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Haemophilia B patients with factor IX inhibitors have particularly unmet needs for conventional therapy.Phase II/III clinical trial, multicentre, open-label, prospective, self-controlled study was conducted to assess MC710 prophylaxis in haemophilia B patients with inhibitors.We enrolled haemophilia patients who had received episodic or prophylactic treatment with bypassing agents up to that time. The participants continued their conventional therapy for 24 weeks and then MC710 was prophylactically infused intravenously every 2 or 3 days at 60 to 120 μg as FVIIa per kilogram of body weight for 24 weeks. The primary endpoint was the annual bleeding rate (ABR) requiring bypassing agents, which was compared intraindividually between the conventional therapy period and the MC710 prophylaxis period.A total of 11 male haemophilia B patients were enrolled. The median ABR ratio for each participant (the prophylaxis period ABR divided by the conventional therapy period ABR) was .33 (2.1/6.5), range from .00 to 3.77. ABR ratios for 9 of the 11 patients ranged from .00 to .60, and 3 of the 9 patients had zero bleeding events during the prophylaxis period. Meanwhile, ABR ratios for the remaining two patients were 2.53 and 3.77, respectively. Although a fibrinogen decrease recovered by the dose reduction was reported for only one participant as the sole adverse drug reaction in this study, no thrombotic events or other safety concerns were reported.MC710 prophylaxis is considered to be decrease the bleeding rate in haemophilia B patients with inhibitors without safety concerns.

Background Inhaled corticosteroids (ICS) are a safe treatment for asthma. However, at higher doses, ICS use has been reported to inhibit adrenocortical function. Objective This study aimed to evaluate the effect of ICS on bone mineral density (BMD) in adult patients with asthma. Methods Ultrasonic bone densitometry was performed in 40 patients (14 men, 26 women, mean age 61.2 years, mean duration of asthma 6.19 years) who were receiving ICS for asthma, and the whole bone density, thickness of cortical bone, and density of cancellous bone of the radius was measured. The age-matched mean was set as 100%. Lifetime cumulative dose of ICS was calculated using all past prescriptions. Results No significant correlations were observed between lifetime cumulative ICS dose and whole bone density (r² = 0.011), cortical bone thickness (r² = 0.022), and cancellous bone density (r² = 0.004). No significant differences were observed between lower and higher lifetime cumulative ICS dose among these BMD parameters (104% vs 97%, 103% vs 99%, and 106% vs 91%, respectively). No significant correlations or differences in lifetime cumulative ICS dose were observed by asthma severity, asthma duration, and pulmonary function. Also, serum markers of bone metabolism showed no significant correlations or differences with lifetime cumulative ICS dose. Conclusions In the entire study population, long-term ICS use was safe and was not associated with an increased risk of osteoporosis.

In Japan, outcome measures for maternal and child health measures such as maternal, perinatal, and infant mortality have consistently shown a trend toward improvement. On the other hand, the problems of the declining birth rate, child abuse, and domestic violence have become evident since the 1990s. In terms of Japan's maternal and child health, it is necessary to take measures to preserve mental health of mothers and children, and also to respond to family issues such as abuse and violence. The services needed such as comprehensive support centers for families with children and new postpartum care programs have been established. It is necessary to further improve the competence of doctors, public health nurses, and midwives working in the maternal and child health field and to promptly construct a cooperation system in the community. J. Med. Invest. 69 : 159-164, August, 2022.

This article presents the experimental analysis of cavitation erosion for two cascade hydrofoil profiles. The aim is to evaluate the change in erosive intensity between a conventional smooth blade surface and one generated by the means of inverse design specifically to reduce cavitation aggressiveness. The applied design strategy consists in imposing a reduced amplitude and gradient at the cavity closure pressure jump in order to bring down the potential energy contained in the vapor sheet. The result is a unique geometry that presents a surface kink located at cavity closure, which successfully smoothes the pressure jump according to computational fluid dynamics (CFD) verification analysis. Here, an experimental rig is constructed and equipped with a pressure sensing system and high-speed imaging to capture the flow field. The measurements for both geometries are first compared against a set of steady-state CFD solutions, which demonstrate the reliability of the inverse design solver for generating targeted flow characteristics in non-cavitating and cavitating conditions. Visual recordings also reveal significant changes in the aspect of the vapor sheet between the two blades indicating a shift in its dynamic behavior. Erosion intensity levels are then measured by paint method at identical conditions. The outcome of the experiment is highly conclusive as a marked reduction in paint erosion is observed for the design geometry. The measured data also serve as a benchmark test for predictive cavitation erosion models by comparing the measured erosion distributions for each blade to those obtained numerically from unsteady CFD.

This paper investigates and compares four commonly used flow transport equation-based cavitation models and their applicability to predict the cavitation performance of an industrial centrifugal pump with a helical inducer. The main purpose of this study is to identify, for this specific application, the most appropriate cavitation model and the associated empirical constants. Each cavitation model is reviewed in detail and the uniqueness of each model is outlined. Each cavitation model is incorporated in a computational fluid dynamics code to study the vaporization and condensation transport rate of the fluid. Experimental tests are conducted on a pump system to determine the true cavitation performance in terms of net positive suction head (NPSH). Experimental results are compared to simulation results for different cavitation models to validate cavitation performance predictions, along with the empirical constants. Lastly, bubble formation, cavitation inception, and bubble growth predicted by each cavitation model are compared with the experimental results. A sensitivity analysis is conducted in order to determine the impact of each set of empirical constants to the condensation and the vaporization rate in the centrifugal pump. Results show that two of the cavitation models exhibit high dependency on the empirical constants in terms of change in vaporization rate. Modifications to empirical constants for two of the four cavitation models are suggested to obtain agreement with the experimentally observed cavitation behavior and better predict NPSH performance for the industrial pump studied.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We previously reported observing GLI3 in medulloblastomas expressing neuronal markers (NM) and/or glial fibrillary acidic protein (GFAP). Furthermore, patients with medulloblastomas expressing NM or GFAP tended to show favorable or poor prognosis, respectively. In the present study, we focused on the role of topoisomerase IIβ (TOP2β) as a possible regulator for neuronal differentiation in medulloblastomas and examined the pathological roles of GLI3, NM, GFAP, and TOP2β expressions in a larger population. We divided 124 medulloblastomas into three groups (NM−/GFAP−, NM +/GFAP−, and GFAP +) based on their immunoreactivity (IR) against NM and GFAP. The relationship among GLI3, NM, GFAP, and TOP2β was evaluated using fluorescent immunostaining and a publicly available single-cell RNA sequencing dataset. In total, 87, 30, and 7 medulloblastomas were classified as NM−/GFAP−, NM + /GFAP−, and GFAP +, and showed intermediate, good, and poor prognoses, respectively. GLI3-IR was frequently observed in NM +/GFAP− and GFAP + , and TOP2β-IR was frequently observed only in NM +/GFAP− medulloblastomas. In fluorescent immunostaining, TOP2β-IR was mostly co-localized with NeuN-IR but not with GFAP-IR. In single-cell RNA sequencing, TOP2β expression was elevated in CMAS/DCX-positive, but not in GFAP-positive, cells. NM-IR and GFAP-IR are important for estimating the prognosis of patients with medulloblastoma; hence they should be assessed in clinical practice.

Shwachman–Diamond syndrome (SDS), an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, is caused by mutations in the Shwachman–Bodian–Diamond syndrome (SBDS) gene, which plays a role in ribosome biogenesis. Although the causative genes of congenital disorders frequently involve regulation of embryogenesis, the role of the SBDS gene in early hematopoiesis remains unclear, primarily due to the lack of a suitable experimental model for this syndrome. In this study, we established induced pluripotent stem cells (iPSCs) from patients with SDS (SDS-iPSCs) and analyzed their in vitro hematopoietic and endothelial differentiation potentials. SDS-iPSCs generated hematopoietic and endothelial cells less efficiently than iPSCs derived from healthy donors, principally due to the apoptotic predisposition of KDR+CD34+ common hemoangiogenic progenitors. By contrast, forced expression of SBDS gene in SDS-iPSCs or treatment with a caspase inhibitor reversed the deficiency in hematopoietic and endothelial development, and decreased apoptosis of their progenitors, mainly via p53-independent mechanisms. Patient-derived iPSCs exhibited the hematological abnormalities associated with SDS even at the earliest hematopoietic stages. These findings will enable us to dissect the pathogenesis of multiple disorders associated with ribosomal dysfunction.

Background: ILD is the most common pulmonary complication in patients with RA. Certain drugs, such as methotrexate, have been associated with the progression of ILD. Therefore, drugs used for treating RA with ILD should be administered carefully. Aims: This study aimed to evaluate the safety of tocilizumab on ILD in patients with RA. Methods: Subjects were 34 patients (17 men, 17 women, mean age 69.4 years) with both RA and ILD. The effect of tocilizumab was evaluated before, 2 months after, and 6 months after administration. Results: Mean levels of matrix metalloproteinase-3 (MMP-3), which is a biomarker of RA disease activity, were 380 ± 370, 214 ± 216, and 208 ± 245 ng/mL, respectively. Significant differences were observed between before and after administration of tocilizumab (before vs 2 months: p Conclusions: The disease activity of RA was significantly improved by administration of tocilizumab, and ILD did not progress. In patients with both RA and ILD, tocilizumab could be administrated safely without progression of ILD.

BACKGROUND The mortality rate from disseminated intravascular coagulation (DIC) is higher in patients with lung cancer than in non-lung cancer patients. Moreover, the prevalence of DIC varies among the pathologic types of lung cancer. This study analyzed the relationship between coagulation factors and the pathologic types of lung cancer. METHODS Twenty-six patients with progressive, inoperable stage IIB or higher lung cancer (20 men, 6 women; mean age 71 years; 11 Adeno, 10 squamous cell carcinoma, and 5 small cell carcinoma) and five healthy volunteers without respiratory disease (3 men, 2 women; mean age 72 years) were enrolled in the study. Blood samples were collected at lung cancer diagnosis, before treatment. RESULTS White blood cell count, platelet count, serum C-reactive protein, fibrin/fibrinogen degradation products, fibrinogen, thrombin-antithrombin complex, and D-dimer levels differed significantly between lung cancer patients and the control group, but not among the pathologic types of lung cancer. Thrombomodulin levels were significantly higher in patients with Adeno and squamous cell carcinoma than in those with small cell carcinoma (P < 0.05 and P < 0.01, respectively). Antithrombin levels were significantly lower in patients with squamous cell carcinoma than in those with Adeno (P < 0.05). CONCLUSION Coagulation disorders may develop secondary to chronic inflammation in patients with progressive lung cancer. DIC in lung cancer may be attributed to changes in anticoagulation factors, such as thrombomodulin and antithrombin, but not in other coagulation factors.

Several factors besides renal function influence serum cystatin C (CysC) levels. The present study evaluates the value of serum CysC and the equation for CysC based estimated glomerular filtration rate (CysC-eGFR) for Japanese children with malignancies. We collected information at 36 time points from 13 patients aged ≤ 17 years with malignancies. We assessed tumor activity, cell recovery phase after chemotherapy, neutropenia phase, inflammation response and medication with granulocyte-colony stimulating factor, steroid, and levothyroxine as risk factors associated with serum CysC levels. Although no 24-h creatinine clearance (CCr) data collected at 36 time points indicated renal dysfunction, serum CysC levels were above and below the reference values at four and five time points, respectively. The frequency of elevated serum CysC levels was higher in patients without therapy or with stable or progressive disease than among those with a complete or partial response (p = 0.0046). The correlation coefficient between CCr and CysC-eGFR was 0.355 (p = 0.054), but this improved to 0.663 (p = 0.0010) when restricted to patients with a complete or partial response. Levels of serum CysC might become elevated regardless of renal function, and CysC-eGFR might become unpredictable during the active phase of tumors. J. Med. Invest. 65:231-235, August, 2018.

Key Clinical Message Hypoglycemia is seldom seen in association with insulinomas, rare autoimmune diseases, and paraneoplastic situations. Paraneoplastic hypoglycemia is known as nonislet cell tumor‐induced hypoglycemia (NICTH). It is also known that a solitary fibrous tumor of the pleura can cause NICTH and that surgical resection is crucial to the success of NICTH treatment.

Objective The mortality rate due to disseminated intravascular coagulation (DIC) is higher in patients with lung cancer than in those without. We examined the effect of treatment with thrombomodulin alfa (TM-α) for DIC in lung cancer patients. Methods Subjects were 57 patients with DIC (43 men, 14 women; mean age, 71.7 years), comprising 31 with lung cancer and 26 without. DIC patients with or without lung cancer did not differ significantly in their background characteristics. Results No significant difference was noted in the mortality rate between patients with lung cancer (61.3%) and those without (57.7%). However, the dose of TM-α was higher for survivors with lung cancer than for non-survivors (473.1 U/kg/day vs. 380.6 U/kg/day; p

A 22-year-old woman visited a hospital to treat her dyspnea which had lasted for some months. Chest X-ray showed hyperlucency in her left upper lung field and chest computed tomography suggested left upper bronchial obstruction with mucoid impaction. She was referred to our hospital for further examination and treatment. Bronchoscopy showed left upper lobar bronchial atresia. Considering her dyspnea worsened in relatively short terms, surgical treatment was chosen and the resection of left upper division was successfully performed.

In this paper, the effect of the inducer tip clearance is studied to understand its impact on the cavitating and noncavitating performance of centrifugal pumps. Helical inducers with constant pitch and with variable (progressive) pitch are considered. Computational fluid dynamics (CFD) simulations of a single stage pump are conducted on each inducer type to determine the cavitating (two-phase) and noncavitating (single-phase) performance for varying inducer tip clearance. The Rayleigh–Plesset cavitation model is used to understand the bubble dynamics under the assumptions of single fluid undergoing no thermal energy transfer between each phase. Experimental tests are conducted on a pump with the variable pitch inducer to determine the true performance in cavitating and noncavitating operating conditions. Experimental results are compared to the simulations to validate the accuracy of the proposed numerical modeling. Net positive suction head (NPSH) with 3% differential head drop is used as a criterion to identify the true cavitation performance of each inducer configuration. It is found that, as the inducer tip clearance increases, excessive back leakage and larger vortex recirculation occur at the tip location. This results in pressure loss within the inducer and, consequently, degrades the cavitation performance. In addition, the change in cavitation performance with the tip clearance is much more evident for variable pitch inducer geometries as compared to the constant pitch case. Furthermore, the impact on the noncavitating performance of inducer tip clearance is found to be minimal.

Morvan syndrome is a rare autoimmune neurological disease characterized by peripheral nerve hyperexcitability, autonomic dysfunction and encephalopathy. Morvan syndrome is often associated with thymoma as a paraneoplastic condition. Here we present a rare case of Morvan syndrome with ectopic hilar thymoma after extended thymectomy for myasthenia gravis.

Cavitation commonly manifests itself as vapour structures attached to the suction surfaces of impeller, runner or propeller blades. The numerical study carried out here seeks to correlate the changes in the behaviour of sheet cavitation to variations in blade geometry. The analysis is run for a two-dimensional stationary cascade. The streamwise loading distribution is the metric used to characterise the geometry. It determines the rate and amount of work generated across the channel and is directly connected to blade surface pressure. In this study, the test sample consists of a set of varying blade profiles characterised by specific loading configurations: foreloaded, aft-loaded or bespoke distributions. Time-resolved simulations of the cavitating flow are generated to study cavity behaviour. Computations are run through Fluent using the SST URANS formulation. The Zwart-Gerber-Belamri homogeneous cavitation model is used to treat cavitation. A range of behaviours are observed for the cavitation patterns. Variations are found in inception conditions, shape and sheet stability. For the latter, two dynamic regimes are identified with a transition point that varies according to the loading profile. A pair of tradeoff relations are also observed: hydrodynamic efficiency versus suction performance and suction performance versus cavity stability. The results demonstrate the capacity of the loading distribution to affect cavitation dynamics.

The following study describes the optimization design procedure of a double-suction pump. BASELINE pump is designed as inlet nozzle diameter 800 mm and impeller outlet diameter 740 mm. Each component of a BASELINE pump, impeller configurations, discharge volute, and the suction casing were determined by DOE (Design of Experiments) and sensitivity analysis. However, finite selected design parameters for each component are mostly restricted to the free surface design of the pump casing. In this study, the optimization method approach along with steady Computational Fluid Dynamics (CFD) is introduced to achieve the high efficiency request of a double-suction pump. To investigate the matching optimization of the impeller and discharge volute at design point, the full parametric geometry of discharge volute was developed referred to the BASELINE shape and Multi-Objective Genetic Algorithm NSGA-II (Non-dominated Sorting Genetic Algorithm II) was used. Optimization result shows that by increasing the volute cross-sectional area from the volute tongue till the circumferential angle 180 deg. provides lower loss. This is due to the improvement achieved for the better distribution of the velocity gradient within the volute. A validated unsteady computational fluid dynamics (CFD) was also employed to investigate the performance difference between optimized volute design and the BASELINE which correlated to the pressure fluctuation and secondary flow behavior inside the cross-sections from 80% to 120% of nominal flow rate. The result shows that the flow distortion in the streamwise direction is stronger with the BASELINE and sensitively affects the operation stability. This is due to the different secondary flow pattern in the cross-sections, hence demonstrating a design direction of desired volute cross-sectional shape for high-performance can be used in a double-suction volute pump.

BACKGROUND The survival rate in patients with Ewing sarcoma family of tumors (ESFT) in Japan was reported to be

To ensure the reliability of multi-stage centrifugal pumps, the prediction of axial thrust is an important issue for the design of balancing device and selection of thrust bearing. However, it is known that the fluid forces acting on rotor could be sensitively affected by the geometrical relations between rotor and stator especially at the low flow rate. Among them, the effect of axial offset of rotor has not been studied sufficiently though the axial offset is easily caused by accumulation of manufacturing tolerances and assembling errors. In this study, experimental/numerical investigations on the effect of axial rotor offset in a final stage model of a three-stage centrifugal pump are carried out. The axial offset is intentionally given to shaft system to the both of discharge/suction side. As a result, the axial thrust is significantly affected by the axial offset in the flow rate range below 50% of the design. It is shown by CFD analysis that this effect of axial offset is caused by the interaction between the back flow from the diffuser and the main flow.

The performance required of a double-suction volute pump differs, depending on its application. High efficiency, low shut off head, design point performance and size are all demands that require trade-offs. Here, Ebara investigates design optimization with Design of Experiments (DoE) and Computational Fluid Dynamics (CFD).

Purpose To report a case of warfarin-response enhancement during administration of ifosfamide and etoposide chemotherapy. Case summary A 15-yearold boy with rhabdomyosarcoma was treated with a regimen of alternating cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) chemotherapy and ifosfamide and etoposide (IE) chemotherapy. During VDC chemotherapy, occlusion of the left middle cerebral artery occurred, and warfarin was started. On day 3 of IE chemotherapy, the patient's international normalized ratio (INR) transiently increased from baseline 2.61 to 5.45. The INR returned to normal within 3 days after warfarin discontinuation. An increase in INR was observed between days 1 and 3 of subsequent cycles of IE chemotherapy but not during VDC chemotherapy. This INR increase was also observed during concomitant use of aprepitant, an inducer of the CYP2C9. Discussion There are no reports describing the interaction between warfarin and IE chemotherapy because coadministration of warfarin and IE chemotherapy is unusual. The Drug Interaction Probability Scale score of this interaction was 7, and it is probable that the enhancement of the warfarin response was caused by an interaction with IE chemotherapy. Moreover, in the present case, the enhancement of warfarin response was observed during concomitant use of aprepitant, which has been reported to weaken the warfarin response. Therefore, this interaction may be quite powerful and may increase the risk of warfarin toxicity. Conclusion A patient who was administered both warfarin and IE chemotherapy experienced a rapid increase in INR, suggesting that INR should be closely monitored in patients receiving warfarin with IE chemotherapy.

The therapeutic effects of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK), depend on their concentrations in blood. Therefore, therapeutic drug monitoring (TDM) is important when these antibiotics are used. In the hematological ward at Tokushima University Hospital, pharmacists have ordered the measurement of blood VCM, TEIC, and ABK concentrations to promote the use of TDM in accordance with an agreed protocol since 2013. Moreover, the infection control team includes several medical disciplines and has advised on the optimal treatment using VCM, TEIC, and ABK since 2013. This study aimed to investigate the clinical effectiveness of these pharmacist interventions. We retrospectively studied 145 cases in which patients were treated with VCM, TEIC, or ABK between January 2012 and December 2013 in the hematological ward at Tokushima University Hospital. The patients were divided into a control group (71 cases) and an intervention group (74 cases), and their clinical outcomes were compared. The rate of achievement of effective drug concentrations significantly increased in the intervention group (74%), compared to the rate in the control group (55%). Moreover, univariate and multivariate Cox proportional hazard regression revealed that pharmacist intervention and appropriate concentrations of anti-MRSA agents were independent factors associated with reduced hospitalization periods in patients with lymphoma. Our study revealed that proactive pharmacist intervention may improve the therapeutic effect of anti-MRSA agents in hematology ward patients.

Background The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient. Methods Twenty-eight patients with asthma who used BFC for alleviation of their symptoms (12 men, 16 women; 60 years old) were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken. Results Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze (1.4 vs. 5.3 or 6.6 days, p

Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5–2.0 l of saline aliquots for 10–30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and β2-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of β2-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.