Publications by authors named "Yusuke Suzuki"

472 Publications

Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Ther Apher Dial 2021 May 31. Epub 2021 May 31.

Department of Medicine, Diabetes Center, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post-hoc analysis of the POLARIS study was performed by stratifying enrolled cases according to pretreatment eGFR levels indicating normal (N) (≥60 mL/min/1.73m ), moderately impaired (M) (≥30 to <60 mL/min/1.73m ), and severely impaired (S) (<30 mL/min/1.73m ) renal function. Significant improvements of proteinuria and renal function were found in group N and, most interestingly, in group M. A tendency for improvement in proteinuria was found in group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 mL/min/1.73m . This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/1744-9987.13694DOI Listing
May 2021

Metabolism of the Pyrethroid Insecticide Momfluorothrin in Lettuce ( L.).

J Agric Food Chem 2021 Jun 27;69(22):6156-6165. Epub 2021 May 27.

Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 4-2-1 Takatsukasa, Takarazuka, Hyogo 665-8555, Japan.

The metabolism of the insecticide momfluorothrin (), 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl ()-(1,3)-3-(2-cyanoprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate, C-labeled at the benzyl or cyclopropyl carbon, was investigated in lettuce. The metabolic profiles were similar between the two active ingredients, - and -. On the leaf surface, gradually volatilized and penetrated into the plant with concomitant degradation to form aldehyde/carboxylic acid derivatives via oxidative cleavage of the propenyl double bond. No isomerization of proceeded at any chiral carbon. In the leaf tissues, underwent ester hydrolysis to give the corresponding alcohol and chrysanthemic acid moieties, followed by glucose conjugation and successive malonic acid or ribose modification. Assuming O or O as the major reactant for the degradation on the plant, the reactivity with the alkenyl group in the substructure methyl (1,3)-3-[()-2-cyanoprop-1-enyl]-2,2-dimethylcyclopropane-1-carboxylate was estimated from the HOMO/LUMO energy at the B3LYP/6-311+G** level, which indicated a lower potential of than analogous pyrethroids due to its electron-withdrawing cyano group.
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http://dx.doi.org/10.1021/acs.jafc.1c00493DOI Listing
June 2021

[COMPARISON OF CLINICAL EFFICACY AND SAFETY BETWEEN CHILDREN AND ADULTS BEFORE AND 1 YEAR AFTER MITE SUBLINGUAL IMMUNOTHERAPY FOR PERENNIAL ALLERGIC RHINITIS].

Arerugi 2021 ;70(3):186-194

Department Otorhinolaryngology, Shiga University of Medical Science.

Background: We studied clinical efficacy and safety after 1 year of mite sublingual immunotherapy (SLIT) for perennial allergic rhinitis in children, compared with adults.

Methods: We compared 121 children under 15 yeas old (81 male, aged 5-14 years, a median of 12 years) and 77 adults (36 male, aged 15-65 years, a median of 26 years) treated with mite SLIT tablet (10000 Japanese Allergy Unit). The clinical efficacy before and 1 year after SLIT was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire (JRQLQ No1) and visual analog scale (VAS). Combined medication was also compared. Adverse events of SLIT were checked at every visit.

Results: All items of JRQLQ No1 scores and VAS after 1 year of mite SLIT, except eye symptoms in adults by JRQLQ No1, were significantly improved in both children and adults. Comparing children and adults, there were no differences in symptoms before and after 1 year. Combined medication score showed a similar result. Adverse events were observed in 57.9% of children and 58.4% of adults, but there were no serious adverse reactions.

Conclusion: There was no difference between children and adults in efficacy and safety of mite SLIT, and both group showed significant improvement of symptoms.
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http://dx.doi.org/10.15036/arerugi.70.186DOI Listing
May 2021

Icatibant promotes patients' behavior modification associated with emergency room visits during an acute attack of hereditary angioedema.

Intractable Rare Dis Res 2021 May;10(2):142-145

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Hereditary angioedema due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) induces an acute attack of angioedema. In 2018, icatibant available for self-possession and subcutaneous self-administration was licensed for on-demand treatment in addition to intravenous C1-INH administration in Japan. We retrospectively evaluated the percentage of attacks in critical parts at emergency room (ER) visits and the time until visiting ER for C1-INH administration before and after the initial prescription of icatibant. The percentage of attacks in critical parts at ER visits before the prescription was 69.2%, but that was 80.0% when patients visited ER for additional C1-INH administration after the self-administration of icatibant. The time from the onset of an acute attack to visiting ER for the additional treatment after the self-administration of icatibant significantly increased from 6.2 h to 19.2 h ( < 0.001). Icatibant, therefore, promoted the patients' behavior modification associated with ER visits for C1-INH administration during an acute attack of HAE-C1-INH.
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http://dx.doi.org/10.5582/irdr.2021.01010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122312PMC
May 2021

Utility of remission criteria for the renal prognosis of IgA nephropathy.

Clin Exp Nephrol 2021 May 11. Epub 2021 May 11.

Department of Nephrology, Juntendo University Faculty of Medicine, Hongo 2-1-1, Bunkyo-Ku, Tokyo, 113-8421, Japan.

Background: Novel criteria for the remission of Immunoglobulin A nephropathy (IgAN) based on an opinion survey of Japanese nephrologists and literature review were proposed in 2013. This single-center, longitudinal retrospective cohort study was conducted to validate this criteria.

Methods: Present study included the IgAN patients diagnosed between 2001 and 2005 in the Juntendo University Hospital. Remission of hematuria was defined as three consecutive dipstick test results of ( -) to ( ±) or a red blood cell count < 5 in urinary sediment per high-power field during at least 6 months. Remission of proteinuria was defined as three consecutive dipstick results of ( -) to ( ±) during at least 6 months. We categorized four groups according to the remission status which was assessed 2 years after the renal biopsy. The primary outcome was a 50% increase in the serum creatinine over the baseline. We evaluated the slope of eGFR decline (mL/min/1.73 m/year) and a decrease in the eGFR of 30% from baseline eGFR as the secondary outcome, respectively.

Results: A total of 74 patients (male: 47.3%, median age: 30 years) were included and were followed for a median of 86.5 months. During the period, forty-one patients achieved neither remission of proteinuria nor hematuria (NR). Twelve patients met the primary study outcome. A survival analysis revealed that the NR had the worst prognosis and the steepest slope of eGFR decline.

Conclusion: Although further validation in a large cohort is necessary, these novel remission criteria for IgAN patients appear to predict the renal prognosis.
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http://dx.doi.org/10.1007/s10157-021-02069-wDOI Listing
May 2021

Nasal-associated lymphoid tissue is the major induction site for nephritogenic IgA in murine IgA nephropathy.

Kidney Int 2021 May 5. Epub 2021 May 5.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan. Electronic address:

Dysregulation of mucosal immunity may play a role in the pathogenesis of IgA nephropathy (IgAN). However, it is unclear whether the nasal-associated lymphoid tissue (NALT) or gut-associated lymphatic tissue is the major induction site of nephritogenic IgA synthesis. To examine whether exogenous mucosal antigens exacerbate the pathogenesis of IgAN, we assessed the disease phenotypes of IgAN-onset ddY mice housed germ-free. These mice were transferred to a specific pathogen-free environment and divided into three groups: challenged with the Toll-like receptor 9 (TLR9) ligand CpG-oligodeoxynucleotide, fecal transplantation, and the untreated control group. The levels of aberrantly glycosylated IgA and IgG-IgA immune complexes were measured in the serum and supernatant of cultured cells purified from the NALT, mesenteric lymph nodes, and Peyer's patch. Although the germ-free IgAN-onset ddY mice did not develop IgAN, they showed aggravation of kidney injury with mesangial IgA deposition after transfer to the specific pathogen-free state. The NALT cells produced more aberrantly glycosylated IgA than those from the mesenteric lymph node and Peyer's patch, resulting in induction of IgG-IgA immune complexes formation. Additionally, TLR9 enhanced the production of nephritogenic IgA and IgG-IgA immune complexes by nasal-associated lymphoid but not gut-associated lymphatic cells. Furthermore, the germ-free IgAN-onset ddY mice nasally immunized with CpG-oligonucleotide showed aggravation of kidney injury with mesangial IgA deposition, whereas those that received fecal transplants did not develop IgAN. Thus, NALT is the major induction site of the production of aberrantly glycosylated IgA in murine IgAN.
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http://dx.doi.org/10.1016/j.kint.2021.04.026DOI Listing
May 2021

Possible Neuroprotective Effects of l-Carnitine on White-Matter Microstructural Damage and Cognitive Decline in Hemodialysis Patients.

Nutrients 2021 Apr 14;13(4). Epub 2021 Apr 14.

Department of Neurology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan.

Although l-carnitine alleviated white-matter lesions in an experimental study, the treatment effects of l-carnitine on white-matter microstructural damage and cognitive decline in hemodialysis patients are unknown. Using novel diffusion magnetic resonance imaging (dMRI) techniques, white-matter microstructural changes together with cognitive decline in hemodialysis patients and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent dMRI and laboratory and neuropsychological tests, which were compared across seven patients each in two groups according to duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment (NSTLC), and (2) long-term l-carnitine treatment (LTLC). Ten age- and sex-matched controls were enrolled. Compared to controls, microstructural disorders of white matter were widely detected on dMRI of patients. An autopsy study of one patient in the NSTLC group showed rarefaction of myelinated fibers in white matter. With LTLC, microstructural damage on dMRI was alleviated along with lower levels of high-sensitivity C-reactive protein and substantial increases in carnitine levels. The LTLC group showed better achievement on trail making test A, which was correlated with amelioration of disorders in some white-matter tracts. Novel dMRI tractography detected abnormalities of white-matter tracts after hemodialysis. Long-term treatment with l-carnitine might alleviate white-matter microstructural damage and cognitive impairment in hemodialysis patients.
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http://dx.doi.org/10.3390/nu13041292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070822PMC
April 2021

Synchronous Primary Lung Adenocarcinoma and Hepatocellular Carcinoma Successfully Treated with a Combination of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel.

Intern Med 2021 Apr 12. Epub 2021 Apr 12.

Department of Respiratory Medicine, Kitasato University Kitasato Institute Hospital, Japan.

Chemotherapy for multiple primary malignancies is challenging. We herein report a case of synchronous primary lung adenocarcinoma and hepatocellular carcinoma (HCC). A 72-year-old man was admitted for the evaluation of an abnormal shadow on his lung. Computed tomography revealed a lung nodule in the right upper lobe and multiple liver masses. He was diagnosed with synchronous primary lung adenocarcinoma and HCC. Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) chemotherapy was efficacious for both tumors. ABCP chemotherapy may be a potential treatment option for synchronous primary lung adenocarcinoma and HCC.
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http://dx.doi.org/10.2169/internalmedicine.6442-20DOI Listing
April 2021

False positive results in severe acute respiratory coronavirus 2 (SARS-CoV-2) rapid antigen tests for inpatients.

J Infect Chemother 2021 Jul 22;27(7):1089-1091. Epub 2021 Mar 22.

Department of Internal Medicine, National Hospital Organization Awara Hospital, Awara, Japan.

Severe acute respiratory syndrome coronavirus 2 rapid antigen detection (RAD) test kits are widely used as primary screening test in Japan because rapid diagnosis of coronavirus disease 2019 (COVID-19) is critical for infection control. We report cases with RAD test false-positive results in a ward for patients with disabilities. RAD tests potentially evoke hospital operational risk. It is desirable that performing PCR test appropriately when patients admitted to a medical treatment ward with COVID-19 symptoms instead of RAD test.
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http://dx.doi.org/10.1016/j.jiac.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983572PMC
July 2021

Characterization of an active LINE-1 in the naked mole-rat genome.

Sci Rep 2021 Mar 11;11(1):5725. Epub 2021 Mar 11.

Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Naked mole-rats (NMRs, Heterocephalus glaber) are the longest-living rodent species. A reason for their long lifespan is pronounced cancer resistance. Therefore, researchers believe that NMRs have unknown secrets of cancer resistance and seek to find them. Here, to reveal the secrets, we noticed a retrotransposon, long interspersed nuclear element 1 (L1). L1s can amplify themselves and are considered endogenous oncogenic mutagens. Since the NMR genome contains fewer L1-derived sequences than other mammalian genomes, we reasoned that the retrotransposition activity of L1s in the NMR genome is lower than those in other mammalian genomes. In this study, we successfully cloned an intact L1 from the NMR genome and named it NMR-L1. An L1 retrotransposition assay using the NMR-L1 reporter revealed that NMR-L1 was active retrotransposon, but its activity was lower than that of human and mouse L1s. Despite lower retrotrasposition activity, NMR-L1 was still capable of inducing cell senescence, a tumor-protective system. NMR-L1 required the 3' untranslated region (UTR) for retrotransposition, suggesting that NMR-L1 is a stringent-type of L1. We also confirmed the 5' UTR promoter activity of NMR-L1. Finally, we identified the G-quadruplex structure of the 3' UTR, which modulated the retrotransposition activity of NMR-L1. Taken together, the data indicate that NMR-L1 retrotranspose less efficiently, which may contribute to the cancer resistance of NMRs.
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http://dx.doi.org/10.1038/s41598-021-84962-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952902PMC
March 2021

Effects of antithrombotic drugs on the results of fecal immunochemical test in colorectal neoplasms screening.

Sci Rep 2021 Feb 23;11(1):4348. Epub 2021 Feb 23.

Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.

Fecal immunochemical test (FIT) is widely used as a colorectal cancer screening tool. Antithrombotic drugs may affect the screening performance of FIT for colorectal tumors. The aim of this study was to clarify the effect of antithrombotic agents on FIT accuracy in screening for colorectal neoplasms. This retrospective study enrolled a total of 758 patients who underwent both FIT and total colonoscopy. The effect of antithrombotic drugs on FIT accuracy in detecting colorectal neoplasms (CN), including colorectal cancer (CRC), advanced adenoma (AA), and non-advanced adenoma (NAA), was examined. Of the 758 patients, 144 (19%) received antithrombotic drugs (administration group). In administration group, 61/144 (42%) cases had CN [CRC:14, AA:15, NAA:32] and 217/614 (35%) cases had CN (CRC:43, AA:56, NAA:118) in non-administration group. The prevalence of CN was not significantly different between the two groups (p = 0.1157). There was no significant difference in sensitivity or specificity of the detection of all types of CN with or without taking antithrombotic drugs. Neither the positive predictive value nor negative predictive value of FIT was affected by antithrombotic drug administration. Taking antithrombotic drugs may not have a large impact on sensitivity, specificity, positive predictive value, or negative predictive value of FIT in screening for CN.
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http://dx.doi.org/10.1038/s41598-021-83007-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902607PMC
February 2021

Cut-off value of C1-inhibitor function for the diagnosis of hereditary angioedema due to C1-inhibitor deficiency.

Intractable Rare Dis Res 2021 Feb;10(1):42-47

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Hereditary angioedema caused by C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare autosomal dominant disease. Primary care physicians sometimes face difficulties in diagnosing HAE-C1-INH owing to fluctuations in C1-INH function levels influenced by blood sampling conditions. International major guidelines do not stipulate a cut-off value of C1-INH function for the diagnosis. We aimed to explore the distribution of C1-INH function levels in patients with HAE-C1-INH and elucidate the influence of blood sampling conditions using healthy volunteers' samples to confirm the cut-off value of C1-INH function. In 48 patients with HAE-C1-INH who visited the Juntendo University Hospital in Japan between 2013 and 2019, C1-INH function levels were evaluated for 160 samples during symptom-free periods and 147 samples during an acute attack. Fluctuations of C1-INH function level were also evaluated for 8 healthy volunteers, wherein the samples were divided into 3 groups according to different sampling conditions. C1- INH function levels in all patients with HAE-C1-INH were found to be < 50%. The average C1- INH function level in healthy volunteers measured soon after blood collection in an appropriate sampling condition was 77% (61-92%) with some having lower C1-INH function levels than the reference value. C1-INH function levels fluctuated unstably in inappropriate sampling conditions. In conclusion, we can confirm that a < 50% C1-INH function level can be used as the diagnostic cut-off value for HAE-C1-INH. Moreover, it is necessary to repeat measurements of C1-INH function level in appropriate blood sampling conditions to accurately diagnose HAE-C1-INH.
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http://dx.doi.org/10.5582/irdr.2020.03099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882089PMC
February 2021

Galactose-deficient IgA1 and nephritis-associated plasmin receptors as markers for IgA-dominant infection-related glomerulonephritis: A case report.

Medicine (Baltimore) 2021 Feb;100(5):e24460

Division of Nephrology and Hypertension, Department of Internal Medicine, St Marianna University School of Medicine, Kawasaki.

Rational: Immunoglobulin A (IgA) nephropathy is a common heterogeneous kidney disease. One of the causes of secondary immunoglobulin A nephropathy is infection-related glomerulonephritis (IRGN), however, its accurate diagnosis is difficult.

Patient Concerns: We report a rare case of an 82-year-old male presenting rapidly progressive glomerulonephritis. Assessment of a kidney biopsy by light microscopy revealed endocapillary glomerulonephritis with subendothelial deposits, such as wire loop lesions and cellular crescents. Immunofluorescence demonstrated strong staining for IgA and C3 along the glomerular capillary. Additional tests included positive staining for nephritis-associated plasmin receptor and positive plasmin activity in the glomeruli. Moreover, IgA and galactose-deficient IgA1 (Gd-IgA1) staining merged using immunofluorescence, followed by confirmation of high serum levels of Gd-IgA1 (9.3 μg/mL) by ELISA was observed.

Diagnosis: The diagnosis of IgA-dominant IRGN was made.

Interventions And Outcomes: We have initiated treatment with intravenous methylprednisolone 500 mg/day for 3 days, followed by oral prednisolone 25 mg/d as rapidly progressive glomerulonephritis. However immunosuppressive therapy was halted because of a poor response, and hemodialysis was initiated.

Lessons: This is a case of IgA-dominant IRGN patient exhibiting positive glomerular staining for nephritis-associated plasmin receptor accompanied with high titers of serum Gd-IgA1. Our observations suggest that serum and kidney tissue of Gd-IgA1 may be useful for the diagnosis of IgA-dominant IRGN.
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http://dx.doi.org/10.1097/MD.0000000000024460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870202PMC
February 2021

A case of hereditary angioedema due to C1-inhibitor deficiency with recurrent abdominal pain diagnosed 40 years after the occurrence of the initial symptom.

Clin J Gastroenterol 2021 Feb 5. Epub 2021 Feb 5.

Department of Nephrology, Faculty of Medicine, Juntendo University, Tokyo, Japan.

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare disease, which induces an acute attack of angioedema mediated by bradykinin. HAE-C1-INH can cause serious abdominal pain when severe edema develops in the gastrointestinal tract. However, because it takes a long time, 13.8 years on average in Japan, from the occurrence of the initial symptom to the diagnosis due to low awareness of the disease, undiagnosed HAE-C1-INH patients sometimes undergo unnecessary surgical procedures for severe abdominal pain. We herein present a 56-year-old patient with HAE-C1-INH, who underwent numerous abdominal operations. He frequently needed hospitalization with the administration of opioid due to severe abdominal pain. However, after he was accurately diagnosed with HAE-C1-INH at 55 years of age, he could start self-administration for an acute attack with icatibant, a selective bradykinin B2 receptor antagonist. Consequently, he did not need hospitalizing for ten months after the beginning of the treatment. A series of an accurate diagnosis and appropriate treatment for HAE-C1-INH improved his quality of life. Thus, HAE-C1-INH should be considered, when we meet patients with unidentified recurrent abdominal pain. This case highlights significance of an early diagnosis and appropriate treatment for HAE-C1-INH.
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http://dx.doi.org/10.1007/s12328-021-01338-1DOI Listing
February 2021

Diabetes mellitus does not influence results of hepatectomy in hepatocellular carcinoma: case control study.

Contemp Oncol (Pozn) 2020 4;24(4):211-215. Epub 2021 Jan 4.

Department of General and Gastroenterological Surgery, Osaka Medical College Mishima-Minami Hospital, Takatsuki City, Osaka, Japan.

Introduction: Patients with diabetes mellitus undergoing hepatectomy for hepatocellular carcinoma (HCC) are at high risk of acquiring perioperative infections. Herein, we investigate the peri-operative impact of diabetes on hepatectomy.

Material And Methods: The surgical outcomes in 363 patients who underwent laparoscopic and open hepatic resection for HCC, with or without diabetes mellitus, were reviewed retrospectively. The association of diabetes mellitus with surgical outcomes and remnant liver regeneration was analyzed. The Student's and χ tests, Mann-Whitney's U test, Wilcoxon's signed-rank test, or Fisher's exact test were used in the statistical analysis.

Results: Of the 363 patients, 136 (37.5%) had diabetes, while 227 (62.5%) did not. After propensity score matching, there were no significant differences between the groups in surgical outcomes such as surgery duration, bleeding amount, and postoperative complication rate. No significant differences were observed between the groups in terms of incidence rates of not only infectious complications, including surgical site infection and remote site infection, but also postoperative complication (Clavien-Dindo grade > IIIA), post-hepatectomy liver failure, and massive ascites. There were no differences in the remnant liver regeneration at 7 days and 1, 2, 5, and 12 months following the surgery between the groups ( = 0.076, 0.368, 0.864, 0.288, and 0.063, respectively). No significant differences between the groups in the overall and recurrence-free survival were observed ( = 0.613 and 0.937).

Conclusions: Remnant liver regeneration in diabetic patients was not morphologically and functionally delayed compared to that in non-diabetic patients. Moreover, diabetes has no effect on the short- and long-term prognosis.
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http://dx.doi.org/10.5114/wo.2020.102825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836278PMC
January 2021

Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy.

J Am Soc Nephrol 2021 Feb 23;32(2):436-447. Epub 2020 Dec 23.

Division of Nephrology, University of Toronto, Toronto, Ontario, Canada

Background: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown.

Methods: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR).

Results: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups.

Conclusions: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.
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http://dx.doi.org/10.1681/ASN.2020030349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054888PMC
February 2021

Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy.

J Autoimmun 2021 Mar 25;118:102593. Epub 2021 Jan 25.

University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Background: IgA nephropathy is thought to be an autoimmune disease wherein galactose-deficient IgA1 (Gd-IgA1) is recognized by IgG autoantibodies, resulting in formation and renal accumulation of nephritogenic immune complexes. Although this hypothesis is supported by recent findings that, in renal immunodeposits of IgA nephropathy patients, IgG is enriched for Gd-IgA1-specific autoantibodies, experimental proof is still lacking.

Methods: IgG isolated from sera of IgA nephropathy patients or produced as a recombinant IgG (rIgG) was mixed with human Gd-IgA1 to form immune complexes. IgG from healthy individuals served as a control. Nude and SCID mice were injected with human IgG and Gd-IgA1, in immune complexes or individually, and their presence in kidneys was ascertained by immunofluorescence. Pathologic changes in the glomeruli were evaluated by quantitative morphometry and exploratory transcriptomic profiling was performed by RNA-Seq.

Results: Immunodeficient mice injected with Gd-IgA1 mixed with IgG autoantibodies from patients with IgA nephropathy, but not Gd-IgA1 mixed with IgG from healthy individuals, displayed IgA, IgG, and mouse complement C3 glomerular deposits and mesangioproliferative glomerular injury with hematuria and proteinuria. Un-complexed Gd-IgA1 or IgG did not induce pathological changes. Moreover, Gd-IgA1-rIgG immune complexes injected into immunodeficient mice induced histopathological changes characteristic of human disease. Exploratory transcriptome profiling of mouse kidney tissues indicated that these immune complexes altered gene expression of multiple pathways, in concordance with the changes observed in kidney biopsies of patients with IgA nephropathy.

Conclusions: This study provides the first in vivo evidence for a pathogenic role of IgG autoantibodies specific for Gd-IgA1 in the pathogenesis of IgA nephropathy.
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http://dx.doi.org/10.1016/j.jaut.2021.102593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997636PMC
March 2021

The Management of Recurrence of Hepatocellular Carcinoma Occurring Within 6 Months After Hepatic Resection: A Comparative Study Using a Propensity Score Matching Analysis.

J Gastrointest Cancer 2021 Jan 20. Epub 2021 Jan 20.

Department of General and Gastroenterological Surgery, Osaka Medical College Mishima-Minami Hospital, 8-1 Tamagawa-shinmachi, Takatsuki City, Osaka, 569-0856, Japan.

Background: Hepatectomy is currently recommended as the most reliable treatment for hepatocellular carcinoma. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial.

Methods: Three-hundred thirty-nine patients who underwent hepatectomy were retrospectively analyzed using a propensity score matching analysis for the risk factors and outcomes for early recurrences within 6 months. The remnant liver volumes and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after surgery. The Student's t test and chi-square test, the likelihood-ratio test, Fisher's exact test, Mann-Whitney U test, or Wilcoxon signed-rank test were used in the statistical analyses.

Results: Early recurrence developed in 41/312 patients (13.1%). Vascular invasion and non-curative resection were independent risk factors for the occurrence of early recurrence (P < 0.001 and < 0.001, respectively). Patients with early recurrence had a poorer prognosis than patients who developed later recurrences (P < 0.001). Patients who underwent surgery or other local treatments had better outcomes (P < 0.001). The changes in remnant liver volumes and laboratory data after postoperative month 2 were not significantly different between the two groups.

Conclusion: Patients with early recurrence within 6 months had a poorer prognosis than patients who developed a later recurrence. However, patients who underwent repeat hepatectomy for recurrences had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival.
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http://dx.doi.org/10.1007/s12029-021-00585-2DOI Listing
January 2021

Differential organ-specific inflammatory response to progranulin in high-fat diet-fed mice.

Sci Rep 2021 Jan 13;11(1):1194. Epub 2021 Jan 13.

Department of Nephrology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Progranulin (PGRN) has been reported to bind tumor necrosis factor (TNF) receptor and to inhibit TNFα signaling. We evaluated the effect of augmentation of TNFα signaling by PGRN deficiency on the progression of kidney injury. Eight-week-old PGRN knockout (KO) and wild-type (WT) mice were fed a standard diet or high-fat diet (HFD) for 12 weeks. Albuminuria, markers of tubular damage, and renal mRNA levels of inflammatory cytokines were higher in HFD-fed KO (KO-HFD) mice than in HFD-fed WT (WT-HFD) mice. Body weight, vacuolization in proximal tubules, and systemic and adipose tissue inflammatory markers were lower in the KO-HFD mice than in the WT-HFD mice. The renal megalin expression was lower in the KO mice than in the WT mice regardless of the diet type. The megalin expression was also reduced in mouse proximal tubule epithelial cells stimulated with TNFα and in those with PGRN knockdown by small interfering RNA in vitro. PGRN deficiency was associated with both exacerbated renal inflammation and decreased systemic inflammation, including that in the adipose tissue of mice with HFD-induced obesity. Improved tubular vacuolization in the KO-HFD mice might partially be explained by the decreased expression of megalin in proximal tubules.
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http://dx.doi.org/10.1038/s41598-020-80940-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806827PMC
January 2021

LCC18, a benzamide-linked small molecule, ameliorates IgA nephropathy in mice.

J Pathol 2021 04 27;253(4):427-441. Epub 2021 Jan 27.

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

IgA nephropathy (IgAN), an immune complex-mediated process and the most common primary glomerulonephritis, can progress to end-stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterisation and target identification, we predicted that a novel ring-fused 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (LCC18) targets the NLRP3 inflammasome, which participates in IgAN pathogenesis. We further developed biomarkers for the disease. We used two complementary IgAN models in C57BL/6 mice, involving TEPC-15 hybridoma-derived IgA, and in gddY mice. Moreover, we created specific cell models to validate therapeutic effects of LCC18 on IgAN and to explain its underlying mechanisms. IgAN mice benefited significantly from treatment with LCC18, showing dramatically improved renal function, including greatly reduced proteinuria and renal pathology. Mechanistic studies showed that the mode of action specifically involved: (1) blocking of the MAPKs/COX-2 axis-mediated priming of the NLRP3 inflammasome; (2) inhibition of ASC oligomerisation and NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC; and (3) activation of autophagy. LCC18 exerts therapeutic effects on murine IgAN by differentially regulating NLRP3 inflammasome activation and autophagy induction, suggesting this new compound as a promising drug candidate to treat IgAN. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5609DOI Listing
April 2021

Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs.

Front Pharmacol 2020 13;11:587689. Epub 2020 Nov 13.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.

Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18-22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.
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http://dx.doi.org/10.3389/fphar.2020.587689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751689PMC
November 2020

Safety and Efficacy of Laparoscopic Liver Resection for Colorectal Liver Metastasis With Obesity.

Am Surg 2020 Dec 7:3134820952448. Epub 2020 Dec 7.

Department of Internal Medicine, Osaka Medical College Mishima-Minami Hospital, Japan.

Introduction: Laparoscopic liver resection (LLR) in obese patients has been reported to be particularly challenging owing to technical difficulties and various comorbidities.

Methods: The safety and efficacy outcomes in 314 patients who underwent laparoscopic or open nonanatomical liver resection for colorectal liver metastases (CRLM) were analyzed retrospectively with respect to the patients' body mass index (BMI) and visceral fat area (VFA).

Results: Two hundred and four patients underwent LLR, and 110 patients underwent open liver resection (OLR). The rate of conversion from LLR to OLR was 4.4%, with no significant difference between the BMI and VFA groups ( = .647 and .136, respectively). In addition, there were no significant differences in terms of operative time and estimated blood loss in LLR ( = .226 and .368; .772 and .489, respectively). The incidence of Clavien-Dindo grade IIIa or higher complications was not significantly different between the BMI and VFA groups of LLR ( = .877 and .726, respectively). In obese patients, the operative time and estimated blood loss were significantly shorter and lower, respectively, in LLR than in OLR ( = .003 and < .001; < .001 and < .001, respectively). There was a significant difference in the incidence of postoperative complications, organ/space surgical site infections, and postoperative bile leakage between the LLR and OLR groups ( = .017, < .001, and < .001, respectively).

Conclusion: LLR for obese patients with CRLM can be performed safely using various surgical devices with no major difference in outcomes compared to those in nonobese patients. Moreover, LLR has better safety outcomes than OLR in obese patients.
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http://dx.doi.org/10.1177/0003134820952448DOI Listing
December 2020

Use of Anti-Dementia Drugs Reduces the Risk of Potentially Inappropriate Medications: A Secondary Analysis of a Nationwide Survey of Prescribing Pharmacies.

Dement Geriatr Cogn Disord 2020 4;49(5):526-532. Epub 2020 Dec 4.

Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aims: As the number of older people with dementia increases, safe pharmacotherapy in this population has attracted attention in recent years. The aims of this study were to clarify the prescribing patterns in older patients who were prescribed anti-dementia drugs and to investigate the association of potentially inappropriate medications (PIMs) with the use of anti-dementia drugs.

Methods: Adults aged ≥65 years, who were prescribed anti-dementia drugs at 585 pharmacies across Japan (N = 7,953), were surveyed. The percentage of prescriptions of anti-dementia drugs and the effect of those prescriptions on PIMs were investigated.

Results: Prescriptions of anti-dementia drugs were found in 4.4% of the entire study population. A multiple logistic regression analysis revealed that the use of anti-dementia drugs reduced the risk of prescribing psychotropic drugs, which represented PIMs, and that a combination of anti-dementia drugs (e.g., cholineesterase inhibitor with memantine) may reduce the risk of prescribing PIMs compared with monotherapy.

Conclusion: The use of anti-dementia drugs was associated with fewer prescriptions of drugs considered as PIMs.
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http://dx.doi.org/10.1159/000512043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949214PMC
June 2021

Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial.

Allergy 2021 Jun 23;76(6):1789-1799. Epub 2020 Dec 23.

Hiroshima University, Hiroshima, Japan.

Background: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients.

Methods: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period.

Results: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%).

Conclusions: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.
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http://dx.doi.org/10.1111/all.14670DOI Listing
June 2021

Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF-PH inhibitors.

Nephrology (Carlton) 2021 Feb 9;26(2):105-118. Epub 2020 Dec 9.

Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Renal anaemia is a common and important complication in patients with chronic kidney disease (CKD). The current standard-of-care treatment for renal anaemia in CKD patients involves ensuring adequate iron stores and administration of erythropoietin stimulating agents (ESA). Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery. Manipulation of the HIF pathway by the use of HIF-prolyl hydroxylase inhibitors (HIF-PHI) has emerged as a novel approach for renal anaemia management. Despite it being approved for clinical use in various Asia-Pacific countries, its novelty mandates the need for nephrologists and clinicians generally in the region to well understand potential benefits and harms when prescribing this class of drug. The Asian Pacific society of nephrology HIF-PHI Recommendation Committee, formed by a panel of 11 nephrologists from the Asia-Pacific region who have clinical experience or have been investigators in HIF-PHI studies, reviewed and deliberated on the clinical and preclinical data concerning HIF-PHI. This recommendation summarizes the consensus views of the committee regarding the use of HIF-PHI, taking into account both available data and expert opinion in areas where evidence remains scarce.
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http://dx.doi.org/10.1111/nep.13835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898910PMC
February 2021

[EFFICACY AND SAFETY OF PEDIATRIC SUBLINGUAL IMMMUNOTHERAPY WITH CEDARCURE IN CLINICAL PRACTICE FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP SEASON].

Arerugi 2020 ;69(9):909-917

Department Otorhinolaryngology, Shiga University of Medical Science.

Background: We studied clinical efficacy and safety of pediatric sublingual immunotherapy of cedar pollinosis in the first follow-up year, compared with adult cases or untreated cases.

Methods: We compared 103 pediatrics under 15 yeas old (age, 10.8±2.6 years; male-to-female ratio, 68;35) and 89 adults (age, 38.9±12.5 years; male-to-female ratio, 34;55) treated with Cidarcure, and untreated 299 patients (age, 31.3±16.0; male-to-female ratio, 144;155). The clinical efficacy was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire and visual analog scale (VAS) during the peak season of moderate amount of pollen dispersal (3582 grains/cm/season) in 2020. Adverse events of sublingual immunotherapy were also checked at every visits.

Results: All patients in both pediatric and adult group successfully maintained the highest dose of 5000JAU as planned. Pediatrics compared with adults showed slightly better effects in all the assessments, but they were not significant. Both pediatrics and adults of sublingual immunotherapy showed significant better effects in all the assessments compared with untreated group. Percentage of total cases of adverse events in pediatric group was low, but it was not significant. Percentage of pruritus of ear and throat was significantly low in pediatric group.

Conclusion: Pediatric sublingual immunotherapy for cedar pollinosis was treated in safe, and reduced symptoms as well as the effects of adults.
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http://dx.doi.org/10.15036/arerugi.69.909DOI Listing
January 2021

Emergent initiation of dialysis is related to an increase in both mortality and medical costs.

Sci Rep 2020 11 12;10(1):19638. Epub 2020 Nov 12.

Department of Nephrology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

The number of patients with end-stage renal disease (ESRD) has been increasing, with dialysis treatment being a serious economic problem. To date, no report in Japan considered medical costs spent at the initiation of dialysis treatment, although some reports in other countries described high medical costs in the first year. This study focused on patient status at the time of initiation of dialysis and examined how it affects prognosis and the medical costs. As a result, all patients dying within 4 months experienced emergent dialysis initiation. Emergent dialysis initiation and high medical costs were risk factors for death within 2 years. High C-reactive protein levels and emergent dialysis initiation were associated with increasing medical costs. Acute kidney injury (AKI) contributed most to emergent dialysis initiation followed by stroke, diabetes, heart failure, and short-term care by nephrologists. Therefore, emergent dialysis initiation was a contributing factor to both death and increasing medical costs. To avoid the requirement for emergent dialysis initiation, patients with ESRD should be referred to nephrologists earlier. Furthermore, ESRD patients with clinical histories of AKI, stroke, diabetes, or heart failure should be observed carefully and provided pre-planned initiation of dialysis.
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http://dx.doi.org/10.1038/s41598-020-76765-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661714PMC
November 2020

Laparoscopic right hemicolectomy for an ascending colon cancer patient with an implantable left ventricular assist device: a case report.

Surg Case Rep 2020 Nov 9;6(1):282. Epub 2020 Nov 9.

Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryou-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Background: Left ventricular assist devices (LVADs) currently play an important role in the treatment of patients with end-stage heart failure who require a bridge to heart transplantation or destination therapy. With the development and improvement of the LVADs, the morbidity and mortality rates are declining and life expectancies increasing, and the number of patients with LVADs requiring non-cardiac surgery is likely to increase. We present the case of a patient with implantable LVAD who underwent laparoscopic right hemicolectomy for ascending colon cancer.

Case Description: The patient was a 66-year-old man who underwent LVAD implantation as a BTT 3 years prior. He suffered from severe anemia at follow-up, and a colonoscopy revealed ascending colon cancer. The LVAD pump was implanted in the epigastrium. The long C-shaped subfascial driveline tunnel was made, and driveline exit site was located on the left lateral abdominal wall. We assessed the positional relationship between the tumor and the driveline using X-ray and three-dimensional computed tomography (3D CT) images. 3D CT image allowed us to easily identify the location of the driveline, and we determined to perform laparoscopic right hemicolectomy. The port sites were decided upon carefully to avoid the driveline injury, and the driveline was marked on the skin before surgery. There were no adhesions in the abdominal cavity, and both the LVAD and the driveline were observable. The trocars were in nearly the same positions as in a standard laparoscopic right hemicolectomy. During the operation, the LVAD and the driveline did not interfere with the trocars. We successfully completed a standard laparoscopic right hemicolectomy despite hemorrhagic tendency. The patient was discharged without any bleeding complications during the postoperative course.

Conclusion: Laparoscopic surgery is feasible and safe for patients with LVADs with intensive preoperative simulation and perioperative prevention of infection.
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http://dx.doi.org/10.1186/s40792-020-01064-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652963PMC
November 2020

Relationship among Left Ventricular Hypertrophy, Cardiovascular Events, and Preferred Blood Pressure Measurement Timing in Hemodialysis Patients.

J Clin Med 2020 Oct 30;9(11). Epub 2020 Oct 30.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8412, Japan.

This study aimed to identify the ideal timing and setting for measuring blood pressure (BP) and determine whether the left ventricular mass index (LVMI) is an independent risk factor associated with increased cardiovascular events in hemodialysis (HD) patients. BP and LVMI were measured at baseline and at 6 and 12 months after HD initiation. BP was monitored and recorded at nine different time points, including before and after HD over a one-week period (HDBP). The mean BP measurement was calculated as the weekly averaged BP (WABP). LVMI was significantly correlated with home BP, in-office BP, HDBP, and WABP. Receiver operating characteristic analysis indicated that the cutoff LVMI value for cardiovascular events was 156 g/m. LVMI and diabetes mellitus were significant influencing factors for cardiovascular events (hazards ratio (95% confidence interval): diabetes mellitus, 2.84 (1.17,7.45); LVMI > 156 g/m, 2.86 (1.22,6.99)). Pre-HDBP, post-HDBP, and WABP were independently associated with higher LVMI in the follow-up periods. Hemoglobin and human atrial natriuretic peptide (hANP) levels were associated with LVMI beyond 12 months after HD initiation. Treatment of hypertension, overhydration based on hANP, and anemia may reduce the progression of LVMI and help identify HD patients at high risk for cardiovascular events.
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http://dx.doi.org/10.3390/jcm9113512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694059PMC
October 2020