Publications by authors named "Makoto Nakamura"

486 Publications

Protocol to test the efficacy and safety of frequent applications of skin electrical stimulation for Leber hereditary optic neuropathy: a single-arm, open-label, non-randomised prospective study.

BMJ Open 2021 Oct 19;11(10):e048814. Epub 2021 Oct 19.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Introduction: Leber hereditary optic neuropathy (LHON) is an acute or subacute inherited optic neuropathy caused by mitochondrial mutations. More than 90% of patients with LHON have one of three point mutations (ie, G3460A, G11778A and T14484C). We previously reported that a 12-week session of skin electrical stimulation (SES) with a 2-week interval significantly improved visual acuity and field tests 1 week after the last stimulation and without adverse effects in 10 cases of LHON carrying the mt DNA G11778A mutation. In the present study, we will examine the magnitude and persistence of the efficacy and presence or absence of adverse events using SES with a more frequent stimulation protocol.

Methods And Analysis: This study will be a single-arm, open-labelled, non-randomised clinical study that analyses 15 cases of LHON with G11778A mutation. All participants will take a portable SES device home and perform SES by themselves every other day for 12 weeks. The logarithm for the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) at 1 week after the last SES will be measured as the primary outcome. LogMAR BCVA will be measured at four and 8 weeks after the last SES treatment. The Humphrey visual field sensitivity test using size V stimulation and critical fusion frequency at 1, 4 and 8 weeks after the last SES session will be secondary outcome measurements. Slit-lamp examination, optical coherence tomography and specular microscopy will also be performed to verify the safety of SES.

Ethics And Dissemination: The protocol was approved by the Institutional Review Board at Kobe University, Japan (Approval No.C190030). This study is in progress and deserves Pre-result. All documents communicating with the ethics committee will be reposited by the researcher. Modifications to the protocol will be reviewed by the ethics committee and implemented after approval. Data monitoring will be performed by a researcher who is not involved in the study every 6 months after approval. The research summary results will be registered in the Japan Registry of Clinical Trials (jRCTs) and made available to participants in accordance with the terms described in the documents. In addition, the results of this study will be presented at domestic and international meetings and published in peer-reviewed journals within a year after data is fixed.

Trial Registration Number: jRCTs052200033.
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http://dx.doi.org/10.1136/bmjopen-2021-048814DOI Listing
October 2021

Case Report: High-Gamma Oscillations on an Ictal Electroencephalogram in a Newborn Patient With Hypoxic-Ischemic Encephalopathy.

Front Pediatr 2021 1;9:679771. Epub 2021 Oct 1.

Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.

Fast oscillations (FOs) >40 Hz in electroencephalograms (EEGs) are associated with ictogenesis and epileptogenesis in adults and children with epilepsy. However, only a few previous studies showed FOs in neonates. Reported frequencies of such neonatal FOs were in the low-gamma (<60 Hz) band and, therefore, they were not high compared to those in pediatric patients. We herein report a newborn patient with severe hypoxic-ischemic encephalopathy (HIE), who showed pathological FOs with a frequency in the high-gamma band. She was born at a gestational age of 39 weeks 4 days by emergency cesarean section because of non-reassuring fetal status. She had focal motor seizures involving unilateral upper and lower limbs lasting for tens of seconds on days 0, 1, 4, 5, 8, and 9 and subclinical seizures on days 4-11. Phenobarbital (PB) was intravenously administered on days 0, 2, 4, 5, and 6. We found FOs that were superimposed on the ictal delta activities using visual inspection and time-frequency analysis on 8-11 days of age. Among them, we detected high-gamma (71.4-100 Hz) oscillations that appeared to be temporally independent of low-gamma activities in the ictal EEG on 11 days of age. To the best of our knowledge, this is one of the earliest reports showing pathological FOs with a frequency of >60 Hz in the high-gamma band in human neonatal seizures, which were previously observed in animal studies. Further studies are needed to elucidate the pathophysiology of ictal FOs in neonatal seizures.
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http://dx.doi.org/10.3389/fped.2021.679771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518698PMC
October 2021

Preterm birth and Kawasaki disease: a nationwide Japanese population-based study.

Pediatr Res 2021 Oct 8. Epub 2021 Oct 8.

Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: Previous studies showed that preterm birth increased the risk for hospital admissions in infancy and childhood due to some acute diseases. However, the risk of preterm children developing Kawasaki disease remains unknown. In the present study, we investigate whether preterm birth increased the morbidity of Kawasaki disease.

Methods: We included 36,885 (34,880 term and 2005 preterm) children born in 2010 in Japan. We examined the association between preterm birth and hospitalization due to Kawasaki disease using a large nationwide survey in Japan.

Results: In log-linear regression models that were adjusted for children's characteristics (sex, singleton birth, and parity), parental characteristics (maternal age, maternal smoking, paternal smoking, maternal education, and paternal income), and residential area, preterm infants were more likely to be hospitalized due to Kawasaki disease (adjusted risk ratio: 1·55, 95% confidence interval: 1.01-2.39). We then examined whether breastfeeding status modified the potential adverse effects of preterm birth on health outcome. Preterm infants with partial breastfeeding or formula feeding had a significantly higher risk of hospitalization due to Kawasaki disease compared with term infants with exclusive breastfeeding.

Conclusions: Preterm infants were at a high risk for Kawasaki disease, and exclusive breastfeeding might prevent this disease among preterm infants.

Impact: Previous studies showed that preterm birth increased the risk for hospital admissions in infancy and childhood due to some acute diseases, however, the risk of preterm children developing Kawasaki disease remains unknown. This Japanese large population-based study showed that preterm infants were at a high risk for Kawasaki disease for the first time. Furthermore, this study suggested that exclusively breastfeeding might prevent Kawasaki disease among preterm infants.
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http://dx.doi.org/10.1038/s41390-021-01780-4DOI Listing
October 2021

Intraocular Endoscopy Resolved Tube Occlusion of an Ahmed Glaucoma Valve.

Case Rep Ophthalmol 2021 May-Aug;12(2):706-711. Epub 2021 Aug 24.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan.

We report a case in which intraocular endoscopy clarified the cause of Ahmed glaucoma valve (AGV) failure with a cloudy cornea. A 42-year-old patient with glaucoma underwent AGV implant surgery to treat secondary glaucoma due to chronic iridocyclitis in his left eye. After AGV, he developed bullous keratopathy (BK) in that eye. After Descemet stripping automated endothelial keratoplasty (DSAEK) was performed to treat BK, the intraocular pressure (IOP) increased and early failure of the DSAEK resulted again in a cloudy cornea. We could not precisely detect any cause of AGV failure with ordinary imaging instrumentation. An intraocular endoscope was used to determine that cause, and we found that the fibrous tissue occluded the tube of the AGV. The IOP decreased soon after the tissue was removed. We conclude that intraocular endoscopy was useful for diagnosing AGV failure with BK.
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http://dx.doi.org/10.1159/000518286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436709PMC
August 2021

Hemodynamic Characteristics After Fontan Procedure in Patients with Down's Syndrome.

Pediatr Cardiol 2021 Sep 8. Epub 2021 Sep 8.

Department of Pediatric Cardiology, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha Higashi-ku, Fukuoka, 813-0017, Japan.

Patients with Down's syndrome (DS) are generally regarded as not being good candidates for the Fontan procedure. However, detailed hemodynamic changes over time are not fully clarified. A retrospective chart review of all patients with DS who underwent the Fontan procedure and 5 times that number of Fontan patients without DS performed in Fukuoka Children's Hospital and Kyushu University Hospital. Seven Fontan patients with DS were identified, and 35 Fontan patients without DS were recruited. During the mean observational periods of 14.7 years and 15.0 years (DS and non-DS, respectively) after the Fontan procedure, only one DS patient died. Central venous pressure (CVP) and transpulmonary pressure gradient significantly increased, and arterial oxygen saturation significantly decreased over time in DS patients after the Fontan procedure compared with those without DS. CVP in DS patients after the Fontan procedure increased over time compared with non-DS patients. Better management including the efficacy of Pulmonary arterial hypertension-specific therapy should be clarified in further studies.
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http://dx.doi.org/10.1007/s00246-021-02727-6DOI Listing
September 2021

The Prevention Measures for COVID-19 and Changes in Kawasaki Disease Incidence.

J Epidemiol 2021 Sep 4. Epub 2021 Sep 4.

Department of Pediatrics, University of Yamanashi.

BackgroundKawasaki disease is suspected to be triggered by previous infection. The prevention measures for COVID-19 have reportedly reduced transmission of certain infectious diseases. Under these circumstances, the prevention measures for COVID-19 may reduce the incidence of Kawasaki disease.MethodWe conducted a retrospective study using registration datasets of patients with Kawasaki disease who were diagnosed in all 11 in-patient pediatric facilities in Yamanashi prefecture. The eligible cases were 595 cases that were diagnosed before the COVID-19 pandemic (from January 2015 to February 2020) and 38 cases that were diagnosed during the COVID-19 pandemic (from March to November 2020). Incidence of several infectious disease were evaluated using data from the Infectious Disease Weekly Report conducted by the National Institute of Infectious Diseases.ResultsEpidemics of various infectious diseases generally remained at low levels during the first nine months (March to November 2020) of the COVID-19 pandemic. Moreover, the incidence of COVID-19 was 50-80 times lower than the incidence in European countries and the United States. The total number of 38 cases with Kawasaki disease for the nine months during the COVID-19 pandemic was 46.3% (-3.5 standard deviation (SD)) of the average (82.0 (SD, 12.7)) for the corresponding nine months of the previous five years. None of the 38 cases was determined to be triggered by COVID-19 based on their medical histories and negative results of severe acute respiratory syndrome coronavirus 2 testing at admission.ConclusionThese observations provide a new epidemiological evidence for the notion that Kawasaki disease is triggered by major infectious diseases in children.
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http://dx.doi.org/10.2188/jea.JE20210132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502831PMC
September 2021

Unusual Gastrointestinal Hemorrhaging Mimicking a Rupture of Solitary Gastric Varices Due to a Gastric Gastrointestinal Stromal Tumor with Exogenous Growth.

Intern Med 2021 Aug 24. Epub 2021 Aug 24.

Department of Gastroenterology and Hepatology, Gamagori municipal hospital, Japan.

Gastric gastrointestinal stromal tumors can lead to upper gastrointestinal hemorrhaging, which is usually caused by dimpling or ulceration on the tumor surface. While rare, pedunculated gastric gastrointestinal stromal tumors outside the stomach can present as a huge mass with delayed complaints. We herein report an unusual hemorrhaging mimicking a rupture of solitary gastric varices due to a pedunculated gastric gastrointestinal stromal tumor. In this case, contrast-enhanced computed tomography was essential for tumor detection. An endoscopic investigation revealed dilated, aberrant veins and arteries in the submucosa of this tumor, recognized as solitary gastric varices.
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http://dx.doi.org/10.2169/internalmedicine.8003-21DOI Listing
August 2021

Multiple Intravitreal Liposomal Amphotericin B for a Case of Endophthalmitis.

Case Rep Ophthalmol 2021 May-Aug;12(2):485-491. Epub 2021 Jun 11.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

We report a case of endophthalmitis which was effectively treated by intravitreal liposomal amphotericin B (L-AMB) injection. A 72-year-old man was referred to our department for positive blood culture of . First ophthalmologic examination revealed a chorioretinal lesion in left eye, and the patient was diagnosed as possible candida chorioretinitis. Despite systemic antifungal therapy, his chorioretinal lesion increased in both eyes and complicated by vitritis. Intravitreal administration of L-AMB was introduced for probable candida endophthalmitis. Finally, improvement of vitritis and regression of chorioretinal lesions were obtained by total of 9 times intravitreal injection. Our case suggests the safety and efficacy of intravitreal L-AMB injection for endophthalmitis.
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http://dx.doi.org/10.1159/000511594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255754PMC
June 2021

Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression.

Sci Rep 2021 06 23;11(1):13125. Epub 2021 Jun 23.

Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4Foxp3 regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.
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http://dx.doi.org/10.1038/s41598-021-92526-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222309PMC
June 2021

The dual-specificity protein kinase Clk3 is essential for Xenopus neural development.

Biochem Biophys Res Commun 2021 Aug 16;567:99-105. Epub 2021 Jun 16.

Amphibian Research Center, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan; Amphibian Research Center, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. Electronic address:

During vertebrate development, the formation of the central nervous system (CNS) is initiated by neural induction and patterning of the embryonic ectoderm. We previously reported that Cdc2-like kinase 2 (Clk2) promotes neural development in Xenopus embryos by regulating morphogen signaling. However, the functions of other Clk family members and their roles in early embryonic development remain unknown. Here, we show that in addition to Clk2, Clk1 and Clk3 play a role in the formation of neural tissue in Xenopus. clk1 and clk3 are co-expressed in the developing neural tissue during early Xenopus embryogenesis. We found that overexpression of clk1 and clk3 increases the expression of neural marker genes in ectodermal explants. Furthermore, knockdown experiments showed that clk3 is required for the formation of neural tissues. These results suggest that Xenopus Clk3 plays an essential role in promoting neural development during early embryogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.005DOI Listing
August 2021

Intraoperative three-dimensional fluorescein angiography-guided pars plana vitrectomy for branch retinal vein occlusion.

Retin Cases Brief Rep 2020 Nov 25. Epub 2020 Nov 25.

1Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine. 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

Purpose: To show surgical results of the intraoperative three-dimensional fluorescein angiography (3D-FA)-guided pars plana vitrectomy (PPV) for branch retinal vein occlusion (BRVO) with vitreous hemorrhage (VH) and neovascularization elsewhere (NVE).

Methods: The NGENUITY 3D ® visualization system was used for the digital assisted vitrectomy (DAV). 3D-FA-guided PPV was performed in three patients with BRVO with VH and NVE.

Patients: 3 eyes with BRVO with VH and NVE RESULTS:: In all eyes, the scatter retinal photocoagulations for nonperfusion area (NPA), depicted as hypofluorescein, and the segmentation and delamination of perivascular fibrovascular proliferative membrane, depicted as hyperfluorescein, could be safely performed on the same screen while implementing intraoperative 3D-FA.

Conclusions: 3D-FA-guided PPV, a novel approach that fully utilizes the advantages of DAV, can be one of useful techniques for the treatment of BRVO with VH and NVE.
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http://dx.doi.org/10.1097/ICB.0000000000001091DOI Listing
November 2020

Factors associated with the development of ocular candidiasis and ocular prognosis with echinocandin therapy for candidemia.

J Ophthalmic Inflamm Infect 2021 Jun 14;11(1):17. Epub 2021 Jun 14.

Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Purpose: To evaluate the factors associated with the development of ocular candidiasis (OC) and ocular prognosis with echinocandin therapy for candidemia.

Methods: The medical records of 56 consecutive patients with a positive blood culture for Candida species between November 2016 and October 2019 were retrospectively reviewed. Information on patient characteristics, isolated Candida species, treatment details for candidemia, and ocular findings were extracted to identify factors associated with OC development.

Results: The leading pathogen of candidemia was Candida albicans (C.albicans) (41.1%). Of 56 patients, 18 (32.1%) were diagnosed with chorioretinitis, categorized as either probable (8 patients) or possible OC (10 patients). There was no case of endophthalmitis with vitritis. The incidence of probable OC was not significantly different between the groups treated with echinocandins and other antifungal drugs (15.2% vs. 11.1%, p = 1.00). In all probable OC cases, systemic antifungal therapy was switched from echinocandins to azoles, and no case progressed to endophthalmitis. A multivariate logistic analysis revealed that female sex (adjusted odds ratio [aOR], 8.93; 95% confidence interval [CI], 1.09-72.9) and C. albicans (aOR, 23.6; 95% CI, 1.8-281) were independent factors associated with the development of probable OC.

Conclusion: One-seventh of patients with candidemia developed probable OC. Given the evidence of female and C. albicans as the factors associated with OC development, careful ophthalmologic management is required with these factors, especially in candidemia. Although echinocandins had no correlation with OC development and did not lead to the deterioration of ocular prognosis, further investigation is required.
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http://dx.doi.org/10.1186/s12348-021-00248-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200333PMC
June 2021

Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells.

Immunohorizons 2021 06 10;5(6):424-437. Epub 2021 Jun 10.

Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Graft-versus-host disease (GVHD) remains to be a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). IL-2-inducible T cell kinase (ITK), a TEC cytoplasmic tyrosine kinase, has an essential role in T cell development and receptor signaling. The ITK/Bruton tyrosine kinase inhibitor ibrutinib has been shown to improve chronic GVHD symptoms; however, the effect of ITK selective inhibition on acute GVHD remains unclear. In this study, we evaluated the pharmacological effects of an ITK selective inhibitor (ITKsi) on acute GVHD using murine bone marrow transplantation models. First, we found that CD4 T cell differentiation toward Th1, Th2, or Th17 was inhibited following ITKsi treatment in a dose-dependent manner while maintaining regulatory T cells in the presence of alloantigens both in vitro and in vivo. ITKsi preferentially inhibited inflammatory cytokine production and in vivo proliferation of alloreactive T cells. We then demonstrated that short-term exposure of donor graft cells to ITKsi significantly delayed the onset of GVHD-associated mortality without compromising the donor cell engraftment and the graft-versus-tumor effect, indicating the potential of ITK selective inhibition in the setting of clinical allogeneic HSCT. These findings suggest that ITK is a potential therapeutic target against GVHD, and the pharmacological ITK inhibitor may serve as a novel strategy for immune regulation after HSCT.
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http://dx.doi.org/10.4049/immunohorizons.2100042DOI Listing
June 2021

TGF-β1 signaling is essential for tissue regeneration in the Xenopus tadpole tail.

Biochem Biophys Res Commun 2021 Aug 5;565:91-96. Epub 2021 Jun 5.

Amphibian Research Center, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. Electronic address:

Amphibians such as Xenopus tropicalis exhibit a remarkable capacity for tissue regeneration after traumatic injury. Although transforming growth factor-β (TGF-β) receptor signaling is known to be essential for tissue regeneration in fish and amphibians, the role of TGF-β ligands in this process is not well understood. Here, we show that inhibition of TGF-β1 function prevents tail regeneration in Xenopus tropicalis tadpoles. We found that expression of tgfb1 is present before tail amputation and is sustained throughout the regeneration process. CRISPR-mediated knock-out (KO) of tgfb1 retards tail regeneration; the phenotype of tgfb1 KO tadpoles can be rescued by injection of tgfb1 mRNA. Cell proliferation, a critical event for the success of tissue regeneration, is downregulated in tgfb1 KO tadpoles. In addition, tgfb1 KO reduces the expression of phosphorylated Smad2/3 (pSmad2/3) which is important for TGF-β signal-mediated cell proliferation. Collectively, our results show that TGF-β1 regulates cell proliferation through the activation of Smad2/3. We therefore propose that TGF-β1 plays a critical role in TGF-β receptor-dependent tadpole tail regeneration in Xenopus.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255271PMC
August 2021

Total body irradiation-based haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide after administration of inotuzumab ozogamicin: A case report.

Leuk Res Rep 2021 22;15:100241. Epub 2021 Apr 22.

Department of Hematology and Oncology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama Prefecture 700-8558, Japan.

Owing to the poor prognosis of relapsed or refractory acute lymphoblastic leukemia (ALL), hematopoietic stem cell transplantation (HSCT) followed by effective salvage therapy is required. Inotuzumab ozogamicin (INO) was developed for ALL refractory to standard chemotherapy. However, previous reports suggest that sinusoidal obstruction syndrome (SOS) risk increases in patients with HSCT receiving INO, especially with dual alkylating agents. We report a case of relapsed Philadelphia chromosome-negative B-ALL where the patient underwent haploidentical HSCT using fludarabine/total body irradiation conditioning and posttransplant cyclophosphamide. Successful engraftment was achieved without SOS development.
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http://dx.doi.org/10.1016/j.lrr.2021.100241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111671PMC
April 2021

Increased expression of Protein S in eyes with diabetic retinopathy and diabetic macular edema.

Sci Rep 2021 05 17;11(1):10449. Epub 2021 May 17.

Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Protein S (PS) is a multifunctional glycoprotein that ameliorates the detrimental effects of diabetes mellitus (DM). The aim of this study was to evaluate the distribution of PS in diabetic retinopathy (DR) and diabetic macular edema (DME). This was a study of 50 eyes with DM (37 with DME, 6 with proliferative DR, and 7 with no DR) and 19 eyes without DM. The level of PS was measured by enzyme immunoassay and was compared between eyes with or without DM, with or without DME, and with severe DME (≥ 350 μm) or mild DME (< 350 μm). We also performed immunohistopathologic evaluations of post-mortem eyes and the cystoid lesions excised during surgery. The aqueous free PS was significantly higher with DM (7.9 ± 1.2 ng/ml, P < 0.01) than without DM (6.1 ± 0.7). The aqueous free PS was significantly elevated with DME (8.2 ± 1.2, P < 0.05) compared to proliferative DR (7.0 ± 1.0) and no DR (7.0 ± 0.7). Eyes with severe DME had significantly higher aqueous free PS than mild DME (8.5 ± 1.3 vs. 7.7 ± 1.0, P < 0.05). Immunohistochemistry showed PS in the outer plexiform layer of the retina and cystoid lesion. The higher expression of PS with DR and DME suggests that PS is involved in their pathogenesis.
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http://dx.doi.org/10.1038/s41598-021-89870-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129118PMC
May 2021

The Impact of the Pulmonary Artery Index and Aortopulmonary Collateral Artery Coil Embolization on Intractable Pleural Effusions After a Fontan Surgery.

Int Heart J 2021 May 15;62(3):559-565. Epub 2021 May 15.

Department of Pediatric Cardiovascular Surgery, Fukuoka Children's Hospital.

An intractable pleural effusion is a common comorbidity of a Fontan operation, occasionally leading to undesirable outcomes. The preventive effect of aortopulmonary collateral (APC) coil embolization against a pleural effusion before a Fontan operation is still controversial.This is a retrospective single-center study; among 227 Fontan cases, 57 cases with complete MRI data were analyzed at first. Factors associated with the duration of pleural drainage (median: 6 (2-41) days) and that of postoperative hospital stay (median: 25 (14-91) days) were analyzed using a multiple regression analysis. The pulmonary artery index (PAI; Nakata index) was associated with both the pleural drainage duration (P < 0.05, r = 0.17) and postoperative hospital stay (P < 0.05, r = 0.10).Thereafter, all the 227 patients were classified into the following three groups: Group A (12 patients in whom the embolization was performed within 30 days before the Fontan surgery), Group B (131 patients in whom the embolization was performed more than 30 days before the Fontan surgery), and Group C (84 patients in whom the embolization was not performed). Patients in Group A were found to be associated with the shortest length of both periods (P < 0.05).Lower PAI values were related to a prolonged pleural drainage duration and postoperative hospital stay. APC coil embolizations may reduce the risk if they are performed shortly (less than 30 days) before the operation.
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http://dx.doi.org/10.1536/ihj.20-498DOI Listing
May 2021

Donor Treg expansion by liposomal α-galactosylceramide modulates Tfh cells and prevents sclerodermatous chronic graft-versus-host disease.

Immun Inflamm Dis 2021 09 4;9(3):721-733. Epub 2021 May 4.

Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background And Aim: Chronic graft-versus-host disease (cGVHD) is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT). α-Galactosylceramide (α-GC) is a synthetic glycolipid that is recognized by the invariant T-cell receptor of invariant natural killer T (iNKT) cells in a CD1d-restricted manner. Stimulation of iNKT cells by α-GC leads to the production of not only immune-stimulatory cytokines but also immune-regulatory cytokines followed by regulatory T-cell (Treg) expansion in vivo.

Methods: We investigated the effect of iNKT stimulation by liposomal α-GC just after transplant on the subsequent immune reconstitution and the development of sclerodermatous cGVHD.

Results: Our study showed that multiple administrations of liposomal α-GC modulated both host- and donor-derived iNKT cell homeostasis and induced an early expansion of donor Tregs. We also demonstrated that the immune modulation of the acute phase was followed by the decreased levels of CXCL13 in plasma and follicular helper T cells in lymph nodes, which inhibited germinal center formation, resulting in the efficient prevention of sclerodermatous cGVHD.

Conclusions: These data demonstrated an important coordination of T- and B-cell immunity in the pathogenesis of cGVHD and may provide a novel clinical strategy for the induction of immune tolerance after allogeneic HSCT.
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http://dx.doi.org/10.1002/iid3.425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342231PMC
September 2021

Effectiveness of supplemental oral calcium drink in preventing citrate-related adverse effects in peripheral blood progenitor cell collection.

Transfus Apher Sci 2021 Aug 24;60(4):103147. Epub 2021 Apr 24.

Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.

Peripheral blood progenitor cells (PBPCs) are a predominant graft source in allogeneic hematopoietic cell transplantation. Citrate-induced hypocalcemia remains the most frequent side effect of PBPC apheresis. Although the method for preventing severe adverse events is established, more efficient prophylaxis is required so that volunteer donors can donate PBPCs without pain and anxiety. We studied 80 healthy donors who underwent PBPC harvest between February 2014 and June 2020. Of these, 23 donors who underwent apheresis between February 2014 and December 2015 received only the standard prophylaxis of intravenous calcium gluconate. Oral calcium drinks were provided to 57 donors who underwent apheresis from January 2016 to June 2020 to supplement intravenous calcium gluconate prophylaxis. The ionized calcium (ICa) levels at multiple time intervals and the hypocalcemic symptoms were evaluated. Oral supplementation with a calcium drink maintained significantly higher ICa levels. Analysis using the inverse probability weighted regression adjustment method suggested that calcium drinks reduced the frequency of citrate-related reactions by 39.2 %. Administering a prophylactic oral calcium drink before apheresis with intravenous administration of calcium gluconate is promising to further reduce citrate-induced hypocalcemia in volunteer donors.
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http://dx.doi.org/10.1016/j.transci.2021.103147DOI Listing
August 2021

Autologous Scleral Pocket Technique for Ahmed Glaucoma Valve Implantation with Pars Plana Tube Insertion for Neovascular Glaucoma.

J Clin Med 2021 Apr 10;10(8). Epub 2021 Apr 10.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

Specific postoperative complications, such as tube exposure and conjunctival erosion, have occurred despite the favorable surgical outcomes of tube shunt surgeries for refractory glaucoma. The new autologous scleral pocket technique is performed by inserting the tube into the vitreous cavity without using a donor scleral patch. The purpose of this study was to evaluate the surgical results of Ahmed glaucoma valve (AGV) implantation using this technique for neovascular glaucoma (NVG), which is one of the representative refractory types of glaucoma. This observational retrospective case series included 15 consecutive eyes of 15 patients with NVG who had undergone AGV implantation at Kobe University between January 2018 and December 2019. The mean preoperative intraocular pressure (IOP) was 37.2 ± 13.8 mmHg and the glaucoma drug score was 4.2 ± 2.2. The mean IOP and glaucoma drug score at 1 year postoperatively decreased to 15.0 ± 4.6 mmHg and 1.3 ± 2.0, respectively ( < 0.001). No significant change in the corneal endothelial cell density following surgery was observed ( = 0.09); however, one patient required an additional trabeculectomy at 7 months postoperatively. No cases of tube exposure or conjunctival erosion were observed at 1 year postoperatively. These results indicated the effectiveness and safety of this technique in patients with NVG.
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http://dx.doi.org/10.3390/jcm10081606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068818PMC
April 2021

Cystotomy with or without fibrinogen clot removal for refractory cystoid macular edema secondary to branch retinal vein occlusion.

Sci Rep 2021 04 19;11(1):8460. Epub 2021 Apr 19.

Division of Ophthalmology, Department of Surgery-Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

To demonstrate the long-term effect of cystotomy with or without fibrinogen clot removal for treatment-resistant cystoid macular edema (CME) secondary to branch retinal vein occlusion (BRVO). Retrospective clinical study. We retrospectively analyzed medical records of 22 eyes of 22 patients with treatment-resistant CME secondary to BRVO with 12 months observation after cystotomy with or without fibrinogen clot removal. Patients included 11 women and 11 men. The mean ± SD age was 72.7 ± 10.2 years. LogMAR-converted best corrected visual acuity (BCVA) was statistically better at 12 months after surgery (0.30 ± 0.30) than preoperative BCVA (0.39 ± 0.27) (p = 0.01). The central sensitivity of microperimetry (dB) was maintained during follow-up (preoperative sensitivity: 25.4 ± 4.1, postoperative sensitivity at 12 months after the surgery: 25.9 ± 4.2, p = 0.69). Twelve months after surgery, there was a significant improvement in the central retinal thickness (CRT) on optical coherence tomography (OCT) (303.7 ± 80.1) (μm) compared with the preoperative CRT (524.2 ± 114.8) (p < 0.01). In 12 months, CME recurred in 3 of 22 eyes. The preoperative reflectivity in cystoid cavity on OCT was significantly higher in patients with fibrinogen clot removal (n = 5) than in patients without fibrinogen clot removal (n = 17) (p < 0.01). For treatment-resistant CME secondary to BRVO, Cystotomy with or without fibrinogen clot removal may be one of the treatment options.
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http://dx.doi.org/10.1038/s41598-021-88149-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055692PMC
April 2021

The Influence of Music on Neurosurgical Cases: A Neglected Knowledge.

J Neurol Surg A Cent Eur Neurosurg 2021 Nov 12;82(6):544-551. Epub 2021 Apr 12.

Division of Neurosurgery, Department of Clinical Medicine, University Witten/Herdecke, Witten, Nordrhein-Westfalen, Germany.

Background:  The human brain can respond to and participate in music. Learning to play a musical instrument requires complex multimodal skills involving the simultaneous perception of several sensory modalities. In case of brain damage, the musician and nonmusician brains may have different capacities for reorganization and neural remapping. We aimed to investigate the effect of music on patients who had a brain tumor and/or underwent a neurosurgical procedure, comparing the recovery of those who had a musical background with those who did not.

Methods:  A literature review was performed to search for any evidence on this issue. We divided the cases into two groups: as group I consisted of the nonmusician patients, while group II consisted of musicians with a neurosurgical disease. Studies were rated from 0 (no effect) to 4 (high effect).

Results:  We found seven published studies as well as case reports. It was observed that the outcomes and quality of life of the musician group were better than those of the control groups or nonmusician patients in all of the investigated studies, but no statistical difference between musicians and nonmusicians was found.

Conclusion:  Music-related structural changes in the brain may occur in musicians. However with limited number of cases, it cannot be assorted the improved recovery in musicians after neurosurgical disease or procedures by his or her enhanced plasticity. There are limited number of cases, for that reason, it cannot be assorted the improved recovery in musicians after neurosurgical disease or procedures by his or her enhanced plasticity. Professional musicians, who are making a living through their musical abilities, may also have a strong motivation to undergo stressful and enduring rehabilitation. An early restart of the musical activity in musicians with neurosurgical disease may lead to better outcomes, better quality of life, and better psychological parameters, in a shorter time than in nonmusicians.
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http://dx.doi.org/10.1055/s-0040-1721017DOI Listing
November 2021

[Acquired hypofibrinogenemia in patients with leukemia during steroid therapy].

Rinsho Ketsueki 2021 ;62(3):193-195

Department of Hematology, Kochi Medical School, Kochi University.

Acquired hypofibrinogenemia is observed in patients with severe liver disease, disseminated intravascular coagulation, and high-volume perioperative fluid replacement. In lymphoblastic leukemia, hypofibrinogenemia is most frequently caused by the administration of L-asparaginase. Here we report the cases of two patients with acquired hypofibrinogenemia that occurred during steroid-containing chemotherapy treatment against lymphoblastic blast crisis of chronic myeloid leukemia in the first case and acute lymphoblastic leukemia in the second case. Administration of steroids repeatedly and promptly caused hypofibrinogenemia, irrespective of the products (prednisolone, dexamethasone, or methylprednisolone) or routes (oral or intravenous) that were used. Monitoring of the fibrinogen levels, especially during the first course of steroid therapy, would be useful for early diagnosis.
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http://dx.doi.org/10.11406/rinketsu.62.193DOI Listing
April 2021

Changes in Gene Expression Profiling and Phenotype in Aged Multidrug Resistance Protein 4-Deficient Mouse Retinas.

Antioxidants (Basel) 2021 Mar 15;10(3). Epub 2021 Mar 15.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

Multidrug resistance protein 4 (MRP4) is an energy-dependent membrane transporter responsible for cellular efflux of a broad range of xenobiotics and physiological substrates. In this trial, we aimed to investigate the coeffects of aging and MRP4 deficiency using gene expression microarray and morphological and electrophysiological analyses of mouse retinas. -knockout (null) mice and wild-type (WT) mice were reared in the same conditions to 8-12 weeks (young) or 45-55 weeks (aged). Microarray analysis identified 186 differently expressed genes from the retinas of aged -null mice as compared to aged WT mice, and subsequent gene ontology and KEGG pathway analyses showed that differently expressed genes were related to lens, eye development, vision and transcellular barrier functions that are involved in metabolic pathways or viral infection pathways. No significant change in thickness was observed for each retinal layer among young/aged WT mice and young/aged -null mice. Moreover, immunohistochemical analyses of retinal cell type did not exhibit an overt change in the cellular morphology or distribution among the four age/genotype groups, and the electroretinogram responses showed no significant differences in the amplitude or the latency between aged WT mice and aged -null mice. Aging would be an insufficient stress to cause some damage to the retina in the presence of MRP4 deficiency.
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http://dx.doi.org/10.3390/antiox10030455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999859PMC
March 2021

Clinical Factors Associated with Low-Contrast Visual Acuity after Reduced-Fluence Photodynamic Therapy in Patients with Resolved Central Serous Chorioretinopathy and Good Baseline Visual Acuity.

Pharmaceuticals (Basel) 2021 Mar 28;14(4). Epub 2021 Mar 28.

Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

This retrospective study was conducted to investigate the clinical factors associated with low-contrast visual acuity after reduced-fluence photodynamic therapy (RFPDT) in patients with resolved central serous chorioretinopathy (CSC) and good baseline visual acuity. A total of 45 eyes of 45 patients with resolved CSC at post-RFPDT and best-corrected visual acuity of >1.0 (logarithm of the minimal angle of resolution [logMAR], 0) at baseline were examined. Visual acuities of both eyes were measured at four contrast levels (100%, 25%, 12%, and 6%) at post-RFPDT. The low-contrast visual acuity (6%, 12%, and 25%) was significantly lower than the 100% contrast visual acuity in the affected eyes. Visual acuities of affected eyes were significantly worse than those of fellow eyes at any contrast levels. The degree of changes in 6% and 100% contrast visual acuities was significantly greater in affected eyes than that in fellow eyes ( < 0.05). The 6% contrast visual acuities in affected eyes at post-RFPDT were significantly associated with the symptom duration ( < 0.05). Patients with a long duration of symptoms might have disturbed low-contrast visual acuities at post-RFPDT even if their baseline visual acuities were good.
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http://dx.doi.org/10.3390/ph14040303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066140PMC
March 2021

A case of panuveitis and retinal vasculitis associated with pembrolizumab therapy for metastatic lung cancer.

Am J Ophthalmol Case Rep 2021 Jun 12;22:101072. Epub 2021 Mar 12.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Purpose: To report a case of panuveitis and retinal vasculitis associated with pembrolizumab therapy for metastatic lung cancer.

Observations: A 71-year-old man, who was diagnosed with metastatic lung cancer (squamous cell carcinoma), presented with blurry vision 2 weeks after the initiation of pembrolizumab monotherapy. His best-corrected visual acuity (BCVA) was 20/20 OU, and slitlamp examination revealed fine keratic precipitates, anterior chamber cells (1+) and flare (1+) in both eyes. Dilated fundus examination showed no remarkable finding in the right eye and vitreous haze (2+), perivascular exudates, and vessel sheathing in the left eye. Fluorescence angiography demonstrated dye leakage from the optic disc and both retinal arteries and veins extending from the posterior to the peripheral retina in both eyes. The patient was diagnosed with panuveitis and retinal vasculitis as Grade 3 immune-related adverse event (irAE). Pembrolizumab was discontinued and oral prednisone 70mg/day was given for 1 week. The dose was reduced to 30mg/day for the next 3 weeks and was then stopped. One month after the treatment, intraocular inflammation became quiescent. With a good response to the treatment of irAE, pembrolizumab was restarted. Recurrence of ocular inflammation occurred over the next 1.5 years, but all of which were successfully treated with sub-Tenon's injection of triamcinolone acetonide (STTA). The patient maintained BCVA of 30/20 OU at the latest visit.

Conclusions And Importance: We showed a case of retinal vasculitis occurred as an irAE of pembrolizumab for metastatic lung cancer. Retinal vasculitis was well managed with transient pembrolizumab discontinuation and oral corticosteroid therapy, and pembrolizumab was restarted with the aid of STTA. As ocular irAEs might be controlled by local corticosteroid therapy, the decision to continue immune checkpoint inhibitor therapy should be made on a case-by-case basis.
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http://dx.doi.org/10.1016/j.ajoc.2021.101072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995477PMC
June 2021

Photodynamic therapy combined with anti-vascular endothelial growth factor therapy for pachychoroid neovasculopathy.

PLoS One 2021 23;16(3):e0248760. Epub 2021 Mar 23.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

This multicenter retrospective study was conducted to evaluate the 1-year treatment outcome of photodynamic therapy (PDT) combined with anti-vascular endothelial growth factor (VEGF) therapy for pachychoroid neovasculopathy (PNV). A total of 42 eyes of 42 patients with treatment-naïve PNV who were treated with PDT combined with intravitreal injections of an anti-VEGF agent (ranibizumab or aflibercept) for 1 year. All eyes showed exudative and/or hemorrhagic changes that affected the fovea at baseline. After the initial combination therapy, subfoveal choroidal thickness (SCT) and central retinal thickness (CRT) were significantly reduced and were maintained as such for 12 months (P < 0.01 in SCT and CRT). The best-corrected visual acuity (BCVA) (0.19 ± 0.30 at baseline) significantly improved at 3 months (0.15 ± 0.29, P < 0.05) and further improved at 12 months (0.10 ± 0.30, P < 0.01) when compared to that at baseline. After the initial combination therapy, 32 eyes (76.2%) required no additional treatments for 12 months. The mean number of additional PDT and intravitreal injections of anti-VEGF agents was 0.1 ± 0.3 and 0.9 ± 1.9, respectively. Of the 42 eyes included in this study, 22 eyes (52.4%) had polypoidal lesions at baseline. No significant differences in SCT, CRT, or BCVA were observed at any time points between eyes with and without polypoidal lesions. Of 20 eyes without polypoidal lesions, only 1 eye (5.0%) needed additional treatments. PNV, especially without polypoidal lesions, can be treated effectively with PDT combined with anti-VEGF therapy with few sessions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248760PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987186PMC
October 2021

Coil embolization and a left ventricular assistive device after arterial switch operation.

Ann Thorac Surg 2021 Mar 19. Epub 2021 Mar 19.

Department of Pediatric Cardiovascular Surgery, Okinawa Prefectural Nanbu Medical Center & Children's Medical Center, 118-1, Arakawa, Haebaru-cho, Okinawa 901-1193, Japan.

Aortopulmonary collateral arteries are frequently found in patients with transposition of great arteries after catheterization. Although most of them are asymptomatic, it may cause heart failure or pulmonary hemorrhage after an arterial switch operation. Here, we report a case of symptomatic aortopulmonary collateral arteries following arterial switch, which necessitated support with a centrifugal pump and left ventricular assistive device owing to severe mitral regurgitation and left atrial hypertension and emergent coil embolization. Hemodynamics dramatically improved following embolization. Postoperative period was uneventful and the infant was released from the hospital on the 14th day.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.026DOI Listing
March 2021

Three-year outcome of sulcus fixation of Baerveldt glaucoma implant surgery.

Acta Ophthalmol 2021 Mar 15. Epub 2021 Mar 15.

Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.

Purpose: The purpose of this study was to evaluate the 3-year surgical outcome of the sulcus fixation of Baerveldt glaucoma implant (BGI), focusing on corneal damage.

Methods: This prospective observational study included 37 patients who underwent a median of two previous glaucoma surgeries and sulcus fixation of BGI for the first time. Each patient's intraocular pressure (IOP), glaucoma drug score, corneal endothelial cell density (ECD), and logMAR-converted best-corrected visual acuity (VA) were measured preoperatively and postoperatively until 36 months after surgery. Complete success was defined as reduced IOP (5-21 mmHg and >20% rate), without corneal damage (postoperative development of decompensation, unmeasurable ECD, or reduction in ECD of >20%), without loss of light perception, and without additional surgery requirement. Qualified success was defined by excluding the corneal criteria from complete success.

Results: A total of 51% (19/37) patients experienced complete treatment success, whereas 86% (32/37) had qualified success. The median IOP (glaucoma drug score) decreased from 26 mmHg (5) to 15 mmHg (2) at three years postoperatively. The median postoperative ECD (reduction rate) decreased from 1838 cells/cm preoperatively to 1587 cells/mm (14%) at one year, 1358 cells/mm (26%) at two years, and 1228 cells/mm (33%) at three years postoperatively. One month after surgery, the VA was significantly reduced from preoperative values but did not decline after that.

Conclusion: Sulcus fixation of BGI was effective for IOP reduction. However, ECD decreased over time.
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http://dx.doi.org/10.1111/aos.14839DOI Listing
March 2021
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