Applicable predictive factors extracted from peak flow trajectory for the prediction of asthma exacerbation.

BACKGROUND: Real-time asthma exacerbation prediction and acute asthma attack detection are essential for patients with severe asthma. Peak expiratory flow (PEF) exhibits a potential for use in long-term asthma self-monitoring. However, the method for processing PEF calculations remains to be clarified. OBJECTIVE: To develop clinically applicable novel exacerbation predictors calculated using PEF records. METHODS: Previously proposed exacerbation predictors, including the slope of PEF, percentage predicted PEF, percentage best PEF, the highest PEF over the lowest PEF within specific periods, and PEF coefficient of variation, in addition to a novel indicator delta PEF moving average (ΔMA), defined as the difference between 14-day and 3-day average PEF values, along with moving average (MA) adjusted for PEF reference (%ΔMA), were verified using the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma data of 127 patients with severe asthma from whom 73,503 PEF observations were obtained. Receiver operating characteristic curves for all predictors were drawn, and the corresponding areas under the curve (AUCs) were computed. Regression analysis for MA and percentage MA were conducted. RESULTS: The most outstanding performance was shown by ΔMA and %ΔMA, with AUC values of 0.659 and 0.665 in the univariate model, respectively. When multivariate models were incorporated with random intercepts for individual participants, the AUC for ΔMA and %ΔMA increased to 0.907 and 0.919, respectively. CONCLUSION: The MA and percentage MA are valuable indicators that should be considered when deriving predictors from the PEF trajectory for monitoring exacerbations in patients with severe asthma. TRIAL REGISTRATION: The Hokkaido-based Investigative Cohort Analysis for Refractory Asthma was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN ID: 000003254). https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003917.

Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD.

BACKGROUND: Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear. METHODS: We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD. RESULTS: Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality. CONCLUSIONS: AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD. TRIAL REGISTRATION: This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).

Relationships of computed tomography-based small vessel indices of the lungs with ventilation heterogeneity and high transfer coefficients in non-smokers with asthma.

Background: The mechanism of high transfer coefficients of the lungs for carbon monoxide (Kco) in non-smokers with asthma is explained by the redistribution of blood flow to the area with preserved ventilation, to match the ventilation perfusion. Objectives: To examine whether ventilation heterogeneity, assessed by pulmonary function tests, is associated with computed tomography (CT)-based vascular indices and Kco in patients with asthma. Methods: Participants were enrolled from the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) study that included a prospective asthmatic cohort. Pulmonary function tests including Kco, using single breath methods; total lung capacity (TLC), using multiple breath methods; and CT, were performed on the same day. The ratio of the lung volume assessed using single breath methods (alveolar volume; VA) to that using multiple breath methods (TLC) was calculated as an index of ventilation heterogeneity. The volume of the pulmonary small vessels <5 mm2 in the whole lung (BV5 volume), and number of BV5 at a theoretical surface area of the lungs from the plural surface (BV5 number) were evaluated using chest CT images. Results: The low VA/TLC group (the lowest quartile) had significantly lower BV5 number, BV5 volume, higher BV5 volume/BV5 number, and higher Kco compared to the high VA/TLC group (the highest quartile) in 117 non-smokers, but not in 67 smokers. Multivariable analysis showed that low VA/TLC was associated with low BV5 number, after adjusting for age, sex, weight, lung volume on CT, and CT emphysema index in non-smokers (not in smokers). Conclusion: Ventilation heterogeneity may be associated with low BV5 number and high Kco in non-smokers (not in smokers). Future studies need to determine the dynamic regional system in ventilation, perfusion, and diffusion in asthma.

Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma.

BACKGROUND: There are knowledge gaps in the potential role of Club cell 16-kDa secretory protein (CC16) in severe asthma phenotypes and type 2 inflammation, as well as the longitudinal effect of CC16 on pulmonary function tests and exacerbation risk in epidemiological studies. OBJECTIVE AND METHODS: To assess whether serum CC16 is associated with eosinophilic inflammation in patients with severe asthma. We also examined the effect of this protein on the annual decline in forced expiratory volume in the first second (FEV1) and the risk of exacerbation using a longitudinal approach. We recruited 127 patients with severe asthma from 30 hospitals/pulmonary clinics in Hokkaido, Japan. The least square means and standard error were calculated for T-helper 2 (Th2) biomarkers and pulmonary function test across CC16 tertiles at baseline. We did the same for asthma exacerbation and annual decline in FEV1 with 3 and 5 years' follow-up, respectively. RESULTS: We found that serum CC16 was inversely associated with sputum eosinophils and blood periostin in a dose-response manner. Baseline CC16 and FEV1/forced vital capacity ratio were positively associated in adjusted models (p for trend = 0.008). Patients with the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 than those with the highest tertile over 5 years of follow-up (p for trend = 0.031, fully adjusted model). We did not find any association of CC16 with exacerbation risk. CONCLUSION: Patients with severe asthma with lower circulatory CC16 had enhanced eosinophilic inflammation with rapid FEV1 decline over time.

Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation.

BACKGROUND: The physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical-physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma. METHODS: A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT. RESULTS: More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics. CONCLUSIONS: The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.

Case Report: Hereditary Fibrosing Poikiloderma With Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) Presenting With Liver Cirrhosis and Steroid-Responsive Interstitial Pneumonia.

Background: Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is an extremely rare disease caused by mutations in FAM111B, and only approximately 30 cases have been reported worldwide. Some patients develop interstitial pneumonia, which may lead to progressive pulmonary fibrosis and poor prognosis. However, no effective treatment for interstitial pneumonia associated with POIKTMP has been reported. Here, we report an autopsy case of POIKTMP, wherein interstitial pneumonia was improved by corticosteroids. Case Presentation: A 44-year-old Japanese man was referred to our hospital due to poikiloderma, hypotrichosis, and interstitial pneumonia. He developed progressive poikiloderma and muscle weakness since infancy. He also had tendon contractures, short stature, liver cirrhosis, and interstitial pneumonia. Mutation analysis of FAM111B revealed a novel and de novo heterozygous missense mutation, c.1886T > G (p(Phe629Cys)), through which we were able to diagnose the patient with POIKTMP. 3 years after the POIKTMP diagnosis, interstitial pneumonia had worsened. After 2 weeks of administrating 40 mg/day of prednisolone, his symptoms and lung shadows improved. However, he subsequently developed severe hepatic encephalopathy and eventually died of respiratory failure due to bacterial pneumonia and pulmonary edema. Autopsy revealed an unclassifiable pattern of interstitial pneumonia, as well as the presence of fibrosis and fatty degeneration in several organs, including the liver, kidney, skeletal muscle, heart, pancreas, and thyroid. Conclusions: We report a case of POIKTMP in which interstitial pneumonia was improved by corticosteroids, suggesting that corticosteroids could be an option for the treatment of interstitial pneumonia associated with this disease.

Further evidence for association of YKL-40 with severe asthma airway remodeling.

BACKGROUND: The chitinase-like protein YKL-40 is associated with airflow limitation on spirometry and airway remodeling in patients with asthma. It remains unclear whether YKL-40 is associated with morphologic changes in the airways and parenchyma or with future progression of airflow limitation in severe asthma. OBJECTIVE: To evaluate the association of circulating YKL-40 levels with morphologic changes in the airways and parenchyma and with longitudinal progression of airflow limitation. METHODS: The patients were participants in the Hokkaido Severe Asthma Cohort Study (n = 127), including smokers. This study consisted of 2 parts. In analysis 1, we analyzed associations between circulating YKL-40 levels and several asthma-related indices, including computed tomography-derived indices of proximal wall area percentage, the complexity of the airways (airway fractal dimension), and the parenchyma (exponent D) cross-sectionally (n = 97). In analysis 2, we evaluated the impact of circulating YKL-40 levels on forced expiratory volume in 1 second (FEV1) decline longitudinally for a 5-year follow-up (n = 103). RESULTS: Circulating YKL-40 levels were significantly associated with proximal wall area percentage and airway fractal dimension (r = 0.25, P = .01; r = -0.22, P = .04, respectively), but not with exponent D. The mean annual change in FEV1 was -33.7 (± 23.3) mL/y, and the circulating YKL-40 level was a significant independent factor associated with annual FEV1 decline (ß = -0.24, P = .02), even after controlling for exponent D (ß = -0.26, P = .01). CONCLUSION: These results provide further evidence for the association of YKL-40 with the pathogenesis of airway remodeling in severe asthma.

Effects of daily 1,000-IU vitamin D-fortified milk intake on skeletal muscle mass, power, physical function and nutrition status in Japanese.

An intervention study was conducted to investigate the effects of daily 1,000-IU vitamin D-fortified milk intake on skeletal muscle mass, power, physical function and nutrition status in 26 healthy people and 8 older adults living in a nursing home. The serum 25-hydroxyvitamin D [25(OH)D] level was 13.4 ±â€…0.8 ng / mL and it markedly increased to 29.6 ±â€…0.9 ng / mL after daily 1000-IU vitamin D-fortified milk intake for 6 months. Handgrip strength (kg) also significantly increased in the 21-50 years and total groups, and male subjects, and the timed up and go test significantly improved in the 21-50 years and total groups, and female subjects after 6-month vitamin D intake. However, there were no significant differences between baseline and post-treatment in the Barthel Index (BI), walking speed (m / sec) or skeletal muscle mass (kg, % of BW, kg / m2). Therefore, the present study suggested that vitamin D-fortified milk intake is effective at improving muscle strength and physical function in Japanese, although further studies are needed, particularly for older adults. J. Med. Invest. 68 : 249-255, August, 2021.

Chemical Composition Control at the Substrate Interface as the Key for FeSe Thin-Film Growth.

The strong fascination exerted by the binary compound of FeSe demands reliable engineering protocols and more effective approaches toward inducing superconductivity in FeSe thin films. Our study addresses the peculiarities in pulsed laser deposition that determine FeSe thin-film growth and focuses on the film/substrate interface, which has only been considered hypothetically in the past literature. The FeSe/MgO interface has been assumed (1) to be clean and (2) to obey lattice-matching epitaxy. Our studies reveal that both assumptions are misleading and demonstrate the tendency for domain-matching epitaxial growth, which accompanies the problem of chemical heterogeneity. We propose that homogenization of the film/substrate interface by an Fe buffer can improve the control of stoichiometry and nanostrain in a way that favors superconductivity even in ultrathin FeSe films. We will also show that on a chemically homogenized FeSe/Fe interface, the control of film texture with preparation conditions is still possible.

Cut-off values for skeletal muscle strength and physical functions in Japanese elderly with walking difficulty.

Age-related changes in muscle strength and physical functions, and the association between vitamin D status and skeletal muscle functions were investigated in 36 men (21-90 years old) and 52 women (21-104 years old). Significant ageing-related decreases in several skeletal muscle functions and serum 25-hydroxyvitamin D [25(OH)D] levels were observed in both men and women. Cut-off values for the Timed up and go (TUG) test, walking speed, handgrip strength and Barthel Index (BI) detecting walking difficulties in the receiver operating characteristic (ROC) analysis were 11.1 sec, 0.60 m / sec, 17.0 kg, and 90.0 in males, and 28.6 sec, 0.43 m / sec, 13.9 kg, and 67.5 in females, respectively. By comparing personal present data of muscle strength with these cut-off values, people can easily understand their process to walking difficulty. Therefore, these results are important and useful to avoid or to delay a handicapped and dependent status by improving the vitamin D level, rehabilitation and nursing care. J. Med. Invest. 68 : 48-52, February, 2021.

Simultaneous quantification of arctigenin and its glucuronide conjugate in mouse plasma using ultra-high performance liquid chromatography coupled to tandem mass spectrometry.

Arctigenin is a natural lignin and a main active component of Fructus arctii, the dried fruit of Arctium lappa. This compound was reported to have some biological activities such as anti-inflammatory, antioxidant, antiviral, renoprotective, and antitumor effects. Arctigenin is mainly metabolized to arctigenin-4'-O-glucuronide by UDP-glucuronosyltransferase. In this study, a simultaneous quantification method was established and validated for measuring arctigenin and arctigenin-4'-O-glucuronide in mouse plasma using ultra-high performance liquid chromatography with tandem mass spectrometry. The assay fulfilled the requirements of the United States Food and Drug Administration guideline for assay validation, with a lower limit of quantification of 2.00 ng/mL for arctigenin and 50.0 ng/mL for arctigenin-4'-O-glucuronide. The recovery rate and matrix effect ranged from 78.4 to 102.8% and 92.5 to 106.3%, respectively, for arctigenin, and 74.3 to 109.2% and 94.9 to 110.2% for arctigenin-4'-O-glucuronide. The method was applied to the measurement of plasma concentrations of arctigenin and arctigenin-4'-O-glucuronide in the plasma of mice after administration of arctigenin. All measured concentrations were within the calibration ranges. Our novel method may be useful to measure plasma arctigenin and arctigenin-4'-O-glucuronide concentrations, and contribute to evaluate the pharmacokinetics of arctigenin and arctigenin-4'-O-glucuronide in mice.

Immune checkpoint inhibitor-induced enteritis assessed using capsule endoscopy.

We performed capsule endoscopy for a patient with immune checkpoint inhibitor-induced enteritis and found multiple erosions or small ulcers in the small intestine. No reports demonstrated the effectiveness of capsule endoscopy for immune checkpoint inhibitor-induced gastrointestinal adverse events, and our case suggests that capsule endoscopy may be useful to evaluate immune checkpoint inhibitor-induced enteritis.

Nivolumab-induced immune thrombocytopenia in a patient with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumor. Nivolumab showed durable antitumor effect in patients with recurrent MPM and was approved for those patients in Japan in 2018. Immune related adverse event (irAE) is occurred in various organs and is suggestive to be related to better outcome of nivolumab. Frequency of hematological irAE is low and there are few reports about hematological irAE and association between irAE and outcome of nivolumab in patients with MPM. We present a case of recurrent MPM who responded to nivolumab treatment and experienced nivolumab-induced immune thrombocytopenia (ITP). Although high dose dexamethasone was administered and platelet count increased transiently, re-administration of dexamethasone was required to maintain normal count of platelet. The careful and intensive management of ITP treatment is necessary in cases who show no response or relapse to initial glucocorticoids treatment. This is the first report about nivolumab-induced ITP and association with response to nivolumab in MPM.

Large cell neuroendocrine carcinoma of the lung that responded to nivolumab: A case report.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare type of lung cancer, accounting for 3% of all lung cancers. The prognosis is poor and the standard therapy has not been well established. Herein, we report a case of advanced LCNEC of the lung that responded to nivolumab. The patient was a 62-year old man with stage IVB LCNEC of the lung. The disease progressed following the administration of second-line chemotherapy, and he was treated with nivolumab 3 mg/kg as the third-line treatment. Although treatment was ceased after two cycles due to interstitial pneumonia, the disease remained stable for approximately six months under observation. There was no other adverse event related to nivolumab. Following patient mortality from tumor progression, PD-L1 expression was observed to be negative (tumor proportion score <1%) by a re-examination of the primary biopsy specimen. The case herein suggests that nivolumab may be a possible treatment option for LCNEC.

Local biosynthesis of corticosterone in rat skeletal muscle.

Adrenal corticosterone plays crucial roles in energy metabolism and immuno-reactivity throughout the body. As we have previously shown that corticosterone biosynthesis in C2C12 myoblasts, we study about corticosterone biosynthesis in rat skeletal muscles. It was found that enzymatic activities producing corticosterone and testosterone except the activity of P450scc in rat skeletal muscle as like as C2C12 cells. The CYP11B mRNA encoding cytochrome P45011ß that mediates 11-deoxycorticosterone hydroxylase activity, producing corticosterone was expressed in skeletal muscles. In immunoblotting analysis, cytochrome P45011ß protein was expressed in rat muscles and whole organs especially higher levels in adrenal and brain. The localizations of corticosterone content and enzymatic activities involved in the production of corticosterone were preferentially observed in gastrocnemius fibers rather than in soleus fibers. The immunohistochemical analysis showed that the fast-twitch or type II muscle fibers positive to antibody against fast myosin heavy chain were preferentially stained with anti-cytochrome P45011ß antibody in the gastrocnemius fiber. In addition, we detected corticosterone biosynthesis from pregnenolone sulfate conjugates in perfusion of the rat hindquarter. Corticosterone is synthesized in rat skeletal muscles and the biosynthesis was localized in the fast-twitch or type II muscle fibers. We speculated that the local synthesized corticosterone might be involved in glucocorticoid-induced muscle atrophy that preferentially occurs in fast muscle fibers, and the initial substrate of the local CORT biosynthesis were supported to be performed from the conjugates such as pregnenolone sulfate circulating in the blood flow.

Relationship between age-related decreases in serum 25-hydroxyvitamin D levels and skeletal muscle mass in Japanese women.

A clearer understanding of skeletal muscle mass (SMM) in middle-aged and elderly individuals is important for maintaining functionality. In the present study, age-related changes in SMM, the threshold of SMM with walking difficulty, intestinal nutrient absorption rate, and various serum factors were examined in Japanese populations of different ages. We used 24-h creatinine excretion as a measure of total body SMM. Age-related decreases in SMM, intestinal nutrient absorption rates, and serum 25-hydroxyvitamin D [25(OH)D] concentrations were significantly higher in women than in men. The cut-off values for SMM (kg), its percentage of total body weight (BW), the SMM index [SMMI] (Kg / m2), and creatinine height index (CHI) (%) in elderly individuals with walking difficulty were approximately 8-10 kg, 17-20% of BW, 3.9-4.6 kg / m2, and 44%, respectively. Serum 25(OH)D concentrations were closely associated with SMM (kg, % of BW, kg / m2) and CHI (%) as well as the intestinal absorption rates of nitrogen (%) and phosphorus (%) in women, but not in men. The present results demonstrate that vitamin D is an important metabolic factor in skeletal muscle, and contributes to the optimal management of skeletal muscle and the prevention of sarcopenia. J. Med. Invest. 67 : 151-157, February, 2020.

Corticosterone biosynthesis in mouse clonal myoblastic C2C12 cells.

Corticosterone (CORT), the major glucocorticoid in rodents, is secreted from the adrenal gland, affects various organs in the body and regulates energy metabolism as a stress response. Although local steroidogenesis of androgens and estrogens in skeletal muscles has been previously reported, local CORT synthesis in skeletal muscle remains unconfirmed. In the present study, we investigated steroidogenic activities in a clonal myoblastic cell line, C2C12 cells. Three enzymes involved in CORT synthesis, 3ß-hydroxysteroid dehydrogenase (3ß-HSD), cytochrome P450c21 and cytochrome P45011ß, were identified in C2C12 cells by detecting the enzymatic reaction products with LC-MS/MS analysis. Only one enzyme that mediates cholesterol cleavage was not detected in the cells. After the addition of pregnenolone-sulfate conjugates to the cell culture medium, pregnenolone was detected and increased according to the incubation time. In conclusion, CORT synthesis occurs in C2C12 cells, and it is suggested that the initial steroidogenesis substrate is the pregnenolone-sulfate conjugate.

Skeletal muscle mass of old Japanese women suffering from walking difficulty in nursing home.

By using 24 hour urinary creatinine levels, skeletal muscle mass (kg), its rate (%) of body weight and creatinine height index (%) were determined in old Japanese women suffering from walking difficulty in nursing home and compare with those of young university students. Those of old subjects showed approximately 30-50%, 36-44% and 44-46% of young subjects, respectively. It is suggested that these values are important and useful biomarkers for the planning and the achievement of rehabilitation program for the maintaining and restoring skeletal muscle mass and for the careful support by registered care workers to aged persons. J. Med. Invest. 65:122-125, February, 2018.

Effects of Cardiac Function with Postoperative Arteriovenous Fistula Blood Flow in Patients with Hemodialysis.

BACKGROUND/AIMS: This study was aimed at evaluating the effect of cardiac function with postoperative arteriovenous fistula (AVF) blood flow in hemodialysis (HD) patients. METHODS: A total of 45 HD patients were examined at the Juntendo University Hospital. The AVF blood flow was measured using ultrasonography, and the cardiac function was measured using echocardiography. Correlation between these parameters and the rate of change in body weight (BW) was analyzed. RESULTS: The number of postoperative days significantly correlated with the AVF blood flow, and it positively correlated with the stroke volume (SV). The postoperative AVF blood flow in patients with reduced ejection fraction (EF) was lower than that in patients with normal EF. The rate of change of BW negatively correlated with that of SV, positively correlated with cardiac output (CO), and positively correlated with CO in patients with an AVF blood flow of more than 1,000 mL/min. CONCLUSION: It appears that the cardiac function can be improved by controlling the BW even in patients with high AVF blood flow.