Publications by authors named "Yoshiyuki Takahashi"

319 Publications

Quantitative evaluation of single-photon emission computed tomography findings in lower extremity possible without computed tomography-based attenuation correction.

Nucl Med Commun 2021 Oct;42(10):1097-1103

Department of Radiological Technology, Hyogo College of Medicine College Hospital.

Objective: For performing accurate quantitative analysis of single-photon emission computed tomography (SPECT)/computed tomography (CT) images, CT-based attenuation correction (CTAC) is considered to be necessary. However, the effect on quantitative values for an examined area close to the body surface, such as in the lower extremity, has yet to be elucidated. We performed the present investigation to determine the possibility of quantitative evaluation using a SPECT standalone device without CT.

Methods: Validation was performed using clinical data of patients who underwent a lower extremity SPECT/CT examination, with grouping based on presence or absence of CTAC, scatter correction and resolution recovery. Using a reference group in which all types of correction were applied, standardized uptake values (SUVs), including maximum (SUVmax) and peak (SUVpeak), were examined in each group and compared.

Results: As compared to the reference group, the difference in quantitative values became smaller in the order of the applied scatter correction and resolution recovery, applied resolution recovery, applied scatter correction, and neither scatter correction or resolution recovery applied groups, with no significant difference between the reference group and that with neither scatter correction or resolution recovery applied. A similar tendency was seen for both SUVmax and SUVpeak.

Conclusions: In bone SPECT quantitative examinations of the lower extremity, quantitative evaluation without CTAC is possible without the use of scatter correction or resolution recovery. Thus, quantitative evaluation can be performed with use of a standalone SPECT device without CT.
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http://dx.doi.org/10.1097/MNM.0000000000001440DOI Listing
October 2021

Prognostic value of the revised International Prognostic Scoring System five-group cytogenetic abnormality classification for the outcome prediction of hematopoietic stem cell transplantation in pediatric myelodysplastic syndrome.

Bone Marrow Transplant 2021 Sep 10. Epub 2021 Sep 10.

Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Aichi, Japan.

Cytogenetic abnormalities are a major risk factor for relapse after hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). We aimed to evaluate the value of the five-group cytogenetic classification according to the revised International Prognostic Scoring System (R-IPSS) for predicting the outcome after HSCT in pediatric patients with MDS. We retrospectively analyzed the Japanese registration data of 242 pediatric patients with MDS. According to the R-IPSS classification, 112 (45.5%) patients had good, 55 (22.7%) had intermediate, 64 (26.4%) had poor, and 11 (4.6%) had very poor cytogenetics. The 5-year overall survival (5yOS) was 72%, 69%, 59%, and 30% in the good, intermediate, poor, and very poor cytogenetic subgroups (p = 0.026), respectively. The very good, good, and intermediate subgroups were grouped into a "standard" subgroup and reclassified into three subgroups (standard, poor, and very poor). Patients with very poor risk had worse 5yOS (hazard ratio 2.17, 95% confidence interval (CI) 1.02-4.61; p = 0.04) and a much higher 5yCIR (hazard ratio 2.52, 95% CI 1.05-6.04; p = 0.04) than those of patients in the standard group in the multivariate analysis, indicating that very poor risk cytogenetic characteristics independently predicted worse outcome after HSCT in pediatric patients with MDS.
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http://dx.doi.org/10.1038/s41409-021-01446-zDOI Listing
September 2021

Hematopoietic stem cell transplantation for infants with high-risk KMT2A gene rearranged acute lymphoblastic leukemia.

Blood Adv 2021 Sep 9. Epub 2021 Sep 9.

National Center for Child Health and Development, Tokyo, Japan.

The role of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2A gene rearrangement (KMT2A-r) is controversial in terms of both its efficacy and potential of acute and late toxicities. In the Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10, by introducing intensive chemotherapy, indication of HSCT was restricted to the patients with high-risk (HR) features only (KMT2A-r and either age <180 days or presence of central nervous system leukemia). Of the 56 HR patients, 49 achieved complete remission. Forty-three patients received HSCT in first remission including the 38 patients receiving protocol-specified HSCT with conditioning consisting of individualized targeted doses of busulfan, etoposide, and cyclophosphamide. Three-year event-free survival (EFS) of 56.8% (95%CI, 42.4%-68.8%) and overall survival of 80.2% (95%CI, 67.1%-88.5%) were accomplished. Univariable analysis showed Interfant-HR criteria and flowcytometric minimal residual disease (MRD) ≥0.01% both at end of induction and at end of consolidation (EOC) were significantly associated with poorer EFS. In the multivariable analysis, positive MRD at EOC was solely associated with poor EFS (P<0.001). Rapid pre-transplant MRD clearance and tailored HSCT strategy in the MLL-10 trial resulted in a favorable outcome for infants with HR KMT2A-r ALL. However, considering the high rate of potentially life-threatening toxicities and risk of late effects, its indication should be further restricted or even eliminated in the future by introducing more effective therapeutic modalities with minimal toxicities. This trial was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.
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http://dx.doi.org/10.1182/bloodadvances.2020004157DOI Listing
September 2021

Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency Patients: a Japanese Retrospective Study.

J Clin Immunol 2021 Aug 27. Epub 2021 Aug 27.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.

Purpose: Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan.

Methods: A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974-2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP).

Results: The 10-year overall survival (OS) of the patients who received HCT in 2006-2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006-2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01).

Conclusion: We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.
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http://dx.doi.org/10.1007/s10875-021-01112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390179PMC
August 2021

Single-Arm Non-Blinded Multicenter Clinical Trial on T-Cell-Replete Haploidentical Stem Cell Transplantation Using Low-Dose Antithymocyte Globulin for Relapsed and Refractory Pediatric Acute Leukemia.

Kurume Med J 2021 Aug 20. Epub 2021 Aug 20.

Department of Pediatric Oncology, Fukushima Medical University Hospital.

Although approximately 70% of pediatric hematological malignancies are curable, approximately 30% remain fatal. No standard treatment is available in patients showing relapse and those with refractory disease. Although different methods are adopted in different hospitals, its efficacy is extremely limited. In recent years, haploidentical stem cell transplantation, involving high-dose cyclophosphamide administration post-transplanta tion, has been used, mainly in adults; however, its application is limited to removal of alloreactive T cells. Multicenter single-arm clinical trials of T-cell replete haploidentical stem cell transplantation (TCR-haplo-SCT) will be conducted in children with relapsed and refractory acute leukemia. After myeloablative conditioning using total body irradiation or busulfan, intensive graft versus host disease prophylaxis is administered, consisting of low-dose rabbit anti-human thymocyte globulin, tacrolimus, methotrexate, and prednisolone. An external control group is set up for the study. The treatment period is around 3 months, and the follow-up period is 2 years from transplantation completion.The aim of this study is to verify the efficacy and safety of TCR-haplo-SCT and present it as a new immune cell therapy for improving survival rate in children with relapsed and refractory acute leukemia.
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http://dx.doi.org/10.2739/kurumemedj.MS663004DOI Listing
August 2021

Genetic Study of Fanconi Anemia in Infancy Revealed FANCI Mutations and Defective ALDH2 Variant: A Case Report.

J Pediatr Hematol Oncol 2021 Jul 23. Epub 2021 Jul 23.

Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Fanconi anemia (FA) is a rare genetic disorder that manifests as congenital abnormalities and bone marrow failure (BMF). Most patients with FA present with BMF within the first decade of life; however, neonate and early infancy BMF is rare. Recent studies have shown that a defective aldehyde dehydrogenase 2 (ALDH2) variant accelerates BMF development in patients with FA. Herein, we described an infant case of FA with compound heterozygous FANCI mutation and the defective ALDH2 variant. Our case developed BMF early probably because of ALDH2 deficiency, while the mild malformation might be because of the locus of FANCI mutation.
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http://dx.doi.org/10.1097/MPH.0000000000002254DOI Listing
July 2021

Usefulness of Quantitative Bone SPECT/CT for Evaluating Treatment Response in a Patient with Mandibular Osteomyelitis.

Case Rep Oncol 2021 May-Aug;14(2):820-825. Epub 2021 Jun 11.

Department of Radiology, Hyogo College of Medicine, Hyogo, Japan.

We report here a case of mandibular osteomyelitis in a 63-year-old female in which quantitative values determined using bone SPECT/CT were useful to evaluate response to antibiotic therapy, hyperbaric oxygen therapy, and sequestomy. After finishing therapy, the chief complaints were well relieved, and posttreatment Tc-99m HMDP bone SPECT/CT examination showed decreased uptake. The maximum standardized uptake value (SUV), peak SUV, mean SUV, metabolic bone volume, and total bone uptake of the untreated lesion were 6.26, 5.16, 3.97, and 11.86 mL and 42.21, respectively, which were decreased to 4.65, 3.90, 2.77, and 9.67 mL and 26.80, respectively, following hyperbaric oxygen therapy and antibiotic administration, and were moreover decreased to 4.28, 3.67, 2.75, and 6.24 mL and 17.19, respectively, after sequestomy. In comparison with pretreatment situation, those parameters were decreased by -25.7, -24.4, -30.2, -18.5, and -36.5%, respectively, following hyperbaric oxygen therapy and antibiotic administration, and moreover by -31.6, -28.9, -30.7, -47.4, and -59.3, respectively, after sequestomy, likely reflecting treatment response. Quantitative bone SPECT/CT may be useful to evaluate bone inflammatory activity and treatment response in a patient with mandibular osteomyelitis.
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http://dx.doi.org/10.1159/000516761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261260PMC
June 2021

Predictive factors of acute respiratory events during initial induction chemotherapy in patients with advanced neuroblastoma.

Cancer Rep (Hoboken) 2021 Jul 13:e1499. Epub 2021 Jul 13.

Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.

Background: Acute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma.

Aims: The present study aimed to identify the predictive factors of ARE, defined as severe hypoxia, during initial induction chemotherapy in patients with newly diagnosed advanced neuroblastoma.

Methods And Results: The medical records of 75 consecutive patients in whom stage III or IV neuroblastoma was newly diagnosed between January 2003 and December 2018 at two medical institutions were retrospectively reviewed. The outcome was ARE, which were assessed by measuring oxygen saturation between days 1 and 14 of initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) or decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO ≤55 mmHg). Possible predictive factors on admission were first screened for using univariate analyses with P = .05, then models of the predictive power of the outcome were evaluated by generating receiver operating characteristic (ROC) curves. Eleven patients (14.7%) had the outcome, including three (4.0%) who required respiratory support in the intensive care unit. The area under the curve of the ROC for the predictive factors screened by univariate analyses was 0.84 (95% confidence interval [CI]: 0.73-0.95) for lactate dehydrogenase (LDH) and 0.90 (95% CI: 0.82-0.98) for the disseminated intravascular coagulation (DIC) score.

Conclusion: The LDH value and DIC score on admission may be clinically useful predictors of ARE during initial induction chemotherapy in patients with advanced neuroblastoma.
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http://dx.doi.org/10.1002/cnr2.1499DOI Listing
July 2021

Death review of children receiving medical care at home.

Pediatr Res 2021 Jul 8. Epub 2021 Jul 8.

Committee on Home Medical Care of Children, Aichi Medical Association, Aichi, Japan.

Background: Children receiving home medical care need special attention to prevent unexpected death. The aim of this study was to clarify the factors contributing to death in children receiving home medical care from the child death review database.

Methods: Children receiving home medical care were enrolled from the child death review database from 2014 to 2016 in Aichi prefecture, Japan, with a population of one million children. Types of medical care and factors contributing to death were examined.

Results: Of the 631 children who died, 40 children (6%) were receiving home medical care (21: tracheostomy; 19: ventilator; 26: suctioning of naso-oral secretions; 19: oxygen inhalation; 32: tube feeding; 6: urethral catheterization; and 1: peritoneal dialysis). The death rate was 50 times that in the general population of children. Ten children had contributory factors that seemed to be preventable. In four children, the families could not replace the tracheostomy tubes during an accident. In three, oxygen saturation or ventilator alarms were not set appropriately. In two, an oxygen cylinder became empty. One child fell down from a seat in a car.

Conclusions: Improvement of devices and correct guidance to caregivers may reduce the death rate in children receiving home medical care.

Impact: Children receiving home medical care, such as tracheostomy care, mechanical ventilation, or tube feeding, need special attention to prevent unexpected death. In this population-based child death review, 6% of children received home medical care, and it was estimated that 1 of 100 children receiving home medical care died per year. One-quarter of the deaths could be preventable by caregiver education or development of devices.
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http://dx.doi.org/10.1038/s41390-021-01606-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265292PMC
July 2021

Clue of Diagnosis for Autoimmune Gastritis.

Digestion 2021 Jul 1:1-8. Epub 2021 Jul 1.

Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo, Japan.

Background: The diagnostic clues for autoimmune gastritis (AIG) can be classified into 2 categories: endoscopic findings and pathological diagnosis. We believe that research on the AIG detection rate by endoscopists could provide a better understanding of the diagnosis of AIG. This study aimed to clarify the ratio of the endoscopic and the pathological diagnoses of AIG.

Methods: We retrospectively reviewed consecutive patients who underwent esophagogastroduodenoscopy (EGD). During their first EGD, the gastric mucosa with C2 atrophy or more was biopsied for pathological evaluation based on the updated Sydney system. A gastric biopsy was also performed after Helicobacter pylori eradication, obtaining specimens from at least 2 sites, the greater curvature of the corpus and the antrum. We enrolled patients who were positive for the anti-parietal cell antibody and were diagnosed with AIG, histologically and/or endoscopically. The detection rates of AIG were compared between endoscopic diagnosis and pathological diagnosis.

Results: A total of 10,822 patients underwent EGD during the study period. Finally, 41 patients with AIG were enrolled, leading to an AIG prevalence of 0.38% in this study. As for the clue leading to AIG detection, 31.7% (13/41) were diagnosed through endoscopy (proximal-predominant atrophy), and 68.3% (28/41) were diagnosed pathologically. The AIG detection rate by endoscopists in the posteradication group was significantly lower than in the H. pylori-negative group (p < 0.05).

Conclusion: Endoscopists frequently overlooked AIG, especially in posteradication cases. Pathological assessment using the updated Sydney system after H. pylori eradication might be a promising strategy to detect AIG better.
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http://dx.doi.org/10.1159/000516624DOI Listing
July 2021

Acquisition of a rare NUP98-BPTF fusion gene associated with recurrence of acute myeloid leukemia.

Pediatr Blood Cancer 2021 Oct 29;68(10):e29201. Epub 2021 Jun 29.

Department of Hematology and Oncology, Shizuoka Children's Hospital, Aoi-ku, Shizuoka, Japan.

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http://dx.doi.org/10.1002/pbc.29201DOI Listing
October 2021

A patient with very early onset FH-deficient renal cell carcinoma diagnosed at age seven.

Fam Cancer 2021 Jun 22. Epub 2021 Jun 22.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by heterozygous germline variants in the fumarate hydratase (FH) gene and is associated with increased susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). HLRCC-associated RCC usually occurs in the middle age, with the median age being 40-44 years. This report describes a seven-year-old (84-month-old) male who developed a large right kidney tumor with multiple cystic lesions that contained enhanced solid components. There was no evidence of distant metastasis. The male patient underwent right nephrectomy and has been recovering well without metastasis or recurrence. Pathological examination revealed that tumor cells with relatively prominent nucleoli and surrounded by halos, were located in a limited area. Immunohistochemical staining was negative for FH. Whole-exome sequencing identified his germline variant in the FH gene and its loss of heterozygosity in the tumor. At nine years (114 months) of age, the male patient showed no recurrence of the tumor. This was the youngest-onset case of HLRCC-associated RCC to date. This report may affect the starting age for future RCC-surveillance programs for patients with HLRCC.
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http://dx.doi.org/10.1007/s10689-021-00268-8DOI Listing
June 2021

Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas.

NPJ Genom Med 2021 Jun 15;6(1):49. Epub 2021 Jun 15.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Pediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.
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http://dx.doi.org/10.1038/s41525-021-00210-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206218PMC
June 2021

Repetitive sleep starts: An important differential diagnosis of infantile spasms.

Epilepsy Behav 2021 08 30;121(Pt A):108075. Epub 2021 May 30.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Developmental Disability Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objective: Repetitive sleep starts (RSS) are clusters of nonepileptic, spasm-like movements occurring during sleep onset. However, their characteristics have yet to be defined. We conducted a clinicoelectroencephalographic study of children with RSS to clarify their detailed characteristics.

Methods: To differentiate starts from epileptic spasms, we recruited children with brief "crescendo-decrescendo" muscle contractions that simultaneously involved the limbs and trunk without electroencephalogram changes, and that fulfilled the following criteria: (1) repeated occurrence (five or more) and (2) manifestation during sleep stage N1-N2. A total of nine children met these criteria. Their clinical information and video-electroencephalogram data were analyzed retrospectively.

Results: The background conditions observed at onset of RSS were perinatal hypoxic-ischemic encephalopathy (n = 4), West syndrome of unknown etiology (n = 1), and traumatic brain injury (n = 1). The age at onset of RSS, the number of starts in a given RSS cluster, the interval between starts, and the duration of surface electromyogram activity were between 3 and 46 months, 5 and 547, <1 and 60 s, and 0.3 and 5.4 s, respectively. None of the median value of these parameters differed between children with and without corticospinal tract injury. During the median follow-up period of 33 months, RSS disappeared spontaneously in five.

Conclusion: This is the largest case series of RSS clarifying their clinicoelectroencephalographic characteristics reported to date. To avoid unnecessary antiepileptic therapies, clinicians should be aware of RSS and distinguish it from other disorders involving involuntary movements or seizures, especially epileptic spasms.
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http://dx.doi.org/10.1016/j.yebeh.2021.108075DOI Listing
August 2021

Sequential MRI Changes After Lateral Lumbar Interbody Fusion in Spondylolisthesis with Mild and Severe Lumbar Spinal Stenosis.

World Neurosurg 2021 Aug 29;152:e289-e296. Epub 2021 May 29.

Department of Orthopaedic Surgery, School of Medicine, International University of Health and Welfare, Otawara, Japan; Department of Orthopaedic Surgery, Spine and Spinal Cord Center, International University of Health and Welfare - Mita Hospital, Tokyo, Japan; Department of Orthopaedic Surgery, International University of Health and Welfare - Narita Hospital, Narita City, Japan. Electronic address:

Objective: We assessed the sequential magnetic resonance imaging changes of indirect neural decompression after minimally invasive lumbar lateral interbody fusion (LIF) combined with posterior percutaneous pedicle screw (PPS) fixation for degenerative spondylolisthesis (DS) according to the severity of preoperative lumbar spinal stenosis.

Methods: A total of 43 patients (mean age, 68.7 years; 16 men and 27 women) with DS who had undergone LIF and closed reduction with PPS fixation were enrolled. The intervertebral levels were divided into the moderate stenosis (MS) group (preoperative cross-sectional area [CSA] of the thecal sac >50 mm) and severe stenosis (SS) group (CSA ≤50 mm). The CSA, ligamentum flavum thickness, and diameter of the thecal sac at the affected level were measured on cross-sectional magnetic resonance images at baseline, immediately postoperatively, and 2 years postoperatively.

Results: For the 31 and 29 intervertebral levels in the MS and SS groups, the mean CSA at baseline, immediately postoperatively, and 2 years postoperatively was 76.9 mm and 35.8 mm, 104.3 mm and 81.4 mm, and 130.9 mm and 105.7 mm, respectively. The mean ligamentum flavum thicknesses at 2 years postoperatively became thinner than that immediately after surgery in both groups (P < 0.01). The mean diameter of the thecal sac at 2 years was longer than that immediately after surgery in both groups (MS group, P < 0.05; SS group, P < 0.01) The expansion ratio of the CSA at 2 years postoperatively was significantly greater in the SS group than that in the MS group (P < 0.01).

Conclusions: Sequential enlargement of the spinal canal was obtained by the thinning of the ligamentum flavum after LIF and PPS fixation in patients with DS with both mild and severe stenosis. The effect of indirect neural decompression was equivalent even in those with severe lumbar spinal stenosis.
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http://dx.doi.org/10.1016/j.wneu.2021.05.093DOI Listing
August 2021

Echocardiography Monitoring of Pulmonary Hypertension after Pediatric Hematopoietic Stem Cell Transplantation: Pediatric Pulmonary Arterial Hypertension and Pulmonary Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Sep 29;27(9):786.e1-786.e8. Epub 2021 May 29.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Pulmonary hypertension (PH) is associated with high morbidity in children undergoing hematopoietic stem cell transplantation (HSCT). However, owing to the lack of sequential echocardiography, the nature of the condition is not fully understood. This study was conducted to investigate whether routine echocardiography performed after HSCT could detect patients with PH at an earlier stage and elucidate the role of intervention using tadalafil. The study population comprised 93 consecutive children age <18 years who underwent a total of 109 HSCTs. All patients underwent routine transthoracic echocardiography during HSCT. Four children (4%) with a median age of 4 years (range, 0.7 to 6 years) were found to have PH, and their median tricuspid regurgitation peak velocity (TRV) was 4.1 m/s (range, 3.5 to 4.2 m/s). PH was diagnosed at a median of 52 days (range, 21 to 118 days) after HSCT. Three of them were diagnosed with neuroblastoma, and 1 was diagnosed with infantile leukemia. One patient developed PH after autologous HSCT, and 3 received killer immunoglobulin-like receptor ligand-mismatched cord blood. Busulfan was used for conditioning in all patients, and the proportion of patients receiving this medication was significantly higher in the PH group compared with the non-PH group (100% versus 30%; P = .011). Three of the 4 patients had a durable response (TRV ≤2.8 m/s) at a median of 46 days (range, 14 to 79 days) after starting treatment with tadalafil. No patient experienced exacerbation of PH, and treatment was completed at median of 96 days (range, 46 to 212 days). Our data suggest that routine echocardiography monitoring after HSCT should be considered in children receiving busulfan, although the precise follow-up timing needs further study. In addition, safe and effective administration of tadalafil must be ensured by close monitoring.
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http://dx.doi.org/10.1016/j.jtct.2021.05.017DOI Listing
September 2021

Relationship between plasma rabbit anti-thymocyte globulin concentration and immunosuppressive therapy response in patients with severe aplastic anemia.

Eur J Haematol 2021 Aug 3;107(2):255-264. Epub 2021 Jun 3.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objectives: Patients with acquired aplastic anemia (AA) without HLA-matched sibling donors or aged >40 years receive immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG). We investigated the relationship between plasma rabbit ATG (r-ATG) concentration and IST response.

Methods: From May 2012 to October 2017, 81 patients with severe AA who required initial IST were included. A 1:1 block randomization was employed for 2.5 and 3.5 mg/kg doses of r-ATG.

Results: No significant difference in response rates was observed between the 2.5 and 3.5 mg/kg groups (63% vs. 58%, P = .894). Median r-ATG concentrations on days 14 and 28 after IST were 15.2 (0.0-97.7) and 1.8 (0.0-74.9 µg/mL), respectively. According to r-ATG concentration, response rates were significantly higher in the group with higher r-ATG concentration than in those with lower r-ATG concentration (day 14, 88% vs. 52%; P = .006 and day 28, 79% vs. 46%; P = .005). In multivariate analysis, higher r-ATG concentrations at day 28 were independent predictors of favorable response to IST at 6 months (odds ratio, 0.29; 95% confidence interval, 0.09-0.93; P = .037).

Conclusions: The present data indicate that higher r-ATG concentration at day 28 resulted in improved IST response.
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http://dx.doi.org/10.1111/ejh.13644DOI Listing
August 2021

Hippocampal Atrophy in Pediatric Transplant Recipients with Human Herpesvirus 6B.

Microorganisms 2021 Apr 8;9(4). Epub 2021 Apr 8.

Department of Pediatrics, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.

The aim of this study was to determine whether human herpesvirus 6B (HHV-6B) infection can impair the hippocampus in pediatric hematopoietic stem cell transplant (HSCT) recipients. Study subjects were pediatric HSCT recipients monitored for HHV-6B infection who underwent brain MRI before and after transplantation. Volumetric analysis of the hippocampus was performed. Of the 107 patients that received HSCT at Nagoya University Hospital Between July 2008 and April 2014, 20 were eligible for volumetric analysis. Eight patients had HHV-6B infection, of whom two had encephalopathy at the time of HHV-6B infection. None of the 12 patients without HHV-6B infection had encephalopathy. The median ratio of the right hippocampal volume from before to after transplantation was 0.93 in patients with HHV-6B infection and 1.02 in without HHV-6B infection ( = 0.007). The median ratio of the left hippocampal volume ratio in patients with and without HHV-6B infection was 0.92 and 1.00, respectively ( = 0.003). Among the eight patients with HHV-6B infection, four had a marked reduction in hippocampal volume (volume ratio < 0.90). Only one of these patients had neurological symptoms at the time of HHV-6B infection. The reduction in the hippocampal volume ratio was higher in pediatric HSCT recipients with HHV-6B infection than those without viral infection. Neurological follow-up may be required for pediatric HSCT recipients with HHV-6B infection.
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http://dx.doi.org/10.3390/microorganisms9040776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068176PMC
April 2021

Effect of high-dose chemotherapy plus stem cell rescue on the survival of patients with neuroblastoma modified by MYCN gene gain/amplification and remission status: a nationwide registration study in Japan.

Bone Marrow Transplant 2021 Sep 28;56(9):2173-2182. Epub 2021 Apr 28.

Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [≤PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation's national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and ≤PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/ ≤ PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91-4.09; P < 0.001). The interaction between MYCN-GA and ≤PR was significant (p = 0.006). Hence, the patients with MYCN-GA with non-remission status at HDC-autoSCR had a significantly poorer prognosis than the other subgroups, suggesting that HDC-autoSCR may be effective in patients with CR/VGPR regardless of MYCN gene status and in patients with MYCN-NGA regardless of remission status.
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http://dx.doi.org/10.1038/s41409-021-01303-zDOI Listing
September 2021

Quantitative bone SPECT/CT applications for primary bone neoplasms.

Hell J Nucl Med 2021 Jan-Apr;24(1):36-44. Epub 2021 Apr 20.

Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 Japan.

Objective: To evaluate the clinical utility of quantitative values obtained with bone single photon emission computed tomography/computed tomography (SPECT/CT) for primary bone neoplasms.

Subjects And Methods: Bone SPECT/CT scans of 23 patients with 19 benign bone neoplasms (5 osteoid osteomas, 4 bone giant cell tumor, 4 osteofibrous dysplasia, 3 intraosseous ganglion, 2 aneurysmal bone cyst, 1 intraosseous hemangioma) and 5 malignant bone neoplasms (2 osteosarcoma, 1 periosteal osteosarcoma, 1 malignancy in bone giant cell tumor, 1 Ewing sarcoma) were retrospectively analyzed with maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), metabolic bone volume (MBV), and total bone uptake (TBU) of primary lesions.

Results: Mean SUVmax of 19 benign and 5 malignant primary bone neoplasms were 6.89±3.26 (range 3.9-15.13) and 10.31±3.19 (5.0-13.45) respectively, with statistically significant difference (P=0.048). Mean SUVpeak of those were 5.87±2.83 (range 3.5-13.63) and 9.18±3.05 (4.09-12.03) respectively, with statistically significant difference (P=0.032). Mean SUVmean of those were 4.43±2.11 (range 2.59-9.37) and 7.13±2.90 (3.3-10.42) respectively, with statistically significant difference (P=0.027). Mean MBV of those were 22.0±30.0 (range 2.47-110.61) and 27.8±39.94 (8.59-99.24) respectively, with no statistically significant difference (P=0.72). Mean TBU of those were 80.64±94.57 (range 10.50-373.57) and 166.60±203.97 (28.68-528.13) respectively, with no statistically significant difference (P=0.17).

Conclusion: Quantitative values obtained with bone SPECT/CT may serve as osteoblastic biomarkers for primary bone neoplasm.
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http://dx.doi.org/10.1967/s002449912304DOI Listing
April 2021

Temporal dynamics of the plasma microbiome in recipients at early post-liver transplantation: a retrospective study.

BMC Microbiol 2021 04 6;21(1):104. Epub 2021 Apr 6.

Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection but poses a risk for severe infectious diseases. Immune modulation and antimicrobials affect the plasma microbiome. Thus, determining the impact of immunosuppression on the microbiome may be important to understand immunocompetence, elucidate the source of infection, and predict the risk of infection in LT recipients. We characterized the plasma microbiome of LT recipients at early post-LT and assessed the association between the microbiome and clinical events.

Results: In this study, 51 patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected at the following time points: 1) within a week after LT; 2) 4 ± 1 weeks after LT; 3) 8 ± 1 weeks after LT; and 4) within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS) with the PATHDET pipeline. Relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period. Microbiome diversity was higher within a week after LT than that at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly increased and the plasma microbiome diversity was significantly lower in patients with acute cellular rejection (ACR) than non-ACR patients. Sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples, and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe clinical condition.

Conclusions: The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients.
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http://dx.doi.org/10.1186/s12866-021-02154-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025517PMC
April 2021

Usefulness of Quantitative Bone Single-Photon Emission Computed Tomography/Computed Tomography for Evaluating the Treatment Response of Bone Metastasis in a Lung Cancer Patient.

Case Rep Oncol 2021 Jan-Apr;14(1):391-396. Epub 2021 Mar 10.

Department of Radiology, Hyogo College of Medicine, Hyogo, Japan.

We report a case of bone metastasis arising from lung cancer, including quantitative values obtained with bone single-photon emission computed tomography/computed tomography (SPECT/CT), which were useful to evaluate the treatment response. The first bone SPECT/CT during pembrolizumab therapy for lung cancer recurrence showed intense Tc-HMDP uptake of the right femur head and mild uptake of the left ribs. After the palliative radiotherapy for the right femur head metastasis and chemotherapy, the second bone SPECT/CT showed a decrease in focal uptake of the right femur hip and increasing uptake of the left ribs. There was also new uptake appearance in the sternum, right rib, spine (Th2, Th9, Th12, L4, S1), and bilateral pelvic bone (left ilium, acetabular cartridge, femur, right ilium and ischium). The change of maximum standardized uptake values (SUVmax) for the right femur head and left third and eighth rib bony metastases were -72.6% (from 22.96 to 6.28), +407.7% (from 2.97 to 15.08), and +229.2% (from 2.60 to 8.56), respectively. The change of whole-lesion metabolic bone volume and total bone uptake was +235.4% (from 22.75 to 76.3 cm) and +219.1% (from 205.0 to 654.09), respectively. Two quantitative bone SPECT/CT images clearly showed the good response of femur head metastasis due to radiotherapy, and progression of other bone metastases regardless of chemotherapy.
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http://dx.doi.org/10.1159/000513907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983545PMC
March 2021

Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor.

J Allergy Clin Immunol 2021 Aug 13;148(2):639-644. Epub 2021 Mar 13.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Background: Type I interferonopathies are a recently established subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA-sensing pathways.

Objective: This study aimed to unveil the molecular pathogenesis of a patient with novel type I interferonopathy, for which no known genetic mutations have been identified.

Methods: We performed the whole-exome sequencing of a 1-month-old boy with novel type I interferonopathy. We also investigated proteasome activities using patient-derived B lymphoblastoid cell lines (LCLs) and normal LCLs transduced with the mutant gene.

Results: Whole-exome sequencing identified a de novo proteasome 20S subunit beta 9 (PSMB9) p.G156D mutation in the patient who developed fever, a chilblain-like skin rash, myositis, and severe pulmonary hypertension due to the hyperactivation of IFN-α. Patient-derived LCLs revealed reduced proteasome activities, and exogenous transduction of mutant PSMB9 p.G156D into normal LCLs significantly suppressed proteasome activities, and the endogenous PSMB9 protein was lost along with the reduction of other immunoproteasome subunits, PSMB8 and PSMB10 proteins. He responded to the administration of a Janus kinase inhibitor, tofacitinib, and he was successfully withdrawn from venoarterial extracorporeal membranous oxygenation. At age 7 months, he received an unrelated cord blood transplantation. At 2 years posttransplantation, he no longer required tofacitinib and experienced no disease recurrence.

Conclusions: We present the case of a patient with a novel type I interferonopathy caused by a de novo PSMB9 p.G156D mutation that suppressed the wild-type PSMB9 protein expression. Janus kinase inhibitor and stem cell transplantation could be curative therapies in patients with severe interferonopathies.
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http://dx.doi.org/10.1016/j.jaci.2021.03.010DOI Listing
August 2021

[Implementing nursing education based on the revision of rules for the designation of public health nurses, midwives, nursing schools, and training schools among nursing universities in Japan].

Nihon Yakurigaku Zasshi 2021 ;156(2):86-91

Ministry of Education, Culture, Sports, Science and Technology.

In 2020, the number of nursing universities in Japan increased to 274. One out of three universities has a nursing school, and the number of nursing universities continues to increase. The Ministry of Education, Culture, Sports, Science and Technology introduced the "Model Core Curriculum for Nursing Science Education in Japan" (MCCNSE) in 2017. The MCCNSE aims to include indispensable nursing competencies to the undergraduate course, enumerating the learning targets that will be useful for students. The MCCNSE includes seven aspects that aim to develop the qualities and abilities of a nurse for a lifetime. A consists of the basic qualities/abilities required by nursing professionals. B comprises social and nursing science. C consists of the basic knowledge necessary for understanding the objectives of nursing, including pharmacological science. D includes basic knowledge of the specialty underlying nursing practice. E comprises the basic knowledge necessary for nursing practice in various settings. F relates to clinical and regional training practice, and G includes research in nursing science. Nursing universities are required to comply with both the School Education Act and the Act on Public Health Nurses, Midwives, and Nurses. Nursing universities are expected to formulate a more complete and original curriculum based on the revision of Rules for the Designation of Public Health Nurses, Midwives, Nursing Schools, and Training Schools.
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http://dx.doi.org/10.1254/fpj.20086DOI Listing
March 2021

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Am J Med Genet A 2021 05 24;185(5):1468-1480. Epub 2021 Feb 24.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.
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http://dx.doi.org/10.1002/ajmg.a.62138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247954PMC
May 2021

Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in .

Pediatr Hematol Oncol 2021 Sep 24;38(6):515-527. Epub 2021 Feb 24.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is [NM_001022.4]. Nearly 180 variants have been reported, including three deep intronic variants outside the splicing consensus sequence (c.72-92A > G, c.356 + 18G > C, and c.411 + 6G > C). We also identified one case with a c.412-3C > G intronic variant. Without conducting transcript analysis, the pathogenicity of these variants is unknown. However, it is difficult to assess transcripts because of their fragility. In such cases, in functional splicing assays can be used to assess pathogenicity. Here, we report functional splicing analysis results of four deep intronic variants identified in our case and in previously reported cases. One splicing consensus variant (c.411 + 1G > A) was also examined as a positive control. Aberrant splicing with a 2-bp insertion between exons 5 and 6 was identified in the patient samples and minigene assay results also identified exon 6 skipping in our case. The exon 6 skipping transcript was confirmed by further evaluation using quantitative RT-PCR. Additionally, minigene assay analysis of three reported deep intronic variants revealed that none of them showed aberrant splicing and that these variants were not considered to be pathogenic. In conclusion, the minigene assay is a useful method for functional splicing analysis of inherited disease.
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http://dx.doi.org/10.1080/08880018.2021.1887984DOI Listing
September 2021

Source contributions to multiple toxic potentials of atmospheric organic aerosols.

Sci Total Environ 2021 Jun 4;773:145614. Epub 2021 Feb 4.

National Institute for Environmental Studies, Tsukuba, Japan.

Fine particulate matter (PM) in the atmosphere is of high priority for air quality management efforts to address adverse health effects in human. We believe that emission control policies, which are traditionally guided by source contributions to PM mass, should also consider source contributions to PM health effects or toxicity. In this study, we estimated source contributions to the toxic potentials of organic aerosols (OA) as measured by a series of chemical and in-vitro biological assays and chemical mass balance model. We selected secondary organic aerosols (SOA), vehicles, biomass open burning, and cooking as possible important OA sources. Fine particulate matter samples from these sources and parallel atmospheric samples from diverse locations and seasons in East Asia were collected for the study. The source and atmospheric samples were analyzed for chemical compositions and toxic potentials, i.e. oxidative potential, inflammatory potential, aryl hydrocarbon receptor (AhR) agonist activity, and DNA-damage, were measured. The toxic potentials per organic carbon (OC) differed greatly among source and ambient particulate samples. The source contributions to oxidative and inflammatory potentials were dominated by naphthalene-derived SOA (NapSOA), followed by open burning and vehicle exhaust. The AhR activity was dominated by open burning, followed by vehicle exhaust and NapSOA. The DNA damage was dominated by vehicle exhaust, followed by open burning. Cooking and biogenic SOA had smaller contributions to all the toxic potentials. Regarding atmospheric OA, urban and roadside samples showed stronger toxic potentials per OC. The toxic potentials of remote samples in summer were consistently very weak, suggesting that atmospheric aging over a long time decreased the toxicity. The toxic potentials of the samples from the forest and the experimentally generated biogenic SOA were low, suggesting that toxicity of biogenic primary and secondary particles is relatively low.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145614DOI Listing
June 2021
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