-drug concentration-time profiles were simulated in the HFIM to represent those following IV and PO dosing, respectively. Each isolate was challenged in duplicate by ETP administered every 24 hours (q24h) for 1, 3 or 7 days of therapy. TBP 600 mg every 8 hours was simulated as a step-down therapy following either 1 or 3 days of ETP treatment as well as a 7-day monotherapy regimen. All active regimens were compared to a no-treatment control as well as ETP 1g q24h for 1 or 3 days followed by a halting of therapy. Samples were collected for enumeration of bacterial populations and observation of simulated PK profiles throughout.A panel of ESBL+ clinical 10 CFU/mL. ETP 1g q24h monotherapy successfully reduced bacterial burdens to below levels of detection over the 7-day period but was followed by regrowth matching that in the no-treatment control when treatment was halted on Days 1 and 3. Similar to ETP, TBP successfully reduced bacterial burdens as a 7-day monotherapy and following 1 and 3 days of IV ETP by preventing growth throughout the remainder of the study.Bacteria grew well in the no-treatment control group, reaching densities > 10These data demonstrate the potential utility of TBP as oral step-down from IV ETP therapy and the need for evaluation as a step-down from other IV therapeutics. Brian D. VanScoy, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Sean Jones, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Haley Conde, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Grant/Research Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC (Grant/Research Support)Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support) Lawrence Friedrich, Pharm.D., Spero Therapeutics  Nicole Cotroneo, Spero Therapeutics  Paul G. Ambrose, Pharm.D., FIDSA, 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC Cidara Therapeutics Inc. (Grant/Research Support)Cipla, USA (Grant/Research Support)Corcept Therapeutics (Grant/Research Support)Cumberland Pharmaceuticals (Grant/Research Support)Debiopharm International SA (Grant/Research Support)Discuva Limited (Research Grant or Support)Emerald Lake Technologies (Grant/Research Support)Enhanced Pharmacodynamics (Grant/Research Support)Entasis Therapeutics (Grant/Research Support)E-Scape Bio (Grant/Research Support)Genentech (Grant/Research Support)Geom Therapeutics, Inc. (Grant/Research Support)GlaxoSmithKline (Grant/Research Support)Hoffmann-La Roche (Grant/Research Support)Horizon Orphan LLC (Grant/Research Support)ICPD Biosciences, LLC Indalo Therapeutics (Grant/Research Support)Insmed Inc. (Grant/Research Support)Institute for Clinical Pharmacodynamics (Employee)Iterum (Grant/Research Support)KBP Biosciences USA (Grant/Research Support)Kyoto Biopharma, Inc. (Grant/Research Support)Matinas (Grant/Research Support)Meiji Seika Pharma Co., Ltd. (Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche S.p.A. (Grant/Research Support)Merck & Co., Inc (Grant/Research Support)Mutabilis (Grant/Research Support)Nabriva Therapeutics AG (Grant/Research Support)Naeja-RGM Pharmaceuticals (Grant/Research Support)Nosopharm SAS (Grant/Research Support)Novartis Pharmaceuticals Corp. (Grant/Research Support)NuCana Biomed (Grant/Research Support)Paratek Pharmaceuticals, Inc. (Grant/Research Support)Polyphor, Ltd. (Grant/Research Support)Prothena Corporation (Grant/Research Support)PTC Therapeutics (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)Roche TCRC (Grant/Research Support)Sagimet (Grant/Research Support)scPharmaceuticals Inc. (Grant/Research Support)Scynexis (Grant/Research Support)Spero Therapeutics (Grant/Research Support)TauRx Therapeutics (Grant/Research Support)Tetraphase Pharmaceuticals (Grant/Research Support)Theravance Biopharma Pharmaceutica (Grant/Research Support)USCAST (Grant/Research Support)VenatoRx (Grant/Research Support)Vical Incorporated (Grant/Research Support)Wockhardt Bio AG (Grant/Research Support)Zavante Therapeutics (Grant/Research Support)Zogenix International (Grant/Research Support)


Dear Editor,Tumour recurrence is the leading cause of glioma mortality. Current therapies based on excised tumour tissues cannot be lastingly effective due to the waning representativeness of in vitro primary tumours for the in vivo glioma caused by the spatiotemporal heterogeneity. Therefore, real‐time in vivo genomic information of the tumour is needed for precision management and longitudinal analysis of glioma recurrence. We here evaluated the clinical applicability of glioma‐derived circulating tumour DNA (ctDNA) from cerebrospinal fluid (CSF) and tumour in situ fluid (TISF), the latter denoting the fluid within surgical cavities,We detected ctDNA in TISF from 36 of 36 (100%) patients during their post‐operative courses. These gliomas covered different subtypes, locations and progression stages (0.3‐42.4 months after primary surgery) Table . Importap = 0.0048) and tumour touching the CSF space (p < 0.005)  from 33 patients Table . In our ) Figure . CSF ctD) Figure . Similarp = 0.0351, Figure We compared the sequencing results of 11 TISF‐CSF sample pairs from the above‐described patients Table . CSF ctDFurther analysis of TISF ctDNA revealed a broad spectrum of single nucleotide alterations. The most frequently observed alternations in the TISF were NF1 and TP53. The most frequently implicated oncogenic signaling pathway was the PI3K/RTK/RAS pathway (86.1%) Figure . We did Comparison of tumour DNA from 34 matched TISF‐tumour pairs revealed huge dynamic heterogeneity during glioma evolution. Overall, the numerical concordance rate of detected mutations between the first TISF and the tumour tissue varied appreciably from 0%–100% (median 10.5%) without superficial clinical relevance Figure . The secBy analyzing genomic information from combined tumour tissues and liquid samples, we identified various progression patterns of glioma, such as linear clonal evolution Figure  and actiIn the end, based on our findings and previous studies,In conclusion, TISF and CSF ctDNA complement tumour tissues for providing real‐time in vivo genomic profiles of glioma, especially, shedding ctDNA into TISF seems a universal property of glioma. Together, the integrated CTT pattern can realize the real‐time knowledge of in vivo glioma genomic information during the clinical course. Together with future patient‐specific multi‐omics panels, this management model should realize personalized management and longitudinal analysis of glioma recurrence.The authors have no conflict of interest to disclose.This work was supported by Science and Technology Tackle Program of Henan Province (grant number: 192102310126) and Joint Project of Medical Science and Technology Tackling Plan of Henan Province (grant number: 201601016).Supporting informationClick here for additional data file.Supporting informationClick here for additional data file.Supporting informationClick here for additional data file.Supporting informationClick here for additional data file.Supporting informationClick here for additional data file.Supporting informationClick here for additional data file.