Introduction: Neutron-activated samarium-153-oxide-loaded polystyrene ([153Sm]Sm2O3-PS) microspheres has been developed in previous study as a potential theranostic agent for hepatic radioembolization. In this study, the therapeutic efficacy and diagnostic imaging capabilities of the formulation was assessed using liver cancer Sprague-Dawley (SD) rat model. Methods: Twelve male SD rats (150–200 g) that implanted with N1-S1 hepatoma cell line orthotopically were divided into two groups (study versus control) to monitor the tumour growth along 60 days of treatment. The study group received an intra-tumoural injection of approximately 37 MBq of [153Sm]Sm2O3-PS microspheres, while control group received an intra-tumoural injection of 0.1 mL of saline solution. A clinical single photon emission computed tomography/computed tomography (SPECT/CT) system was used to scan the rats at Day 5 post-injection to investigate the diagnostic imaging capabilities of the microspheres. All rats were monitored for change in tumour volume using a portable ultrasound system throughout the study period. Histopathological examination (HPE) was performed after the rats were euthanized at Day 60. Results: At Day 60, no tumour was observed on the ultrasound images of all rats in the study group. In contrast, the tumour volumes in the control group were 24-fold larger compared to baseline. Statistically significant difference was observed in tumour volumes between the study and control groups (p < 0.05). The SPECT/CT images clearly displayed the location of [153Sm]Sm2O3-PS in the liver tumour of all rats at Day 5 post-injection. Additionally, the [153Sm]Sm2O3-PS microspheres was visible on the CT images and this has added to the benefits of 153Sm as a CT contrast agent. The HPE results showed that the [153Sm]Sm2O3-PS microspheres remained concentrated at the injection site with no tumour cells observed in the study group. Conclusions: Neutron-activated [153Sm]Sm2O3-PS microspheres demonstrated excellent therapeutic and diagnostic imaging capabilities for theranostic treatment of liver cancer in a SD rat model. Further studies with different animal and tumour models are planned to validate this finding.  At Day 28, 83% of rats showed a significant decrease in tumour size after intra-tumoral injection of [153Sm]Sm2O3-PS microspheres while the tumour was not observed in one of the rats. At Day 42, tumours were not observed in 33% of the rats and most of the rats showed a good tumour response. At Day 60, no tumour was observed on the ultrasound images of all rats in the study group. In contrast to the control group, the tumour volume was increased progressively over time.3 and 391 ± 88 mm3, respectively. The tumours in the control group showed a progressive growth from 391 ± 88 mm3 at Day 0 to 9507 ± 3095 mm3 at Day 60, which was about 24-fold larger compared to baseline. Statistically significant difference was observed in tumour volume between the study and control groups (p < 0.05). All rats in the study group (100%) showed good response after treated with the [153Sm]Sm2O3-PS microspheres while all rats in the control group (100%) showed poor response. 153Sm]Sm2O3-PS microspheres accumulated at the injection site with no detectable leakage of the microspheres in other organs. The SPECT, CT, and hybrid SPECT/CT images of a rat in the study group are presented in 153Sm]Sm2O3-PS microspheres were also visible on the CT images as a radiopaque agent. The location of the microspheres within the tumour can be seen clearly on the CT images acquired at Day 3 and Day 60 post-injection as shown in In addition to the gamma imaging capability, the Sm2O3-PS microspheres, a relatively novel formulation of theranostic radiopharmaceutical had been developed as a potential radioembolization agent for liver cancer. In order to investigate the therapeutic and diagnostic imaging capabilities of the microspheres, the microspheres were administered intra-tumourally into the liver tumour of the SD rat model. The radiation damage to the surrounding healthy liver tissues is negligible as 153Sm emits medium energy β− particles, which have a mean tissue penetration of 0.8 mm and a maximum penetration of 4.0 mm. The low energy γ-rays (103 keV) only contributes to about 28% of the overall decay but it is useful for diagnostic imaging using a gamma camera. The γ imaging capabilities of 153Sm has been shown in the previous studies to investigate gastrointestinal motility using 153Sm-loaded radiotracer Sm2O3-PS microspheres. The microspheres were retained at the tumour site that can be clearly visualized on the SPECT/CT images at Day 5 post-injection. Additionally, the microspheres were visible significantly on the CT images taken at Day 3 and Day 60 post-injection. This is a remarkable finding and added to the benefit of 153Sm as a CT contrast agent. A study by Nakayama et al. Sm2O3-PS microspheres was used, and the microspheres were injected into the central area of the tumour. Because 153Sm has a mean tissue penetration of 0.8 mm and a maximum penetration of 4.0 mm, the positive therapeutic effects are highly dependent on the shape of the tumour. In the case when the tumour has an irregular shape, multiple injections may be more effective than a single injection as suggested by Junfeng et al. [153Sm]Sm2O3-PS microspheres depending on the size and shape of the tumour, as well as the normal liver function should be able to increase the treatment efficacy, however this is not within the scope of this study. Future studies should include radiation dosimetry to improve the treatment outcomes.In this experiment, a single fixed-volume injection of -glass microspheres survived during 2–16 months of follow-up. The tumour volume reduction achieved 91% and all patients experienced relief of symptoms as well as improvement in general conditions. Complete necrosis and fibrosis of the tumours were observed in HPE in 7 out of 8 patients after treatment, with only 1 patient showed a small focus of tumour tissue. Tian et al. [90Y]-glass microspheres on liver cancer patients and encouraging outcomes have been observed. The patients had dramatic improvement in their clinical conditions where 90.6% of the tumour foci became smaller, with echogenic or blood flow changes on liver sonograms. At the end of the study, 27 of 33 patients were still alive after treatment (12–32 months).Intra-tumoural injection of radiopharmaceutical for liver cancer treatment has been conducted in the past 20 years as a promising approach in treating unresectable solid liver tumours ,33,34,35n et al.  also per166Ho]Ho-macroaggregate or chitosan radioactivity was well accumulated within 56 hepatoma of 50 patients with no detectable extrahepatic uptake of radioactivity in lung, bowel, kidney and other organs. Overall, therapeutic effect was achieved in 41 patients (82%) where the tumours in 32 patients (64%) were completely treated, 7 patients had recurrence of treated tumour and failed in 2 patients. The same observation was found by Kim et al. [166Ho]Ho-chitosan with complete tumour necrosis was achieved in 11of 12 patients (91.7%) with HCC lesions < 2 cm and in 31 of 40 patients (77.5%) with HCC lesions < 3 cm after 2 months. Furthermore, the survival rates were 87.2%, 71.8%, and 65.3% at 1, 2, and 3 years, respectively. Throughout the long-term follow up period, tumours were recurred in 28 patients, of which 24 recurred at another intrahepatic site. Another clinical study using phosphorus-32 (32P) BioSilicon given intra-tumourally to patients with unresectable HCC showed all target tumours reduced in size at 12 weeks, with a complete response (100% regression) in 2 of the 8 patients [32P]P-BioSilicon. In Lee et al.  study, im et al.  using Sm2O3-PS microspheres is an effective therapeutic agent with potential imaging capabilities for liver cancer treatment tested in a SD rat model. A good response rate of 100% was achieved in the study group (n = 6) where all the liver tumours disappeared in all rats at 60 days post-treatment, with no hepatoxicity or other abnormalities seen in these rats. The [153Sm]Sm2O3-PS microspheres showed its imaging capabilities where the microspheres can be visualized on SPECT/CT and CT images. This study demonstrated that neutron-activated [


Therefore, a novel fluid that overcomes the limitations of most fluids is necessary for most patients, particularly diabetic and older patients. Pyruvate is a natural potent antioxidant/nitrosative and anti-inflammatory agent. Exogenous pyruvate as an alkalizer can increase cellular hypoxia and anoxia tolerance with the preservation of classic glycolytic pathways and the reactivation of pyruvate dehydrogenase activity to promote oxidative metabolism and reverse the Warburg effect, robustly preventing and treating hypoxic lactic acidosis, which is one of the fatal complications in critically ill patients. In animal studies and clinical reports, pyruvate has been shown to play a protective role in multi-organ functions, especially the heart, brain, kidney, and intestine, demonstrating a great potential to improve patient survival. Pyruvate-enriched fluids including crystalloids and colloids and oral rehydration solution (ORS) may be ideal due to the unique beneficial properties of pyruvate relative to anions in contemporary existing fluids, such as acetate, bicarbonate, chloride, citrate, lactate, and even malate. Preclinical studies have demonstrated that pyruvate-enriched saline is superior to 0.9% sodium chloride. Moreover, pyruvate-enriched Ringer’s solution is advantageous over lactated Ringer’s solution. Furthermore, pyruvate as a carrier in colloids, such as hydroxyethyl starch 130/0.4, is more beneficial than its commercial counterparts. Similarly, pyruvate-enriched ORS is more favorable than WHO-ORS in organ protection and shock resuscitation. It is critical that pay attention first to improving abnormal saline with pyruvate for ICU patients. Many clinical trials with a high dose of intravenous or oral pyruvate were conducted over the past half century, and results indicated its effectiveness and safety in humans. The long-term instability of pyruvate aqueous solutions and para-pyruvate cytotoxicity is not a barrier to the pharmaceutical manufacturing of pyruvate-enriched fluids for ICU patients. Clinical trials with sodium pyruvate-enriched solutions are urgently warranted.There have been ongoing debates about resuscitation fluids because each of the current fluids has its own disadvantages. The debates essentially reflect an embarrassing clinical  Fluid therapy is the first and essential treatment in perioperative and critical care patients. However, the selection of crystalloids and/or colloids, which depends on the pathophysiologic mechanism of various diseases; the fluid composition, property, and availability; and even clinicians’ individual preference, remains greatly debatable as each anion, such as acetate, bicarbonate, chloride, citrate, and lactate, in commercial fluid products has its own limitations in the resuscitation of critical care patients, generally contributing to iatrogenic resuscitation injury. In the past 3 decades, it has been well established that pyruvate, a weak acidic anion and the core element of glucose metabolism, holds unique beneficial physiological and pharmacological properties superior to those of the above-mentioned anions in current commercial fluids including intravenous (IV) crystalloids and colloids, as well as oral rehydration solution/salt (ORS). This review focuses on the essence of current fluid debates and the advantages, necessity, and potential clinical uses of sodium pyruvate-enriched fluids.Normal saline  has been the most popular fluid in clinical practice for approximately 200 years. High-chloride saline including NS and hypertonic saline has a fatal limitation in that it induces iatrogenic hyperchloremia , 4. In hTo overcome the limitations of NS, Ringer’s and lactated Ringer’s solutions were produced around a century ago. Previous evidence shows that balanced fluid (lactated/acetated Ringer’s solution (LR/AR) or acetate-based Plasma-Lytes) is advantageous over NS in critically ill adults , 8, specIt has long been known that the serum lactate level is negatively associated with the reversibility of shock and is an independent risk factor of patients’ mortality in ICUs , 14. NotEvidently, there is no consensus on the type of IV fluid, either crystalloids  or colloids , that is the best for most patients , as eachOn the other hand, the volume and speed of fluid delivery are also a critical concern in various clinical settings. Individualized goal-directed therapy (IGDT) is currently optimal in perioperative fluid management and critical care patients, but it still faces challenges. IGDT did not improve early renal function in a recent renal transplant study with a porcine model . Althougstatus quo that all current fluid products are not quite satisfactory in most clinical settings as an ideal selection, especially in ICU patients with severe and complex comorbidities. Therefore, a novel optimal fluid that overcomes most of the limitations of current fluids is warranted for most patients in a wide variety of severe clinical scenarios, particularly diabetic and elderly patients with or without organ comorbidities.Generally, although current fluids play an important role in healthcare, the ongoing debates about resuscitation fluids essentially reflect a crucial embarrassing clinical Pyruvate is a key metabolite of glycolysis, which is reduced to lactate in anoxia or enters oxidative metabolism in the tricarboxylic acid (TCA) cycle in normoxia and hypoxia. The exogenous pyruvate metabolic profile in the intracellular environment can be simply illustrated, as shown in Exogenous pyruvate in aqueous solutions is a unique anion that has pluripotent beneficial physiological and pharmacological properties to protect multi-organ structures and functions against various noxious insults, such as cardiogenic, hemorrhagic, traumatic, and septic shock. Specifically, pyruvate is a potent alkalizer used in preventing and treating hypoxic lactic acidosis, which is not only lethal but also lacks an ideal treatment agent in clinical practice . RecentlAn experiment conducted in 2012 showed that pyruvate protects the function of red blood cells (RBCs), which are the most abundant tissues in humans and exclusively depend on anaerobic glycolysis to produce glycolytic ATP due to the absence of mitochondria . Moreove+/NADH) ratio, restored pyruvate kinase (PK), and retarded the sorbitol pathway by the competitive inhibition of aldose reductase, resulting in the promotion of classic glycolytic pathways (db/db mice (Pyruvate stimulates pyruvate dehydrogenase (PDH) via the direct inhibition of PDH kinase (PDK), similar to dichloroacetate  , 31, andpathways . It also/db mice . Alterna/db mice –36.Several pieces of preclinical evidence revealed that pyruvate protected from diabetic cataract and retinopathy and increased blood insulin levels , 37, 38.+]) through the LDH reduction reaction, which is a systemic alkalizing enzymatic reaction, coupled with an increase in the NAD+/NADH ratio, and the gluconeogenesis pathway in the cytosol in addition to oxidative phosphorylation in the mitochondria   . A recentabolism . There ainjuries , 42, 50.injuries .As previously discovered, pyruvate can directly stimulate the hypoxia-inducible factor-1α-erythropoietin (HIF-1α-EPO) signal pathway by inhibiting the HIF-prolyl hydroxylase domain (PHD) to avoid HIF-1α proteasomal degradation in both hypoxia and normoxia and the subsequent elevation of the gene expression and content of EPO , 52. Thedb/db mice (Sodium pyruvate like methyl pyruvate works as an insulin stimulator. Pyruvate metabolism in the mitochondria is intimately involved in glucose-stimulated insulin secretion (GSIS) and the PC activity, on which pyruvate oxidative metabolism partially depends. PC facilitates the anaplerotic flux, which also plays a critical role in insulin secretion from pancreatic islets , 58. It /db mice . Therefo/db mice , 40. Int/db mice . Further/db mice . Thus, p/db mice .+ cellular levels and the increase in senescence cells (a permanent cell cycle arrest but living cell) in tissues are closely associated with natural aging  functions and extended the healthy lifespan in mice. A pilot study in patients with idiopathic pulmonary fibrosis first showed promising clinical improvements with oral senolytics . The data also demonstrate the inhibition of inflammatory reactions of RBCs by pyruvate, as shown by the reduction of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) in plasma (paO2) and systemic and cerebral oxygen delivery and consumption in shock IV resuscitation, further demonstrating the attenuation of tissue hypoxia by pyruvate  in preserving ATP generation and ATPase activity in the RBCs of dogs simulated bypass surgical procedures in vitro . The ATPn plasma . RBCs asn plasma . As aforn plasma . In thisn plasma . Furtherpyruvate , 44. Oraydration . Additioydration . The pyrFurthermore, IV pyruvate saline protection of the kidney was first preliminarily reported in China a decade ago in rats subjected to burn shock with 50% TBSA III , compared to an equal volume of NS infusion, although pyruvate renoprotection had been earlier investigated , 72; theOn the other hand, studies have demonstrated the advantages of PR over LR in shock resuscitation, particularly in effectively correcting hypoxic lactic acidosis, inhibiting apoptosis, and prolonging survival in animal studies , 44, 76.It is worth noting that the regular pyruvate concentration (28 mM) with a low dose was as efficient as high doses for metabolic improvement and multi-organ protection in early reports , 43.Importantly, a very small amount of pyruvate in cardioplegia showed apparent cardio-protection in clinical bypass surgery . In paraFurthermore, early studies documented that pyruvate-based PDS (P-PDS) was much more effective than regular commercial lactate-based PDS (L-PDS) in improving human blood neutrophils’ intracellular pH and superoxide generation , 80. RegAll these indicate that pyruvate replacement of current anions, such as acetate, chloride, and lactate, in carrier solutions of colloids would robustly improve the clinical benefits of synthetic or natural colloids, although malate has not been compared till now.It is rational and expected that on a monolithic view, pyruvate as a novel component in fluid therapy would greatly ameliorate the prognosis of diseases and clinical outcomes, particularly under IGDT, in perioperative fluid management and ICU patients, especially those with diabetes and elders, as the initial clinical indication. For example, clinical studies demonstrate that major abdominal surgery can induce a substantial PDH decrease with glucose metabolic dysregulation in muscles, probably due to an increase in PDK activity and insulin resistance , 85. ThuSodium pyruvate has been intravenously infused in humans since the 1930s. One early study used IV 3.5 g% pyruvate at 10 mg/kg (20 ml/70 kg) for 1–1.5 min in 21 healthy subjects and 27 patients subjected to Vit B1 deficiency ; anotherin vitro before infusion  in the 1990s, which was the sole commercial pyruvate-compounded solution stored at 4°C for the rejuvenation of stored RBCs infusion . Early dn humans , 92.in vitro  studies  in a modified Pyr-ORS formula, which increases intestinal mucosal blood flow, energy metabolism, and Naterparts , 78, 106terparts , which iterparts , 78. Recterparts . Taken tterparts . ORS theterparts ; howeverterparts .Based on the current understanding of fluid therapy in ICU patients, it is recommended to prescribe fluids based on the condition of each individual patient and to understand the benefits of each solution regarding an individual ICU patient, as both are crucial . In cont+] production. It is worth noting that EP works in animals but not in humans  in fluid resuscitation, such as the Ringer’s ethyl pyruvate solution (REPS), functions as well as sodium pyruvate , which sn humans , and it n humans . Moreoven humans , whereasin vitro are almost not limitations or barriers to the pharmaceutical manufacturing of pyruvate-enriched fluids for clinical use. Randomized clinical trials of pyruvate in fluid resuscitation are urgently warranted.Pyruvate is a multifactorial beneficial anion superior to the current anions, such as acetate, bicarbonate, chloride, citrate, lactate, and others, found in crystalloids and colloid fluids used for resuscitation. Pyruvate can protect metabolic homeostasis and multi-organ function in varying injuries in addition to avoiding iatrogenic adverse effects, such as resuscitation injury, of current fluids used in clinical resuscitation. Regarding the overall concept, the clinical advent of pyruvate-enriched formulations introduces a novel generation of fluid therapy to overcome the limitations of current fluids and be the first preferable fluid employed in most patients. Pyruvate applications would end the fluid debate; profoundly improve prognostic outcomes in ICU patients, especially those with diabetes and older patients; shorten the hospital stay; and enhance the quality of social healthcare. Clinicians and drug manufacturers should recognize that the long-term instability of pyruvate aqueous solutions and para-pyruvate cytotoxicity The author is a retired independent medical researcher. The opinions or assertions contained herein are not a reflection of the view of Fresenius Medical Care, Dialysis Centers in Chicago, IL, United States.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.FQZ prepared the entire manuscript draft and finally completed and revised the current version of the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The manogepix prodrug fosmanogepix is in Phase 2 development for the treatment of invasive mold infections caused by Aspergillus and rare molds (NCT04240886) and has completed Phase 2 studies for candidemia (NCT03604705) and C. auris (NCT04148287) infections. We evaluated the in vitro activity of manogepix and comparators against 2,810 geographically diverse fungal isolates collected in the SENTRY Surveillance Program during 2020-2021 and stratified them by infection type.Manogepix is a new antifungal with a novel mechanism of action and potent Antifungal susceptibility testing of manogepix and comparator agents was conducted according to CLSI M27 (2017) and M38 (2017) guidelines. Fungal surveillance isolates were collected from medical centers located in North America , Europe , Asia-Pacific , and Latin America . Infection sites included bloodstream infections , pneumonia in hospitalized patients , skin and skin structure infections , urinary tract infections , intra-abdominal infections , and other infection types (19.3%).in vitro activity against Candida spp. isolates  regardless of infection type (Table). Similarly, manogepix was highly active against 534 Aspergillus spp. isolates . Manogepix was active against 53 Cryptococcus neoformans var. grubii , 19 Fusarium spp. , 12 Lomentospora prolificans , and 17 Scedosporium spp. isolates .Manogepix demonstrated potent in vitro activity against Candida spp., Aspergillus spp., C. neoformans var. grubii, and rare molds, including Fusarium spp., L. prolificans, and Scedosporium spp. isolates. Notable activity was also demonstrated by manogepix against C. auris isolates. Further clinical development of fosmanogepix in difficult-to-treat, resistant fungal infections is warranted.Manogepix showed potent Michael D. Huband, BS, AbbVie: Grant/Research Support|Melinta: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.


Processing of the available experimental data on particles settling in shear-thinning polymer solutions is performed. Conclusions imply that sedimentation should be recursive, since settling also occurs within the sediment. To capture such an effect, a mathematical model of two continua has been developed, which corresponds to experimental data. The model is consistent with basic thermodynamics laws. The rheological component of this model is a correlation formula for gravitational mobility. This closure is justified by comparison with known experimental data available for particles settling in vertical vessels. In addition, the closure is validated by comparison with analytical solutions to the Kynch one-dimensional equation, which governs dynamics of particle concentration. An explanation is given for the Boycott effect and it is proven that sedimentation is enhanced in a 2D inclined vessel. In tilted vessels, the flow is essentially two-dimensional and the one-dimensional Kynch theory is not applicable; vortices play an important role in sedimentation. Particulate fluids are common in both natural and industrial processes. Fiber-reinforced polymers, detergents, blood, and drilling muds are some examples where particles are present in a suspending fluid ,2. SedimLaboratory study based on the gamma-ray attenuation technique reveals significant differences in the behavior of particles settling in Newtonian and non-Newtonian fluids . ParticuIn order to develop a theory of settling, it is first necessary to understand the interaction of a single particle with a carrier fluid and the mutual interaction between two particles.Clearly, the dynamics of a particles can be strongly affected by the rheology of the interstitial fluid. In Ref. , some prIn this work, a different approach is used. In order to take into account particle–fluid and particle–particle interactions, particles are considered as a phase, which can be described within the continuum mechanics approach. As a result, the entire suspension becomes a two-velocity continuum, with the fluid and the solid phases enjoying some rheological constitutive laws. Such a method was validated in the recent paper concerning the Boycott sedimentation effect, which stated that enhanced sedimentation occurs in a tilted vessel .In a great number of papers , particlAn important point of the theory is that interaction forces between phases for reversible processes without dissipation effects can be uniquely identified while reconciling the energy conservation equation, both with other conservation laws and the basic thermodynamic principles. As far as dissipative processes are concerned, the interaction forces are introduced, fitting the general deGroot–Mazur principles of irreversible thermodynamics . The LanThe principle goal of the present paper is to adjust the method of  for the V contains a fluid (index f) and a granular phase (index s). Volume, mass, and pressure of the fluid and the granular phases are denoted by f and s stand for fluid and solid phases, respectively.Let us consider a joint flow of two continua when an arbitrary volume j-phase with The quantitiesGenerally, the phase pressures  in Ref. , it is ak stand for the velocity, the viscous part of the stress tensor, the particle concentration flux vector, and the interface friction coefficient, respectively.Let A, i.e., i-th component of the vector In what follows, we use the tensor notations. Given two vectors p, c, Neglecting the rotation of particles and thermal effects, it follows from  that theD is defined by the formulaRheological assumptions are formulated as follows. Given a velocity field n satisfies the shear thinning condition The fluid phase is considered to be a non-Newtonian fluid. This implies thatGiven the volume fraction of the solid phase Here, closure , with ϕsOne more rheological equation is the Fick law :(12)l=−γDue to the mass conservation laws , EquatioLet us formulate a hypothesis of incompressibility. It is assumed that the mud volume fraction ows from  that. Th. Th(17)∂Under the incompressibility hypothesis, pressure is no longer a thermodynamic parameter and does not satisfy the equation of state. It is now included in the list of unknown functions, as in the case of Navier–Stokes models of a viscous incompressible fluid. Densities can be restored from equalities .The diffusion coefficients  in Ref. , where dFor the case of sedimentation, the particle Reynolds number g being the gravitation acceleration, the formula y-axis directed upwards. In what follows, flows are considered in the tilted cell With V, Given the reference values As a result of passage to dimensionless variables, the following dimensionless parameters and functions appear:In the new variables, the rheological equations become Omitting the primes, we find that the functions The diffusion coefficients First, we consider settling in a Newtonian fluid where ows from  and 12)n=1 and ηOn the other hand, some authors  apply thfunction . Compari∂c∂t+div,,(36)Hsh, wi, wi27), For both the fluxes All the calculations in the present paper are carried out with the use of the open-source PDE Solver FreeFEM++ based on the finite element method. To obey the restriction that the mean volume velocity is divergence-free, the method of artificial compressibility is applied. At each time step, the concentration field is calculated by the Galerkin-characteristics method, which is implemented in FreeFEM++ through the “convect” function. Next, the Navier–Stokes equations are solved to define velocity and pressure. To tackle nonlinearity, iterations are carried out until convergence. Then, a transition is made to the next time step. A weak formulation of the problem and a detailed description of the algorithm are given in Ref. . The ParIn experiments with blood, A. Boycott (1920) noticed that erythrocyte particles settled faster in an inclined test tube than in a vertical one. Since that time, many attempts have been made to explain this effect in terms of the theory of particle motion in a viscous fluid. For this purpose, additional hydrodynamic forces were introduced, such as the Archimedes force, the Magnus force, etc. Forces were even used that obviously depended on time and on prehistory, such as the Basset–Boussinesq force . In our Let us consider the issue of particle deposition in a 2D tilted tube within the model –27). No. No27).  in Ref. , calculaA. Let us introduce the reduced volume of the clear fluid regiont effect . The resc in the vertical cell, are shown in Streamlines of the mean volume velocity The recent paper  is dedicOne can process the Moreira  experimey, Indeed, let us address vertical flows along the variable Equation  reduces quation (∂c∂t+∂F(cof B(c), ,32,33.To describe such a choice, we first consider settling in a Newtonian fluid. Normally, the slip velocity should be determined experimentally. The Richardson–Zaki correlations Ret<<1 .Let us set eader to  for the  problem:∂c∂t+∂F. E. EFrz(c)y decreases in time at each point y above the height y below the height y from this layer.According to the experiment data in the case of a Newtonian fluid , sedimenTo address such issues of monotonicity in the case of shear thinning fluids, we argue as in Ref.  and lookIt is assumed for simplicity that e values6a=b=1,d=e valuesa=b=1,d=0y, We performed calculations of concentration profile versus the vertical variable It is worth to remark that loss of monotonicity is also observed for the flux The physical meaning of violation of the monotonicity property is as follows. There is a middle layer of the vessel where, at first, the concentration increases due to the sediment going from bottom to top. Then, the concentration in this layer decreases due to a sufficiently pure liquid going from top to bottom. Thus, this effect is the result of the interaction of waves traveling in opposite directions.Let us summarize the arguments formulated in favor of the new choice  for the equation  guaranteequation  is consiequation  is achieA two-continua mathematical model for description of particles settling in a shear thinning polymer solution is developed. A correlation formula for the gravitational mobility in Fick’s law is derived and numerical results on sedimentation are consistent with experiments on settling of particles in polymer solutions. In fact, we justify a suitable correlation for the dependence of mobility on particle concentration. The main arguments are based on the Kynch (1952) theory, in which sedimentation of dense suspension is considered as a concentration wave. A zone with a high concentration of particles is first formed at the bottom of a vessel; then, this zone propagates upward like a shock wave. From our calculations, sedimentation of particles in polymer solutions is recursive, since settling is also observed inside the sediment. Sedimentation in a tilted vessel is addressed and it is proven that the Boycott effect also holds in a polymer solution. Comparison with Newtonian carrier fluid is performed.


Adropin is a peptide hormone encoded by Energy Homeostasis Associated gene. Adropin modulates energy homeostasis and metabolism of lipids and carbohydrates. There is growing evidence demonstrating that adropin enhances insulin sensitivity and lowers hyperlipidemia in obese mice. The aim of this study was to investigate the effects of daily administration of adropin for four weeks in mice with experimentally induced type 2 diabetes (T2D). Adropin improved glucose control without modulating insulin sensitivity. Adropin reduced body weight, size of adipocytes, blood levels of triacylglycerol and cholesterol in T2D mice. T2D mice treated with adropin had lower liver mass, reduced hepatic content of triacylglycerol and cholesterol. Furthermore, adropin attenuated elevated blood levels of hepatic enzymes  in T2D mice. In T2D mice, adropin increased the circulating adiponectin level. Adropin had no effects on circulating insulin and glucagon levels and did not alter pancreatic islets morphology. These results suggest that adropin improves glucose control, lipid metabolism and liver functions in T2D. In conjunction with reduced lipid content in hepatocytes, these results render adropin as an interesting candidate in therapy of T2D. Adropin is a peptide hormone encoded by Energy Homeostasis Gene . AdropinObesity is a major risk factor in T2D. Derangements of glucose and lipid metabolism with hyperglycemia and hyperlipidemia are hallmarks of T2D . Insulinp ≤ 0.05). Adropin reduced fructosamine levels in diabetic animals . In contrast, adropin had no effect on fructosamine levels in healthy mice. Diabetic mice treated with adropin had improved glucose tolerance as judged from decreased AUC for glucose . Adropin failed to affect insulin sensitivity in both, healthy as well as T2D animals.Next, we performed insulin tolerance test in healthy and T2D mice treated with or without adropin. As shown in T2D mice had lower levels of insulin in the circulation as compared with healthy animals A. CirculNext, we assessed beta and alpha cell morphology in healthy and T2D mice. Insulin-immunoreactive area in pancreatic islets was reduced in mice with T2D E–K. HoweAs shown in In addition, we studied adipocytes area in healthy and T2D mice. T2D mice F had incIn addition, for the T2D mice treated with adropin, the elevated levels of triacylglycerol I and choT2D mice had increased liver mass, hepatic triacylglycerol and cholesterol content, as compared to healthy animals A–C. AdroT2D mice had lower levels of adiponectin and higher levels of leptin in blood, as compared to healthy animals A,B. AdroIn the present study, we characterize the effects of chronic adropin administration in mice with experimentally induced T2D.T2D is characterized by impaired glucose control and enhanced insulin resistance . Here, wIn addition to impaired glucose control and insulin resistance, pancreatic beta cell loss and impaired insulin, and glucagon production secreted hallmark T2D ,23. As eIn contrast to insulin, circulating glucagon level was similar in all experimental groups. By contrast there are studies reporting elevated glucagon level glucagon in T2D patients . Others Taken together, these results collectively suggest that the beneficial effects of adropin on glucose control are rather independent on insulin and glucagon regulation. To confirm this assumption, we next assessed the effects of adropin on morphology of pancreatic beta and alpha cells. Adropin failed to affect morphology of pancreatic beta and alpha cells which support the hypothesis that an improved glucose control in response to chronic adropin appears to be independent upon the pancreatic islet cells regulation. Rhesus macaques fed a high-sugar diet [Obesity is a major risk factor for the development of T2D . The losgar diet . Moreovegar diet . Althouggar diet . Furthergar diet . In addigar diet ,32. TherAlterations in body weight in T2D patients are often associated with dyslipidaemia, which is manifested by increased triacylglycerol and cholesterol level in the circulation as well as liver steatosis ,34. In oIn addition, it was reported that adropin overexpression in mice is associated with reduced serum levels of triacylglycerol . DiscussObesity and T2D are characterized by alterations in adipokines productions . Both adOur study has several limitations. For example, we did not assess body composition in all experimental groups. Moreover, food intake and energy expenditure were not investigated in this study. Furthermore, rodent model of diabetes, which was used in our study, does not completely reflect the human condition . TherefoIn summary, we demonstrate here that adropin improves glucose control without affecting systemic insulin sensitivity and pancreatic alpha and beta cell morphology. Furthermore, our results show that adropin improves lipid metabolism, liver functions and increases adiponectin in T2D mice. We cautiously speculate that these results indicate that adropin may be considered as an interesting player in therapy of T2D.34–76 (>98%) was obtained from Novazym . Unless otherwise specified, all other reagents were purchased from Sigma-Aldrich .AdropinC57BJ/6 male mice were obtained from the Mossakowski Medical Research Centre Polish Academy of Sciences . Animals were housed under standard conditions .After 2 weeks of acclimatization, 8 week-old mice weighing 20 ± 2 g were divided into two groups. One group (n = 24) was fed normal diet and the second group (n = 24) was fed high-fat diet (HFD) providing 50% energy from fat . Both groups were fed ad libitum for 10 weeks. After 10 weeks, HFD animals were injected with a single dose of streptozotocin (50 mg/kg body weight). After 3 days, non-fasting blood glucose levels were measured in all animals. If blood glucose level was lower than 10 mmol/L, the injection of STZ (50 mg/kg body weight) was repeated. Next, healthy and diabetic groups were randomly divided into two groups (n = 12 in each group). Healthy and diabetic animals were fed a normal or high fat diet for four weeks and treated with or without adropin for four weeks, as described below.Adropin (100 nmol/kg of body weight) was injected intraperitoneally (i.p.) daily for a total of four weeks. Control animals were treated with the same volume of phosphate buffered saline (PBS), as vehicle. Animals were fasted for three hours prior to sacrifice. Collected tissues were frozen in liquid nitrogen and stored at −80 °C. Blood plasma was aliquoted and stored at −80 °C.ipGTT and ipITT were performed as previously described .Metabolic profile was assessed using colorimetric assays according to the manufacturer’s protocol. The levels of triglycerides , total cholesterol (Cat. No.: C7510), and fructosamine (Cat. No.: F7546) were measured using assay kits purchased from Pointe Scientific . The activities of alanine aminotransferase , aspartate aminotransferase , γ-glutamyltransferase  and alkaline phosphatase  in the serum were determined using Pointe Scientific assays (Pointe Scientific). Glucagon (Cat. No.: 10-1281-01) and insulin ultrasensitive ELISA kits (Cat. No.: 10-1249-01) were from Mercodia . Leptin was determined using Mouse Leptin ELISA Kit .2O2 (vol./vol.). Next, sections were incubated for one hour with primary antibodies diluted 1:400 ; anti-glucagon SAB4501137, Sigma-Aldrich) and for 30 min with a secondary antibody biotinylated complex, and then for 30 min with an enzyme label streptavidin-HRP . Immunoreactivity was revealed using 3,3′-diaminobenzidine as the chromogen and counterstained with Hematoxylin Solution Gill No. 2 for 30 s, washed gently in distilled water, and 5 min in tap water. Next, sections were dehydrated in the increasing ethanol series and incubated for 10 min in xylene, finished by coverslip sealed mounting using Roti Histokit . The specificity of immunohistochemical staining was tested by omitting primary antibodies. These tests showed no staining. Percent of insulin and glucagon immunoreactivity was evaluated using ImageJ 1.53k software .In brief, pancreatic tissue fragments were fixed in Bouin solution, then embedded in paraffin and cut into 3–4 μm sections. After deparaffinization , the sections were rehydrated. Antigenic sites were unmasked by warming three times for 5 min in 0.01 mol/l citrate buffer (pH 6.0) in a microwave oven. After cooling at room temperature, the sections were washed in PBST (pH 7.4) and incubated for 15 min with 3% HTo evaluate the area of adipocytes, epididymal adipose tissue fragments were fixed Bouin’s solution, embedded in paraffin, cut into 3-μm-thick sections and stained with hematoxylin and eosin (HE). Adipocytes area was determined using an LSM 510 inverted microscopy and Axio Vision Rel. version 4.6 software . HE staining of liver was performed the same.g. Then the supernatant was transferred to the new tubes and mixed with 0.2 mL of H2O. Probes were centrifuged again, and the upper phase was aspirated. A total of 20 µL of lower phase were transferred into the new tubes. In the next stage, the samples were evaporated using a vacuum concentrator . After evaporation into the tubes, 150 µL of cholesterol or triglyceride reagent were added and samples were mixed for 10 min. After this time, 100 µL aliquots from each tube were transferred to a 96-well plate, and the absorbance was read using a Synergy 2 Biotek microplate reader .Lipid extraction was performed using the Folch method . In briep < 0.05 (*) was considered to indicate a statistically significant difference.Data are demonstrated as the mean ± standard error of the mean. ANOVA followed by the Bonferroni post hoc test for comparison between groups was used.


A major challenge in the treatment of cancer is predicting patients’ responses to anticancer drugs. Thus, preclinical assays that reflect patients’ responses to treatments are of utmost importance in clinical oncology and in developing new drugs. 3D tumour models such as spheroids and ex vivo tumour explants are appropriate preclinical models. However, the short-term longevity and low throughput of these models limit their application. To address this, we present a computer-controlled drug screening platform that enables multiplexed delivery of several biochemical reagents such as cellular dyes to 3D tumour models. The platform enables testing up to nine distinct treatment conditions  on more than a hundred 3D tumour models. Moreover, it is compatible with clinical histopathology practice for further manipulation and treatment response analyses of tumour models.Anticancer drugs have the lowest success rate of approval in drug development programs. Thus, preclinical assays that closely predict the clinical responses to drugs are of utmost importance in both clinical oncology and pharmaceutical research. 3D tumour models preserve the tumoral architecture and are cost- and time-efficient. However, the short-term longevity, limited throughput, and limitations of live imaging of these models have so far driven researchers towards less realistic tumour models such as monolayer cell cultures. Here, we present an open-space microfluidic drug screening platform that enables the formation, culture, and multiplexed delivery of several reagents to various 3D tumour models, namely cancer cell line spheroids and ex vivo primary tumour fragments. Our platform utilizes a microfluidic pixelated chemical display that creates isolated adjacent flow sub-units of reagents, which we refer to as fluidic ‘pixels’, over tumour models in a contact-free fashion. Up to nine different treatment conditions can be tested over 144 samples in a single experiment. We provide a proof-of-concept application by staining fixed and live tumour models with multiple cellular dyes. Furthermore, we demonstrate that the response of the tumour models to biological stimuli can be assessed using the platform. Upscaling the microfluidic platform to larger areas can lead to higher throughputs, and thus will have a significant impact on developing treatments for cancer. A major impediment to cancer treatment is predicting the response of patients to anti-cancer drugs as they have an extremely low clinical approval rate in drug development programs ,2,3. ImpNew culture platforms that can improve survival and high-throughput drug screening on 3D tumour models, while remaining fully compatible with gold-standard tissue analysis, are promising avenues to improve pre-clinical drug testing. In this article, we present a platform that bridges the concepts behind well plates and perifusion-based microfluidics. The platform uses open-space microfluidic laminar flow confinement to stream reagents within isolated flow sub-units over a large number of various 3D tumour models. Open-space microfluidic systems are channel-free and contact-free fluidic processors that deliver reagents directly over the sample . Pioneer® 184 silicone elastomer kit, Dow Corning, Midland, MI, USA) was used to seal the holder foundation-PMMA slab interface and form a liquid-tight environment inside the holder foundation. Flow rates were controlled using AF1 microfluidic pressure pumps and microfluidic flow sensors . Microfluidic chips for drug testing on MDTs were fabricated using our previously published protocol ) stimulation. The NF-κB transcription factor is reported to play a role in tumour angiogenesis and invasiveness and is a possible target to improve the clinical diagnosis and prognosis . NF-κB r2) in this article. However, PCDs of up to 144 2 pixels have been produced routinely in our laboratory with successive reagent changes as fast as 1 change per 30 s. This makes the PCD drug screening platform appealing for highly parallel and dynamic assays. The reconfigurable sizes and numbers of pixels along with the fast reagent change will speed up the throughput.The need to improve the predictive power of in vitro and ex vivo model systems to maximize the chances of success in clinical trials has made 3D tumour models, such as microdissected tissue and cancer cell line spheroids, attractive in preclinical settings ,65. Thus® [2 incubator. Experiments using primary human tumour tissues will also be a matter of future investigation.Compared to traditional well plate-based approaches  and thei® , our plaTo address the need for efficient preclinical drug screening assays, we have utilized an open-space microfluidic platform for multiplexed delivery of reagents to 3D tumour models. The proposed drug screening platform allows for testing different reagents on 144 tumour models in a single experiment and is amenable to various 3D tumour models such as spheroids or ex vivo tumour explants. Several proof-of-concept applications are demonstrated. The platform has the potential for higher throughput culture and analysis of 3D tumour models and will be of great benefit to the pharmaceutical drug development and personalized cancer medicine fields.


The defect had primary closure. The patient evolved without postoperative complications and was discharged on the 14th postoperative day. The surgical specimen came with negative circumferential margins. However, the deep margin was microscopically positive. Due to deep involvement, the patient underwent adjuvant radiotherapy. Currently, the patient is under clinical follow-up and has no evidence of tumour recurrence. DT is a rare tumour, with unpredictable courses. Surgery can be considered in the progression of lesions. Treatment is justified by long survival after a heart transplant and in DT patients. DT is a differential diagnosis to be considered in progressive growth lesions.We will report a case of a desmoid tumour (DT), which developed at the surgical site of the pacemaker after a late childhood heart transplant. Patients with idiopathic dilated cardiomyopathy followed up in the paediatric cardiology service. It evolved with the dissociation of ventricular rhythm caused by severe heart failure, which led to the implantation of a cardiac resynchronization device prior to heart transplantation. The progression to end-stage heart disease culminated in a heart transplant at 12 years old. One year after the transplant, at the age of 13 years, he presented a progressively growing mass on the generator site of the resynchronization device. The initial decision was to remove the device. During the removal surgery, there was no haematoma or fluid collection. However, there was a progression of the lesion. The lesion was biopsied with the anatomopathological diagnosis of a DT. Resection surgery happened 4 months after the start of the mass growth. At that time, the tumour reached 20 cm in diameter. The lesion infiltrated the pectoralis major muscle and this muscle was resected partially  Heart transplantation is the treatment of choice for children with refractory congenital heart disease and cardiomyopathies. The tumours are transplant-related complications with challenging management.A desmoid tumour (DT) is a rare type of tumour. DT consists of clonal fibroblastic proliferation from deep fascia or soft tissues. The tumour has unpredictable behaviour: spontaneous regression, maintenance, and growth are possible. DT does not give metastasis. However, local recurrence is frequent .In this paper, we report DT in a heart transplantation patient. To our knowledge, it is the first case of such association. This case had challenging management due to the development and growth phase of adolescence in addition to the post-heart transplant status with the oncologic disease.A brown male had idiopathic dilated cardiomyopathy (DCM), which required a cardiac resynchronization device implant at 10-year-old due to severe heart failure with ventricular rhythm dissociation. He had no other past medical issues and also no familiar related disease. Due to the progression to end-stage heart disease, the patient had a heart transplant at 12 years old. The anatomopathological report of the explant confirmed idiopathic DCM. He used tacrolimus and mycophenolate for immunosuppression and without graft dysfunction. One year after the transplant, at the age of 13 years, he presented a progressively growing mass on the generator site of the resynchronization device. The initial decision was to remove the device. During the surgical procedure, there was no haematoma or fluid collection.en bloc with the lesion  being part of the familial adenomatous polyposis. There are also sporadic mutations related to DT . In the In one study with 192 included patients with DT, 11% of the sample was paediatric. In this subgroup, the median age is 15 years, with female predominance of 64%. The median tumour size was 5.3 cm. In children, all tumour sites were extra-abdominal. Lesions were predominant in the extremities, and only 15% were in the trunk , despite the 10-year overall survival rate being higher than 90% . In paedNew lesions after transplantation require investigation and diagnosis, considering immunosuppression. DT is a rare aetiology; however, this disease consists of differential diagnoses for growing lesions. Regarding the heart transplant, there is a good outcome in post-operatory survival, which justifies the treatment of DT. Paediatric patients also have the particularity of developing tissues, and this should be taken into account to decide the therapeutic approach.


Although research generally showed that holding materialistic beliefs would lead to poor developmental outcomes, few studies have used adolescent delinquency as an outcome measure. In addition, the intervening processes between materialism and adolescent developmental outcomes are unclear. In particular, it is not clear how materialistic beliefs influence egocentrism and adolescent delinquency. Methodologically, the existing studies have several weaknesses, including small samples, cross-sectional research designs, and being limited to people living in Western cultures. Using two waves of data collected from Sichuan, China (N = 4981), we studied the predictive effect of adolescent materialism on delinquency and the mediating role of egocentrism. Over two occasions separated by six months, students aged 11 and above responded to a questionnaire evaluating adolescent materialism, egocentrism, and delinquency . Results of multiple regression analyses suggested that materialism at Time 1 positively predicted Time 2 egocentrism. Additionally, Time 1 materialism positively predicted the level and change in Time 2 delinquency. Finally, based on 5000 bootstrap samples with gender, age, ethnic group, and Time 1 delinquent behavior as covariates, PROCESS analyses showed that egocentrism partially mediated the influence of Time 1 materialism delinquency and its change at Time 2. This study suggests that materialistic beliefs shape egocentrism, which further strengthens adolescent delinquent behavior. This study also replicates the findings of a pioneer study in China reported previously. For adolescents, the desire to possess trendy commodities may contribute to delinquent behavior such as stealing. In a report on knife crime in London, Lais  used theWhile common sense suggests that material possession and material consumption lead to happiness, research findings do not provide strong support for this belief. Dittmar, Bond, Hurst and Kasser  reviewedIn another review, Kasser  pointed In a pioneer study on the relationships between materialism and egocentrism and adolescent delinquency in the Chinese context, Shek et al.  reportedConceptually, there are several issues surrounding the linkage between materialism and well-being. The first issue is the conceptualization of well-being and the related measures. In the literature, while researchers have used different measures of well-being, such as subjective well-being , self-evaluation , mental disorders , and health risks, antisocial behavior has seldom been used as a developmental outcome indicator, particularly in adolescents. Moreno et al.  conceiveStudies have shown that materialism is strongly related to impulsive behavior  that comRegarding the linkage between values and delinquency, Bilsky and Hermann  remarkedThe second conceptual issue concerns the relationship between materialism and different dimensions of “self”. Primarily, there are views suggesting that self-related constructs such as negative self-appraisal and low self-esteem are causes or concomitants of materialism ,24. In cIn the model proposed by Donnelly, Ksendzova, Howell, Vohs and Baumeister , it is sTheoretically, as very few studies have explored the mediating mechanism of the association between materialism and personal well-being, we do not know much about the mediators involved. As pointed out by Górnik-Durose, while numerous studies have revealed the negative influence of materialism on individual well-being, “mechanisms underlying this association still remain partially unexplained”  p. 305)530,31]. Shek, Li, Zhu and Shek  also poiSecond, regarding the assessment of materialism, Kasser  explicitFinally, most of the studies in the field are Western studies. Shek, Li, Zhu and Shek  argued tRegarding Confucianism, Low  comparedWith reference to the conceptual and methodological limitations in this field, we attempted to conduct two waves of longitudinal data to investigate the relationships between materialism, egocentrism, and delinquency, with egocentrism proposed as the mediating factor. Specifically, we asked four research questions as follows:Research Question 1: What are the relationships between adolescent materialism and delinquency concurrently and longitudinally? According to previous findings , we hypoResearch Question 2: Is adolescent materialism related to egocentrism at a single time point and over time? Based on the preceding discussion, we proposed that materialism would positively predict egocentrism at each wave and over time (Hypotheses 2a and 2b);Research Question 3: What are the concurrent and longitudinal relationships between egocentrism and adolescent delinquency? According to past findings , we expeResearch Question 4: Does egocentrism mediate the relationship between materialism on delinquency? Based on the findings of Shek, Li, Zhu and Shek , we hypoTo overcome the limitation of the predominance of cross-sectional studies, we employed a short-term longitudinal design with a collection of data with a six-month interval between the two waves of data in five schools in Chengdu. There were 623 and 317 public primary and junior secondary schools, respectively, and 156 schools admitting both primary and junior secondary students in Chengdu in 2020 . Among tBefore data collection, we obtained ethical approval from Sichuan University and consent from the school, parents, and students. Wave 1 data were collected from December 2019 to January 2020 before the COVID-19 outbreak in Wuhan, China, and the school lockdown. Wave 2 data were collected between June 2020 and July 2020 after the resumption of schools because of the gradual stabilization of the pandemic in China. During the data collection, two well-trained research assistants were present in the classrooms. As we focused on adolescents in this paper, we utilized data collected from adolescents aged 11 years or above . There were 4981 students who completed the questionnaire at both waves  with 2566 male students (51.5%) and 2415 female students (48.5%). A total of 143 students refused to participate in the study.During the data collection process, the research assistants and schoolteachers helped go through the questionnaires quickly to ensure students responded to all questions without looking at the students’ responses. Then the research assistants collected the completed questionnaires without the involvement of the teachers. All the data were kept confidential by the research team without revealing any personal information in the research outputs.Shek et al.  developeBased on the data collected from 1658 adolescents, Shek, Yu and Siu  developeTo assess delinquency, we employed a validated 12-item scale that covers delinquent behaviors in the previous year ,39. SomeThe respondents were also invited to give information on their socio-demographic background  through self-report. Compared to Shek, Li, Zhu and Shek , there wAs students’ data were nested within groups (class and schools), we examined the intra-class correlations for the variables under investigation. Results showed that the mean intra-class correlation was 0.045. Based on the recommendation of Guo , there if2, which is an informative and standardized measure to evaluate effect size for multiple regressions [f2 larger than 0.02, 0.15, and 0.35 represent small, medium, and large effect sizes, respectively. Finally, PROCESS analyses were performed to assess the mediating effect of egocentrism on the prediction of materialism at Wave 1 on delinquency and its change at Wave 2 [A series of hierarchical multiple regression analyses was conducted to answer the research questions. This approach has commonly been used in the field ,46. At eressions . Accordiressions  recomment Wave 2 .r = 0.238 and 0.103, respectively, p < 0.001). Regarding the change in materialism, egocentrism, and delinquency over the two waves, results of paired t-tests (N = 4981) showed that Wave 1 materialism  and egocentrism  were lower than Wave 2 materialism  and egocentrism , respectively. However, Wave 1 delinquency  was higher than Wave 2 delinquency .β = 0.34, p < 0.001, Cohen’s 2f = 0.120 and β = 0.18, p < 0.001, Cohen’s 2f = 0.034, respectively) and Wave 2 .For the concurrent predictors of adolescent delinquency , after cβ = 0.22, p < 0.001, Cohen’s 2f = 0.048 and β = 0.09, p < 0.001, Cohen’s 2f = 0.008, respectively). We also examined the influence of Wave 1 materialism and egocentrism on the change in delinquency at Wave 2 by controlling delinquency scores. β = 0.08, p < 0.001, Cohen’s 2f = 0.006). While the predictive effect of egocentrism at Wave 1 on change in delinquency at Wave 2 was not found , egocentrism at Wave 2 predicted the change in Wave 2 delinquency  after controlling the covariates.For predictions over time see , materiaβ = 0.20, p < 0.001, Cohen’s 2f = 0.040) and its change over time  after controlling the covariates.Results revealed that materialism significantly predicted egocentrism at Wave 1 and Wave 2. Additionally, Wave 1 materialism predicted Wave 2 egocentrism . The findings showed that Wave 2 egocentrism partially mediated the relationship despite the small effect size.The present study responded to the conceptual and methodological limitations of the existing studies on the relationships between materialism and well-being ,6, and tThere are also two advances in this study. First, as adolescent delinquency has seldom been used as a measure of well-being in the existing studies , this stRegarding Research Question 1, multiple regression results showed that materialism was a significant concurrent and longitudinal predictor of adolescent delinquency as well as its change over time. While acknowledging the small effect size of the significant effect, the present finding expands the literature on the predictive relationship between materialism and adolescent delinquency . In partConcerning Research Question 2, Wave 1 materialism predicted egocentrism at both waves as well as change in egocentrism over time. These findings underscore the close linkage between materialism and egocentrism and suggest that materialistic beliefs may lead to exaggeration of the importance of oneself and focus on oneself. The link between materialism and egocentrism can be understood in terms of the self-focused attributes of materialism—focusing on what one possesses and what one lacks (envious of the possessions of others) as well as not being willing to share one’s possessions with others. As there are few studies in this area, further studies should be conducted to examine how materialism is related to different dimensions of egocentrism. At the macro level, it would be interesting to explore the relationship between materialism  and egocentrism at the national level.Concerning Research Question 3 on the predictive effect of egocentrism on delinquency, the present findings are consistent with the previous findings that adolescent delinquency was related to egocentrism and lack of empathy . AlthougNevertheless, alternative interpretations may explain the associations between adolescent materialism and delinquency observed in the present study. For example, there may be other variables, such as low socioeconomic status, dysfunctional values and beliefs, and undetected mental health problems, that underly both materialism and delinquency among adolescents. Additionally, adolescent misconduct may reinforce their unhealthy orientation. For example, externalizing behavior predicted adolescents’ morality in one year . Thus, iRegarding how to prevent adolescent delinquency, the present findings suggest that it is helpful to minimize materialistic beliefs and egocentrism. One possibility is to strengthen the developmental assets in adolescents, such as promoting their spirituality  and social awareness , and building up positive and healthy self-identity  through positive youth development (PYD) programs ,55,56. BAnother contribution of the study is that we replicated the findings of Shek, Li, Zhu and Shek . BasicalThe crisis of replication has been highlighted in the literature. Freese and Peterson remarked, “science is presently in the throes of a crisis of replication”  (p. 148)Of course, it is understandable that the delinquent behavior of the students may be affected during COVID-19. For example, because of the restriction of social interaction and having online schooling, the chance of engaging in some delinquent behavior  would reduce. In the present study, we actually found that delinquent behavior decreased across time. With reference to the reflections highlighted in Shek , there iAlthough this study replicates the findings of Shek, Li, Zhu and Shek , we shouFourth, although there is support for the reliability and validity of the measures of materialism and egocentrism , there is a need to collect further data on the concurrent validity and social desirability of the measures. In addition, we used self-report delinquent behavior in the present study. In future, it would be helpful to include official statistics on adolescent crimes so that we can have a more holistic picture of this problem area. However, as some adolescent delinquent behavior may not be captured by the criminal justice system , official statistics also have limitations. Furthermore, many researchers are still relying on self-report measures of delinquency in their studies of adolescent delinquency ,66. As aFifth, besides the issue of self-report delinquency, as we asked the participants to report their delinquent behavior in the past year and the interval between the two waves was around six months, there may be an overlap in the delinquency measures at these two waves. However, as we also assessed the predictive effect of Wave 1 materialism on the change in Wave 2 delinquency, this problem may be partially minimized.r = −0.15) for the relationship between materialism and personal well-being . As Dittmar et al. suggested, the use of multifaceted measures of materialist values can help clarify the effects of different aspects of materialism orientations on personal well-being.Sixth, it is noteworthy that the magnitude of the effect size surrounding the significant findings is small. Hence, we should be aware of the differences between statistical and practical significance. Although statistical significance demonstrated significant effects, these effects may not be large for practical outcomes, which should be interpreted with caution. However, we should note several points. First, the magnitude of effect sizes is usually not very high in social science research, particularly in longitudinal studies ,69. SecoNevertheless, the present findings replicated the findings reported in Shek et al.  and provBy replicating the findings of Shek, Li, Zhu and Shek , this st


The processes underpinning solid tumour growth involve the interactions between various healthy and tumour tissue components and the vasculature, and can be affected in different ways by cancer treatment. In particular, the growth-limiting mechanisms at play may influence tumour responses to treatment. In this paper, we propose a simple ordinary differential equation model of solid tumour growth to investigate how tumour-specific mechanisms of growth arrest may affect tumour response to different combination cancer therapies. We consider the interactions of tumour cells with the physical space in which they proliferate and a nutrient supplied by the tumour vasculature, with the aim of representing two distinct growth arrest mechanisms. More specifically, we wish to consider growth arrest due to (1) nutrient deficiency, which corresponds to balancing cell proliferation and death rates, and (2) competition for space, which corresponds to cessation of proliferation without cell death. We perform numerical simulations of the model and a steady-state analysis to determine the possible tumour growth scenarios described by the model. We find that there are three distinct growth regimes: the nutrient- and spatially limited regimes and a bi-stable regime, in which both growth arrest mechanisms are simultaneously active. Thus, the proposed model has the features required to investigate and distinguish tumour responses to different cancer treatments.The online version contains supplementary material available at 10.1007/s11538-022-01034-2. Solid tumour growth is a complex process involving interactions between multiple different cell types, e.g. healthy, tumour and immune cells, as well as other tissue components such as the extra-cellular matrix and the vasculature. Each of these, and their interactions, can be affected in different ways by anti-cancer therapies, which has prompted extensive experimental and theoretical research on tumour growth dynamics. In particular, many mathematical models, of varying complexity, have been proposed to describe tumour growth. These models typically include a single, or a grouping of, growth-limiting process(es) which can significantly influence treatment response. In this paper, we propose an ordinary differential equation (ODE) model of tumour growth that distinguishes between two alternative mechanisms for growth arrest of a tumour population. In this way, our simple model lends itself to future studies of the effectiveness of different combination cancer therapies.Tumour growth dynamics. Tumour growth is typically separated into two stages: the avascular and the vascular stages  models, discrete, individual-based models (IBMs) and hybrid models combining differential equations and IBMs. For detailed reviews of spatially averaged continuum models, see Murphy et al.  therefore poses itself.Structure of the paper. In the present paper, we aim to derive a model of vascular tumour growth that retains the simplicity of phenomenological models, while providing additional mechanistic insight and capturing the key behaviour of more complex models. We focus on vascular tumours as, in practice, tumours are likely to have reached this stage by the time they are detected. Further, the effect of various treatments on the vasculature can be significant, especially when considering combination treatments. A main feature we seek for our model is that it can distinguish between two alternative growth-limiting mechanisms: growth arrest in response to nutrient deficiency, which translates into the balancing of cell proliferation and death,growth arrest in response to competition for space, which translates into a cessation of all proliferation, with no cell death.As a result, the model provides a means to understand how mechanisms of growth limitation may affect tumour responses to treatment, particularly when both mechanisms are simultaneously active.This paper is structured as follows. In Sect. V, as a model parameter (rather than a dynamic variable) which influences the availability of nutrient and space and, thus, the tumour’s carrying capacity. We make this simplifying assumption in order to limit the complexity of the ODE model we are proposing, which enables us to focus on our aim of describing two different growth-limiting mechanisms using a model that exhibits rich solution structure despite its simplicity. We will come back to this point in the Discussion.In this section, we present a new model of vascular tumour growth, which considers the interactions of a tumour with the physical space in which it is growing and a nutrient supplied by the tumour vasculature. Our first key simplifying assumption is that the vascular volume remains constant during tumour growth. In particular, we neglect angiogenesis and vascular remodelling and view the vascular volume, T and the nutrient concentration by c, we propose the following system of time-dependent ODEs:T and V; the available free space is There is a fixed amount of physical space, T, need space and nutrient in order to proliferate. We assume that they proliferate at a rate proportional to the nutrient concentration, c, and the amount of free space available, S, with constant of proportionality Tumour cells, c for Below a fixed nutrient concentration, c, chosen to be oxygen, is supplied by the tumour vasculature, V, at a rate that is a monotonically decreasing function of c for A nutrient, entclass1pt{minimac for maintenance at a rate proportional to c, with rate constant c for proliferation at a rate proportional to the proliferation rate, with a conversion factor Tumour cells consume In order to reduce the number of parameters in our model, we non-dimensionalise the system ..5).Numerical setup. We solve the ODE system (E system –5) for  for Numeg and k. Further, we consider a biologically realistic range of possible values for the remaining parameters. Our dimensionless parameter choices, listed in Table The focus of this work is on characterising the qualitative behaviour of the model and assessing its suitability for benchmarking combination cancer treatments. As such, accurately estimating parameter values by fitting the model to experimental data is beyond the scope of this work. We instead combine parameter values from different sources in the literature and preliminary numerical simulations to fix the values of mentclass2pt{minimA key simplifying assumption we make in defining the model parameters is that the dimensionless rate of cell death due to nutrient starvation, Simulating tumour growth. For fixed values of mentclass2pt{minimc, alongside Fig. c is above or below the oxygen threshold for severe hypoxia, We note also that the tumour-specific parameters mentclass2pt{minimmentclass2pt{minimmentclass2pt{minimWe now perform a steady-state analysis for the system –5) in o in o5) iSpatially Limited Steady States. In this case, the nutrient is plentiful  defined by (T(c) intersects tions of –12b) by byNutries. Using , we find c (i.e. ) when thT(c) is defined by ..18\documT(c) provided in  when whenSpatNutrient-Limited Steady States. We can perform a similar stability analysis for T and c for these steady states. Therefore, we establish the sign of e system  when \dohat Eqs. –12b) ho hoNutrieGiven the signs of each component of the Jacobian evaluated, respectively, at T change as In the two previous sections, we defined the steady-state solutions for Eqs. –5), det, det5), T automatically attains either a SL or a NL steady state. As We see that, if entclass1pt{minimaSpatially limited growth: the tumour has access to sufficient nutrient to keep growing until it runs out of physical space to occupy; growth stops due to density-dependent inhibition which stops cell proliferation without any cell death.Nutrient-limited growth: the tumour grows until the birth of new cells balances the death of cells due to nutrient starvation; growth stops due to nutrient-dependent inhibition.Bi-stability: the system is bi-stable and the tumour can grow to a NL or SL steady state, depending on the initial conditions. By considering trajectories in the phase plane, it is possible to show that, given initial conditions that satisfy Combining all of the preceding results, we conclude that, depending on Understanding tumour growth dynamics is essential for investigating tumour response to treatment. This is why developing tumour growth models and extending them to study treatment response has been at the forefront of mathematical oncology research for many years. As increasing numbers of models are proposed, a key question is how to balance the biological detail of a model with its analytical tractability and suitability for data fitting and parameter estimation. We have attempted to strike that balance by proposing an ODE model of vascular tumour growth which retains the simplicity of phenomenological models while incorporating some mechanistic details. In addition, a key goal was to develop a model that incorporates two alternative mechanisms for tumour growth arrest.By studying the behaviour of the model –5) nume nume5) nV, which was held constant in the tumour growth model presented in this paper. Since the tumour steady state depends on the oxygen consumption rates, Despite the simplicity of the model, we expect that it can provide additional insight compared to other models of tumour growth, which typically only represent a single growth-limiting mechanism  chan chanV isV: this is beyond the scope of the present work. Even so, we can illustrate the potential of our current model for studying combination treatments using the following example.These possible variations of tumour steady-state values and growth regimes in response to treatment 1 highlight how such a treatment can be effective at reducing long-term tumour burden, especially in the case of SL tumours. In particular, the preceding analysis emphasises that treatment of SL tumours should be designed to drive the system into the NL regime, where the larger spatially limited tumour steady state does not exist and the tumour is guaranteed to evolve to a reduced volume. It would therefore be interesting to consider the effect of combining treatment 1 with another treatment such as chemotherapy that, say, causes tumour cell damage. However, elucidating tumour response to such a combined treatment would require us to consider the dynamics of the tumour cells and vasculature and their interactions. In particular, we would need to extend our model to include a further ODE to account for the dynamics of Suppose that we combine a treatment, here called treatment 2, which causes tumour cell damage in an oxygen-dependent manner (e.g. radiotherapy) with another treatment, here called treatment 3, which can re-oxygenate the tumour (e.g. mild hyperthermia). Treatment 2 alone causes a decrease in tumour volume, whose magnitude depends on how cell death due to the treatment and nutrient deficiency compares to cell proliferation. By increasing the oxygen concentration in the tumour, treatment 3 has three key effects: (i) increasing the cell kill caused by treatment 2, (ii) increasing the proliferation rate of tumour cells and (iii) decreasing the rate of cell death due to nutrient deficiency (if the death rate is nonzero). Thus, applying treatment 3 before treatment 2, we predict a synergistic benefit of combining the treatments if the magnitude of the decrease in tumour volume is larger than that achieved by treatment 2 alone. We illustrate this scenario in Fig. Given the effects of re-oxygenation previously described, we claim that NL tumours are more likely to respond poorly to this combination treatment than SL tumours. Suppose that we have two tumours at steady state, one NL and one SL. Recall that, at equilibrium, the rates of cell proliferation and cell death balance for NL tumours and nutrient availability is growth rate limiting, whereas for SL tumours equilibrium is achieved when mechanical constraints halt cell proliferation throughout the entire tumour mass, i.e. nutrient is not limiting and there is no cell death. Re-oxygenation (treatment 3) perturbs the NL steady state, but not the SL steady state. More specifically, re-oxygenation allows cell proliferation to outweigh cell death due to nutrient deficiency, and therefore, the NL tumour can grow past its pre-treatment volume before the cell-damaging treatment (treatment 2) is applied. As a result of this additional tumour growth due to treatment 3, the increase in cell kill by treatment 2 due to re-oxygenation may not be sufficient to enhance the tumour’s response compared to treatment 2 alone. Thus, the combination treatment may fail. In contrast, re-oxygenating the SL tumour increases the average oxygen concentration in the tumour without affecting the rates of cell proliferation and cell death as they both remain zero. By doing so, treatment 3 only increases cell kill by treatment 2, which increases the efficacy of treatment 2 and ensures that there is a benefit of combining the treatments. We illustrate the expected responses of steady-state NL and SL tumours to treatment 2 alone and to a combination of treatment 3 followed by treatment 2 in Fig. Treating tumours that are not at steady state, we also expect to observe a percentage increase in tumour growth due to re-oxygenation that is larger in NL than SL tumours: while the growth rates of NL and SL tumours both increase due to enhanced proliferation, that of NL tumours is further increased by a decrease in cell loss. As previously explained for NL tumours at steady state, a sufficiently large increase in tumour growth following treatment 3 can negatively impact the success of the combined treatment. All of the preceding considerations imply that, by using the tumour growth model presented in this paper to study tumour response to this combination treatment, we can expect varying treatment outcomes depending on tumour type and growth-limiting mechanism.As mentioned in the Introduction, our simple model exhibits complex behaviour that lends itself to investigating and distinguishing between the response of different tumours to a range of combination cancer therapies. While we have illustrated this briefly with the two preceding hypothetical scenarios, a detailed investigation into how this model can be exploited to address specific combination treatments will be presented in a future paper. More specifically, we aim to extend the tumour growth model to incorporate tumour response to different treatments and then use the resulting dynamic model to conduct an in-depth study of treatment outcome. In particular, we seek to explore whether the response to treatment is sensitive to the mechanisms underpinning tumour growth and to the form of tumour growth assumed. If so, we may also be able to discern the underlying mechanisms from observed responses to treatment. Moreover, our simplifying assumption that vascularisation is constant allowed us to analyse the system in depth and find behaviours that depend critically on the level of vascularisation. Hence, future work will incorporate more realistic vascular dynamics. The extensions of the study presented here will help to identify optimal, patient-specific treatment combinations and to increase our understanding of high variability in treatment response between patients.Supplementary file 1 (pdf 29 KB)Below is the link to the electronic supplementary material.


Staphylococcus aureus (MSSA) and Pseudomonas aeruginosa (PSA). S. aureus (SA) and PSA are common pathogens causing pneumonia in cystic fibrosis (CF) patients. In this study, the in vitro susceptibilities of DLX and comparator quinolones were determined for clinical isolates from US CF patients collected during 2019-2021.Delafloxacin (DLX) is a broad-spectrum fluoroquinolone antibacterial approved in the US for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections. DLX is indicated to treat CABP caused by multiple pathogens, including methicillin-susceptible Isolates from CF patients hospitalized with pneumonia were consecutively collected at 17 US medical centers participating in the SENTRY Surveillance Program. Sites submitted 1 isolate per patient per infection episode. Isolate identification was determined at each site and confirmed using MALDI-TOF at JMI Laboratories. Susceptibility testing was performed according to CLSI broth microdilution methodology. FDA interpretive criteria were used for DLX, and CLSI (2022) criteria were applied to comparators.A total of 115 SA, including 72 MSSA and 67 PSA, were submitted. Susceptibilities (%S) to DLX, levofloxacin (LEV), and moxifloxacin (MOX) for MSSA are shown in the table. As MOX does not have breakpoints for PSA, ciprofloxacin (CIP) was tested. Against all SA, %S was 73.9%, 67.0%, and 67.0% for DLX, LEV, and MOX, respectively. DLX had the highest %S against MSSA (94.4%). The %S to LEV and MOX was 87.5% and 87.5%. DLX was also more active than comparators against PSA, with DLX 68.7%S, while LEV was 43.3%S and CIP was 50.7%S.in vitro data suggest that DLX could be a useful therapy when coverage of both MSSA and PSA is needed.DLX had good activity against recent CF isolates from US hospitals, and had the highest percent susceptibility of the quinolones tested against MSSA and PSA. These Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Michael D. Huband, BS, AbbVie: Grant/Research Support|Melinta: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.


This study aimed to assess the predictive value of invasive and non-invasive dynamic parameters for evaluation of fluid responsiveness after off-pump coronary artery bypass grafting.PiCCO and PPVNK), stroke volume variation, heart–lung interaction index, and plethysmogram variability index before and after standard fluid challenge test.Thirty-two adult patients after off-pump coronary surgery were enrolled into a single-center pilot prospective observational study. After arrival to the intensive care unit, all patients received standard fluid challenge test to assess fluid responsiveness. The patients with an increase in cardiac index ≥ 15% after the test were defined as fluid responders. We measured pulse pressure variation using 2 monitoring systems . Response to standard fluid challenge test was predicted by dynamic assessment of PPVPiCCO (area under the curve 0.84), PPVNK (area under the curve 0.71), stroke volume variation (area under the curve 0.77), and heart–lung interaction index (area under the curve 0.77) (P < .05). The plethysmogram variability index value did not demonstrate any predictive ability regarding fluid responsiveness .After intensive care unit admission, the absolute values of stroke volume variation, PPVIn patients after off-pump coronary surgery, both invasive parameters such as pulse pressure and stroke volume variations and non-invasive parameter such as heart–lung interaction index are able to predict fluid responsiveness. Thus, these dynamic parameters can be used to guide fluid therapy during the early postoperative period after off-pump coronary surgery. PiCCO, PPVNK), stroke volume variation, and heart–lung interaction index (HLI)) can be used for the evaluation of fluid responsiveness after off-pump coronary artery bypass grafting.Dynamic parameters  and stroke volume variation (SVV) can be obtained from the arterial pressure curve. However, these parameters are invasive and can be associated with specific complications.14 Among non-invasive parameters, both heart–lung interaction index (HLI) and plethysmogram variability index (PVI) are based on plethysmogram changes during respiration phases. The HLI represents respiratory variation of plethysmogram obtained from pulse oximetry and analyzed by the ventilator. The PVI is also a novel algorithm allowing automated and continuous calculation of the respiratory variations in the pulse oximetry waveform amplitude. However, despite several studies of non-invasive dynamic parameters in cardiac surgery,16 the role of PVI and HLI for fluid management of patients after off-pump coronary surgery is still unsettled.Historically, the static markers of cardiac preload, such as central venous pressure (CVP), pulmonary artery occlusion pressure, or heart volumes, have been used to guide the fluid balance in cardiac surgery.Thus, the aim of our study was to assess the predictive value of invasive and non-invasive dynamic parameters for the evaluation of fluid responsiveness after off-pump coronary artery bypass grafting (OPCAB).−2, and constant atrial fibrillation.The study was performed in a 900-bed university hospital . Thirty-two adult patients after elective OPCAB were enrolled in a prospective observational study. The study protocol and the informed consent form were approved by the Ethical Committee of Northern State Medical University . Written informed consent was obtained from every patient. Exclusion criteria were age <18 and >80 years, morbid obesity with body mass index > 40 kg m−1), fentanyl (2.5-3.0 µg kg−1), and pipecuronium bromide (0.1 mg kg−1). Anaesthesia was maintained using sevoflurane (0.5-3.0 vol.% at the end of expiration) and fentanyl (2.0-4.0 µg kg−1 h−1). Depth of anaesthesia was adjusted to maintain bispectral index (BIS) values between 40 and 60 .All patients were intubated using the standard induction technique with sodium thiopental  with tidal volume of 6-8 mL kg−1 of predicted body weight, flow of 1 L min-1, and positive end-expiratory pressure of 5 cm H2O. The value of FiO2 was set to at least 50% or higher to achieve intraoperative SpO2 above 95%. The respiratory rate was adjusted to maintain end-tidal CO2 values within 30-35 mm Hg. Fluid therapy included an infusion of Ringer’s lactate at rates of 6-7 mL kg−1 h−1 before and during surgery and 2-3 mL kg−1 h−1 during the first 6 h after operation.In all cases, preoxygenation with 80% OAll patients were operated by the same team of surgeons using Acrobat SUV OM-9000S  device for stabilization of the heart during OPCAB.−1 h−1) to maintain BIS values within 60-70. Respiratory support in ICU was provided by a G5 ventilator  using pressure-controlled ventilation mode with parameters of intraoperative ventilation.After surgery, all patients were transferred to the postoperative cardiac intensive care unit (ICU) and sedated with continuous infusion of propofol  to all patients. After the initial stabilization of respiratory and hemodynamic parameters, all patients received 7 mL kg−1 of crystalloids within 10 minutes .17 We performed monitoring of mean arterial pressure (MAP), SVV, and PPVPiCCO using femoral artery (PiCCO2). We also assessed PVVNK using radial artery and Nihon Kohden patient monitor. Heart–lung interaction index  and PVI  were assessed non-invasively, using finger probes. Both parameters measure the maximal and minimal plethysmographic waveform amplitudes over a given period of time and calculate the percentage difference between the 2. All parameters were measured and recorded before and after sFCT. In addition, we assessed cardiac index (CI), extravascular lung water index (EVLWI), and global end-diastolic volume index (GEDVI) using transpulmonary thermodilution (PiCCO2). During the study, we measured arterial blood gases and lactate concentration. The patients with an increase in CI ≥ 15% after sFCT were defined as fluid responders.20We provided invasive hemodynamic monitoring  curve analysis and calculated area under the ROC curve (AUC). The optimal cut-off point for dynamic parameters was determined by maximum value of the Youden Index (maximizing sensitivity and specificity). For post hoc intragroup comparisons, P value < .01 was considered as statistically significant. In all other cases, P value < .05 was regarded as statistically significant.For data collection and analysis, we used the Statistical Package for Social Sciences (SPSS), version 17.0 software . Due to the pilot design of the study, the sample size was limited to 32 patients. All the variables were expressed as median . The groups were compared using Mann–Whitney We enrolled 22 males and 10 females in the study. Main demographic and clinical data are presented in PiCCO, PPVNK, and HLI in fluid responders .We observed difficulties in registration of PVI after admission to the ICU in 3 patients. We also had difficulties in registration of HLI in 7 patients with bradycardia. Interestingly, these patients had a hazard ratio (HR) of 47 (41-51) beats/min, whereas in patients with normal HLI, signal HR was 69 (57–78) beats/min (P < .05). There were no significant changes in MAP, CVP, EVLWI, or serum lactate concentration (not shown).As expected, the fluid load test was accompanied by the increase in CI and GEDVI in responders (9 and has shown the predictive role of SVV and PPV during sFCT in off-pump coronary surgery. Among a variety of invasive hemodynamic parameters, SVV and PPV have been accepted as reliable predictors of fluid responsiveness in different critical care scenarios including cardiosurgical patients.22 Notably, we observed an increase of CI after sFCT by >15% in less than half of patients after OPCAB that confirms the role of complex hemodynamic monitoring for guiding fluid therapy in this setting.4 Both PPVPiCCO requiring femoral artery catheterization and less-invasive PPVNK obtained from radial artery were able to predict the effects of standard fluid load. The decreased specificity of PPVNK is probably related to differences in access for monitoring of arterial wave, leading to a more pronounced vasomotor increase in the radial artery with signal dampening.Our study represents the continuation of analyzing data from the previous investigation of fluid responsiveness23 It is worth noting that we observed bradycardia below 50 beats/min as an additional limitation of HLI. Moreover, the conditions associated with decrease in peripheral perfusion such as shock, vasopressor support, hypothermia, and several other clinical situations, as well as motion artifacts can result in loss of pulse oximetry signal.24 These limitations are also a hallmark of PVI.25 In our study, we have not confirmed the usefulness of PVI in the detection of fluid responsive patients after OPCAB that is consistent with the results of Ganter et al.16 The absence of predictive role of PVI for fluid responsiveness in these studies can be related with specific characteristics of cardiosurgical patients including disorders of peripheral microcirculation, decreased cardiac output, and requirement in inotrope/vasopressor support.15 However, the study of Haas et al.26 demonstrated the satisfactory predictive ability of PVI after cardiopulmonary bypass. Notably, this study defined responders as the patients with increase in CI after fluid load by 10% but not by 15% like in other investigations.16 In addition, several studies confirmed the predictive value of PVI before surgery, but not postoperatively, when peripheral perfusion can be compromised by additional confounding factors.28 The discrepancy of our results regarding PVI in comparison with HLI is probably related to the difference in mathematical algorithms for calculation of these parameters.Heart–lung interaction index has also shown a good predictive value for fluid responsiveness, an important benefit of this novel parameter is non-invasiveness. The HLI assessment is based on the amplitude of the plethysmogram variability that requires mechanical ventilation. The well-recognized limitations of this approach and other methods for monitoring of fluid responsiveness include spontaneous respiratory activity, open chest conditions, and low tidal volume.There are some limitations of studied variables. In addition to perfusion abnormalities that can compromise the plethysmogram signal, one of them is the presence of arrhythmia, which frequently complicates the postoperative period of cardiac surgery and dramatically affects the accuracy of dynamic parameters. Thus, although atrial fibrillation was one of exclusion criteria, the interpretation of HLI for assessment of fluid responsiveness in our study was compromised by bradycardia observed in 22% of patients. 23In our study, the fluid responsiveness was not associated with main clinical outcomes. It is reasonable to argue that the augmentation in CI following fluid load is often transient and does not result in a steady increase of oxygen transport. Therefore, a positive value of dynamic parameter for fluid responsiveness should not automatically lead to fluid administration and must be assessed simultaneously with metabolic response and other hemodynamic characteristics.In patients after off-pump coronary surgery, both invasive parameters such as pulse pressure and stroke volume variations and non-invasive parameter such as HLI are able to predict fluid responsiveness during the early postoperative period. Thus, these dynamic parameters can be used to guide fluid therapy during the early postoperative period of OPCAB.