Dose of nafamostat mesylate during continuous kidney replacement therapy in critically ill patients: a two-centre observational study.

BACKGROUND: Nafamostat mesylate is an anticoagulant used for critically ill patients during continuous kidney replacement therapy (CKRT), characterised by its short half-life. However, its optimal dosage remains unclear. This study aimed to explore the optimal dosage of nafamostat mesylate during CKRT. METHODS: We conducted a two-centre observational study. We screened all critically ill adult patients who required CKRT in the intensive care unit (ICU) from September 2013 to August 2021; we included patients aged ≥ 18 years who received nafamostat mesylate during CKRT. The primary outcome was filter life, defined as the time from CKRT initiation to the end of the first filter use due to filter clotting. The secondary outcomes included safety and other clinical outcomes. The survival analysis of filter patency by the nafamostat mesylate dosage adjusted for bleeding risk and haemofiltration was performed using a Cox proportional hazards model. RESULTS: We included 269 patients. The mean dose of nafamostat mesylate was 15.8 mg/hr (Standard deviation (SD), 8.8; range, 5.0 to 30.0), and the median filter life was 18.3 h (Interquartile range (IQR), 9.28 to 36.7). The filter survival analysis showed no significant association between the filter life and nafamostat mesylate dosage (hazard ratio 1.12; 95 CI 0.74-1.69, p = 0.60) after adjustment for bleeding risk and addition of haemofiltration to haemodialysis. CONCLUSIONS: We observed no dose-response relationship between the dose of nafamostat mesylate (range: 5 to 30 mg/h) and the filter life during CKRT in critically ill patients. The optimal dose to prevent filter clotting safely needs further study in randomised controlled trials. TRIAL REGISTRATION: Not applicable.

Unfractionated heparin versus nafamostat mesylate for anticoagulation during continuous kidney replacement therapy: an observational study.

BACKGROUND: Unfractionated heparin sodium and nafamostat mesylate have long been used as anticoagulants in continuous kidney replacement therapy (CKRT) where citrate is unavailable. This study aimed to determine whether heparin or nafamostat mesylate used during CKRT was associated with a longer filter life. METHODS: In this single-centre observational study, we included adult patients who required CKRT and used heparin or nafamostat mesylate for their first CKRT in the intensive care unit from September 1, 2013, to December 31, 2020. The primary outcome was filter life (from the start to the end of using the first filter). We used propensity score matching to adjust for the imbalance in patients' characteristics and laboratory data at the start of CKRT and compared the outcomes between the two groups. We also performed restricted mean survival time analysis to compare the filter survival times. RESULTS: We included 286 patients, 157 patients on heparin and 129 patients on nafamostat mesylate. After propensity score matching, the mean filter life with heparin was 1.58 days (N = 91, Standard deviation [SD], 1.52) and with nafamostat mesylate was 1.06 days (N = 91, SD, 0.94, p = 0.006). Multivariable regression analysis adjusted for confounding factors supported that heparin was associated with a longer filter life compared with nafamostat mesylate (regression coefficient, days, 0.52 [95% CI, 0.15, 0.89]). The between group difference of the restricted mean filter survival time in the matched cohort was 0.29 (95% CI, 0.07-0.50, p = 0.008). CONCLUSION: Compared to nafamostat mesylate, heparin was associated with one-third to one-half a day longer filter life. TRIAL REGISTRATION: Not applicable.

Necessity of neutrophil-to-lymphocyte ratio monitoring for hypothyroidism using nivolumab in patients with cancer.

BACKGROUND: Low neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with a favorable therapeutic response to nivolumab. The activation of immunocompetent cells such as lymphocytes exhibits an antitumor effect; however, the development of excessive immune responses in autologous organs along with the breakdown of self-tolerance causes immune-related adverse events, including hypothyroidism. Therefore, the possibility that NLR is associated with immune response shows that NLR can be not only a predictive factor for good response to nivolumab but also a predictive factor for the development of hypothyroidism. AIM: To evaluate whether continuous NLR monitoring during nivolumab treatment is useful for predicting the incidence and onset period of hypothyroidism. METHODS: This retrospective study comprised patients who received nivolumab for treating all types of cancer at our hospital between January 2015 and December 2019. The NLRs of patients were measured before each administration, and the patients were followed up till the administration of 12 doses. NLR at treatment initiation was compared between patients with and without hypothyroidism. Patients who developed hypothyroidism were categorized into three groups: those with NLR < 3.5, 3.5 to < 5, and ≥ 5 according to their maximum NLR from treatment initiation to hypothyroidism development. Further, the onset periods of hypothyroidism were compared between the groups. RESULTS: Overall, 104 patients were included in the analysis. Twenty-one patients developed hypothyroidism throughout the observation period. NLR at treatment initiation was significantly lower (2.54 ± 1.21 vs 4.58 ± 4.03; P = 0.017) in patients with hypothyroidism than in those without hypothyroidism, and patients with NLR < 5 had a significantly higher incidence of hypothyroidism than those with NLR ≥ 5 (26%: 20 of 78 patients vs 4%: 1 of 26 patients; P = 0.022). Additionally, treatment continuity in patients with hypothyroidism was significantly longer than in those without hypothyroidism (median not reached vs 7 times administration, P = 0.010). Patients with maximum NLR < 3.5 until the development of hypothyroidism had a significantly earlier onset of hypothyroidism than those with maximum NLR ≥ 5 (hazard ratio for low tertile [NLR < 3.5] vs high tertile [NLR ≥ 5]: 5.33, P = 0.011). CONCLUSION: Low NLR at treatment initiation increases the incidence of treatment-induced hypothyroidism. Furthermore, its persistence may be a risk factor for the early onset of hypothyroidism.

Prediction of Severe Cisplatin-Induced Neutropenia Using Serum Albumin Concentration-A Retrospective Study.

BACKGROUND: Cisplatin that is used in the treatment of gastric cancer not only has gastrointestinal side effects but also has a high serum protein-bound fraction. Reduction of serum albumin concentration may cause increase the risk of cisplatin- induced neutropenia. Hence, alteration of serum albumin concentration poses a major safety issue during anticancer therapy. METHODS: For gastric cancer patients who received cisplatin plus S-1 therapy, we investigated the relationship between the serum albumin concentration before cisplatin administration in the treatment course during which the neutrophil count reached nadir and the neutrophil count fluctuation after cisplatin administration. RESULTS: In the grade 3-4 neutropenia and grade 0-2 neutropenia groups, the mean serum albumin concentration before cisplatin administration was 3.39±0.60 and 3.85±0.59 g/dL, respectively; in the former group were significantly lower than in the latter group(p=0.006). Lower serum albumin concentrations before cisplatin administration were significantly correlated with a decrease in neutrophil count after cisplatin administration(r=0.463, p<0.001). According to the receiver operating characteristic curve analysis, patients with serum albumin concentrations below 3.25 g/dL before cisplatin administration exhibited a significantly higher incidence of grade 3-4 neutropenia(odds ratio: 4.33). CONCLUSIONS: Decreased serum albumin levels were found to be strongly associated with the prediction of the development of severe neutropenia. Our findings emphasize serum albumin concentration needs to be evaluated before each administration of cisplatin.

[Elucidation of Influential Factors on Nausea Associated with Olaparib Administration].

Olaparib, an anticancer drug, requires daily administration, frequently causing nausea. Elucidation of the influential factors for nausea is important for continuing treatment. We retrospectively examined 23 patients who received olaparib treatment and were divided into nausea and no-nausea groups, according to antiemetic prescriptions during treatment. We compared the patients' background and laboratory values between the 2 groups. Nine patients developed nausea and 14 did not, with mean body weights at treatment initiation of 49.9±9.8 kg and 60.0±13.9 kg, respectively. Body weights were significantly lower in the nausea than in the no-nausea group. Four weeks after olaparib administration, the logarithmic difference in the fluctuation of the neutrophil count was -0.145±0.154 and 0.095±0.242, while the fluctuation of the lymphocyte count was -0.169±0.053 and -0.060±0.110 in the nausea and no-nausea groups, respectively, with the former significantly lower than the latter. The treatment period for the nausea group was significantly longer than that for the no-nausea group. Since olaparib is administrated as a flat dose, the dose per body weight increased in underweight patients. Thus, being underweight might have impacted the efficacy of olaparib, including the development of side effects such as nausea and hematotoxicity.

4D street view: a video-based visualization method.

We propose a new visualization method for massive supercomputer simulations. The key idea is to scatter multiple omnidirectional cameras to record the simulation via in situ visualization. After the simulations are complete, researchers can interactively explore the data collection of the recorded videos by navigating along a path in four-dimensional spacetime. We demonstrate the feasibility of this method by applying it to three different fluid and magnetohydrodynamics simulations using up to 1,000 omnidirectional cameras.

[Effect of Hypoalbuminemia on Severe Neutropenia Induced by Paclitaxel Monotherapy and Paclitaxel plus Ramucirumab Combination Therapy in Patients with Gastric Cancer].

Hypoalbuminemia is often observed in patients receiving chemotherapy for gastric cancer. The risk of hematologic toxicity is increased by the pharmacokinetic alteration of paclitaxel(PTX)owing to high serum protein binding in patients with hypoalbuminemia. Here, we examined the relationshipbetween the frequency of GradeB3 neutropenia and serum albumin concentration in 30 patients receiving PTX monotherapy, and 29 patients receiving PTX plus ramucirumab(RAM)combination therapy-a second-line treatment for advanced/recurrent gastric cancer. The number of patients who developed GradeB3 neutropenia was 8(27%)and 14(48%)of those who received monotherapy and combination therapy, respectively, with mean serum albumin concentrations of 3.31 g/dL and 3.15 g/dL, respectively. Serum albumin concentrations were significantly lower in the GradeB3 neutropenia group than in the non-GradeB3 neutropenia group in both regimens. When the serum albumin concentration of patients receiving PTX or PTX plus RAM was below the cut-off values of 3.75 g/dL and 3.45 g/dL, respectively, the odds ratio of GradeB3 neutropenia was 12.25 and 7.33, respectively. Hypoalbuminemia was associated with the development of chemotherapy-induced GradeB3 neutropenia, in patients with gastric cancer treated with either PTX monotherapy or PTX plus RAM combination therapy. Therefore, not only neutrophils but also serum albumin concentration should be monitored during chemotherapy.

[Identification of the Risk Factors for Cabazitaxel-Induced Neutropenia with Preventive Administration of Pegfilgrastim].

Prophylaxis using pegfilgrastim is recommended to prevent cabazitaxel-induced neutropenia. We observed GradeB3 neutropenia in a patient after administration of cabazitaxel, despite prophylaxis using pegfilgrastim. To identify the risk factors associated with GradeB3 neutropenia, we retrospectively investigated the records of 10 patients who received prophylaxis with pegfilgrastim after administration of cabazitaxel. They were divided into GradeB3 neutropenia and non-GradeB3 neutropenia groups, and we compared the background data and laboratory values between the 2 groups. A univariate analysis revealed that hypoalbuminemia was significantly observed in patients with cabazitaxel-induced GradeB3 neutropenia. The incidence of GradeB3 neutropenia was significantly high in patients with serum albumin levels<3.6 g/dL. Cabazitaxel has a high rate of protein binding; moreover, serum albumin levels<3.6 g/dL might be associated with high concentrations of unbound cabazitaxel, and thus an increase in the incidence of GradeB3 neutropenia. Therefore, hypoalbuminemia at the time of administration of cabazitaxel may be a risk factor related to the development of GradeB3 neutropenia.

Zonal flow formation in the Earth's core.

Zonal jets are very common in nature. Well-known examples are those in the atmospheres of giant planets and the alternating jet streams found in the Earth's world ocean. Zonal flow formation in nuclear fusion devices is also well studied. A common feature of these zonal flows is that they are spontaneously generated in turbulent systems. Because the Earth's outer core is believed to be in a turbulent state, it is possible that there is zonal flow in the liquid iron of the outer core. Here we report an investigation at the current low-viscosity limit of numerical simulations of the geodynamo. We find a previously unknown convection regime of the outer core that has a dual structure comprising inner, sheet-like radial plumes and an outer, westward cylindrical zonal flow. We numerically confirm that the dual-convection structure with such a zonal flow is stable under a strong, self-generated dipole magnetic field.

Formation of current coils in geodynamo simulations.

Computer simulations have been playing an important role in the development of our understanding of the geodynamo, but direct numerical simulation of the geodynamo with a realistic parameter regime is still beyond the power of today's supercomputers. Difficulties in simulating the geodynamo arise from the extreme conditions of the core, which are characterized by very large or very small values of the non-dimensional parameters of the system. Among them, the Ekman number, E, has been adopted as a barometer of the distance of simulations from real core conditions, in which E is of the order of 10(-15). Following the initial computer simulations of the geodynamo, the Ekman number achieved has been steadily decreasing, with recent geodynamo simulations performed with E of the order of 10(-6). Here we present a geodynamo simulation with an Ekman number of the order of 10(-7)-the highest-resolution simulation yet achieved, making use of 4,096 processors of the Earth Simulator. We have found that both the convection flow and magnetic field structures are qualitatively different from those found in larger-Ekman-number dynamos. The convection takes the form of sheet plumes or radial sheet jets, rather than the columnar cell structures that are usually found. We have found that this sheet plume convection is an effective dynamo and the generated current is organized as a set of coils in the shape of helical springs or at times as a torus.

Amino acid residues affecting the activities of human cytochrome P450 2C9 and 2C19.

The amino acid residues affecting the substrate specificity of human cytochrome P450 CYP2C9 and CYP2C19 for their metabolic activities were investigated using chimeras and mutant enzymes, which were constructed by replacing the corresponding residues. Although CYP2C19 showed nearly the same tolbutamide hydroxylase activity as CYP2C9, the activities for the CYP2C19(H99I) mutant and the chimeras that replaced residues 1-212 were much lower than those for CYP2C19. The activities of the CYP2C19(H99I) mutant and the chimeras that replaced residues 228-340 were lower than those for CYP2C19 toward S-mephenytoin, aminopyrine, and testosterone. These results suggest that residues in substrate recognition site (SRS) 3 and 4 are important for the substrate specificity, whereas His99 is important in the substrate binding of CYP2C19. For the 4'-hydroxylation of diclofenac, CYP2C9 had a lower K(m) and a higher V(max) than CYP2C19. Although the V(max) values for the CYP2C9(1-288)/CYP2C19(289-490) chimera and the CYP2C9(I99H, V292A, F295L, I331V) mutant were comparable to those for CYP2C9, its K(m) value was comparable to that for CYP2C19. The V(max) and K(m) values for the CYP2C19(1-288)/CYP2C9(289-490) chimera were comparable to those for CYP2C19, and the activity by CYP2C9(1-230)/CYP2C19(231-490) chimera was negligible. These results suggest that the residues 292, 295, and/or 331 of CYP2C9 are essential for the recognition of substrate in CYP2C9 and that the residues of 231-288 including SRS 3 are important for the metabolizing capacity of CYP2C9.

Repeated and sudden reversals of the dipole field generated by a spherical dynamo action.

Using long-duration, three-dimensional magnetohydrodynamic simulation, we found that the magnetic dipole field generated by a dynamo action in a rotating spherical shell repeatedly reverses its polarity at irregular intervals (that is, punctuated reversal). Although the total convection energy and magnetic energy alternate between a high-energy state and a low-energy state, the dipole polarity can reverse only at high-energy states where the north-south symmetry of the convection pattern is broken and the columnar vortex structure becomes vulnerable. Another attractive finding is that the quadrupole mode grows, exceeding the dipole mode before the reversal; this may help to explain how Earth's magnetic field reverses.