Publications by authors named "Takeshi Yoshida"

397 Publications

Identification of small compounds regulating the secretion of extracellular vesicles via a TIM4-affinity ELISA.

Sci Rep 2021 Jun 29;11(1):13471. Epub 2021 Jun 29.

WPI Nano Life Science Institute (NanoLSI), Kanazawa University, Kanazawa, Japan.

Extracellular vesicles (EVs) are secreted from most cells and play important roles in cell-cell communication by transporting proteins, lipids, and nucleic acids. As the involvement of EVs in diseases has become apparent, druggable regulators of EV secretion are required. However, the lack of a highly sensitive EV detection system has made the development of EV regulators difficult. We developed an ELISA system using a high-affinity phosphatidylserine-binder TIM4 to capture EVs and screened a 1567-compound library. Consequently, we identified one inhibitor and three activators of EV secretion in a variety of cells. The inhibitor, apoptosis activator 2, suppressed EV secretion via a different mechanism and had a broader cellular specificity than GW4869. Moreover, the three activators, namely cucurbitacin B, gossypol, and obatoclax, had broad cellular specificity, including HEK293T cells and human mesenchymal stem cells (hMSCs). In vitro bioactivity assays revealed that some regulators control EV secretion from glioblastoma and hMSCs, which induces angiogenesis and protects cardiomyocytes against apoptosis, respectively. In conclusion, we developed a high-throughput method to detect EVs with high sensitivity and versatility, and identified four compounds that can regulate the bioactivity of EVs.
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http://dx.doi.org/10.1038/s41598-021-92860-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242084PMC
June 2021

CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M-positive lung cancer after osimertinib.

Int J Clin Oncol 2021 Jun 11. Epub 2021 Jun 11.

Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC).

Methods: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance.

Results: We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib.

Conclusions: CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.
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http://dx.doi.org/10.1007/s10147-021-01947-3DOI Listing
June 2021

Efficacy of long-term adrenocorticotropic hormone therapy for West syndrome: A retrospective multicenter case series.

Epilepsia Open 2021 Jun 28;6(2):402-412. Epub 2021 May 28.

Epilepsy and Surgery Comprehensive Epilepsy Center Seirei Hamamatsu General Hospital Hamamatsu Japan.

Objectives: Long-term adrenocorticotropic therapy (LT-ACTH), which consisted of 2-4 weeks of daily injections of adrenocorticotropic hormone (ACTH) and subsequent months of weekly injections, was tried for relapsed West syndrome (WS) or other intractable epilepsies in small case reports. Our aim was to explore the efficacy of LT-ACTH for preventing WS relapse, as well as the prevalence of its adverse events.

Methods: This is a retrospective, nationwide, multicenter case series of patients with WS who underwent LT-ACTH. Clinical information of the patients and protocol of LT-ACTH were collected from participating institutes in this study. We defined clinical response to ACTH as achievement of hypsarrhythmia and epileptic spasms resolution. Patients who responded to daily ACTH injections were identified and assessed whether they experienced WS relapse during/after the weekly ACTH injection period. The outcome was measured by the nonrelapse rate at 24 months after daily ACTH injections using the Kaplan-Meier method.

Results: Clinical information of 16 children with WS was analyzed. The median age at LT-ACTH initiation was 14.5 months (range: 7-68 months). Thirteen (81%) patients had previously undergone conventional ACTH treatment. The LT-ACTH regimens comprised a median of 16 days of daily injections (range: 11-28 days) and 10 months of weekly injections (range: 3-22 months). Seven patients experienced WS relapse during/after subsequent weekly ACTH period, and the nonrelapse rate at 24 months after daily injections was estimated at 60.6% (95% confidence interval: 32.3%-80.0%). Height stagnation, hypertension, and irritability were observed; lethal adverse events were not reported.

Significance: Our study firstly explored the efficacy of LT-ACTH for preventing WS relapse. LT-ACTH might be a treatment option for patients with relapsed or intractable WS; however, we note that our study is limited by its small sample size and the lack of an appropriate control group.
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http://dx.doi.org/10.1002/epi4.12497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166796PMC
June 2021

Individualized ventilatory management in patients with COVID-19-associated acute respiratory distress syndrome.

Respir Med Case Rep 2021 31;33:101433. Epub 2021 May 31.

The Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

Due to the coronavirus disease 2019 pandemic, the number of coronavirus disease 2019-associated acute respiratory distress syndrome is rapidly increasing. The heterogeneity of coronavirus disease 2019-associated acute respiratory distress syndrome contributes to the complexity of managing patients. Here we described two patients with coronavirus disease 2019-associated acute respiratory distress syndrome showing that the bedside physiological approach including careful evaluation of respiratory system mechanics and visualization of ventilation with electrical impedance tomography was useful to individualize ventilatory management.
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http://dx.doi.org/10.1016/j.rmcr.2021.101433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165976PMC
May 2021

Isolated sixth nerve palsy as an initial presentation of primary angiitis of the central nervous system.

Brain Dev 2021 May 27. Epub 2021 May 27.

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

Background: Primary angiitis of the central nervous system (PACNS) is a newly-emerging disease, and it is known that early diagnosis with treatment is important for the improvement of prognosis.

Case Description: Here, we report the case of a previously healthy 13-year-old girl who presented with right eye abduction failure, attributed to isolated right sixth nerve palsy, as the initial symptom of PACNS. Magnetic resonance angiography (MRA) showed stenosis in the distal portion of the right internal carotid artery, and delay alternating with nutation for tailored excitation (DANTE)-prepared contrast-enhanced magnetic resonance imaging confirmed vasculitis at the same site. The patient was subsequently treated with three courses of pulse corticosteroid therapy (methylprednisolone intravenously 30 mg/kg/day for three consecutive days). Diplopia completely resolved within 3 months after three course of steroid pulse therapy, and when taking 10 mg PSL daily. Follow-up MRA confirmed complete resolution of the arterial narrowing, and no relapse was observed after 2 months of steroid cessation.

Discussion: This case report illustrates an unusual presentation of PACNS with isolated sixth nerve palsy. PACNS was thought to cause insults on a single cranial nerve either through local spread of inflammation or hypoxic-ischemic insults on the nerve root due to involvement of feeding microvessels. The decision to perform imaging studies in cases of isolated sixth nerve palsy remains controversial because of the possibility of spontaneous recovery. Our case supports the existing literature that recommends that even an isolated symptom of unilateral abducens nerve palsy requires timely imaging studies.
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http://dx.doi.org/10.1016/j.braindev.2021.05.003DOI Listing
May 2021

Osteosarcoma-Derived Small Extracellular Vesicles Enhance Tumor Metastasis and Suppress Osteoclastogenesis by miR-146a-5p.

Front Oncol 2021 4;11:667109. Epub 2021 May 4.

Department of Immunology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

Osteosarcoma is the most frequent type of primary bone tumor in children and adolescents, thus care for patients with malignant osteosarcoma is strongly required. The roles of small extracellular vesicles (SEVs) in enhancing metastases have been demonstrated in multiple tumors, but they are still poorly understood in osteosarcoma. Hence, this study investigated the effects of SEVs on progression and the tumor microenvironment in mice and patients. In an orthotopic implantation study, we found that osteosarcoma-derived SEVs had the potential to enhance metastases and angiogenesis. In addition, osteosarcoma-derived SEVs decreased the number of mature osteoclasts . osteoclastogenesis studies revealed that the inhibition of osteoclast maturation by osteosarcoma-derived SEVs was mediated by suppressing the NF-κB signal pathway. MicroRNA analysis of SEVs from different malignant human osteosarcomas revealed that miR-146a-5p was involved in the inhibition of osteoclastogenesis. In osteosarcoma patients, lower numbers of osteoclasts in biopsy specimens at the first visits were correlated with higher malignancy. These findings indicated that osteosarcoma-derived SEVs enhance distant metastasis of osteosarcomas by inhibiting osteoclast maturation, which may be a useful prognostic marker. This diagnostic method may enable to predict malignancy at early stage, and help to provide optimal care to patients with risk of high malignancy.
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http://dx.doi.org/10.3389/fonc.2021.667109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130824PMC
May 2021

Recurrent NFIA K125E substitution represents a loss-of-function allele: Sensitive in vitro and in vivo assays for nontruncating alleles.

Am J Med Genet A 2021 Jul 11;185(7):2084-2093. Epub 2021 May 11.

Advanced Insect Research Promotion Center, Kyoto Institute of Technology, Kyoto, Japan.

Nuclear factor I A (NFIA) is a transcription factor that belongs to the NFI family. Truncating variants or intragenic deletion of the NFIA gene are known to cause the human neurodevelopmental disorder known as NFIA-related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the NFIA-related disorder who shared a missense variant p.Lys125Glu (K125E) in the NFIA gene. Patient 1 was a 6-year-old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14-month-old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild-type human NFIA in Drosophila caused developmental defects such as eye malformation and premature death, while that of human NFIA K125E variant allele did not. nfia-deficient zebrafish embryos showed defects of midline-crossing axons in the midbrain/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild-type human NFIA, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of HES1 promoter in cultured cells. Taken together, we concluded that the K125E variant in the NFIA gene is a loss-of-function mutation.
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http://dx.doi.org/10.1002/ajmg.a.62226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251549PMC
July 2021

Expanding the spectrum of reactive arthritis (ReA): classic ReA and infection-related arthritis including poststreptococcal ReA, Poncet's disease, and iBCG-induced ReA.

Rheumatol Int 2021 Aug 1;41(8):1387-1398. Epub 2021 May 1.

Department of Internal Medicine and Rheumatology, Juntendo University Koshigaya Hospital, Saitama, Japan.

Reactive arthritis (ReA) is a form of sterile arthritis that occurs secondary to an extra-articular infection in genetically predisposed individuals. The extra-articular infection is typically an infection of the gastrointestinal tract or genitourinary tract. Infection-related arthritis is a sterile arthritis associated with streptococcal tonsillitis, extra-articular tuberculosis, or intravesical instillation of bacillus Calmette-Guérin (iBCG) therapy for bladder cancer. These infection-related arthritis diagnoses are often grouped with ReA based on the pathogenic mechanism. However, the unique characteristics of these entities may be masked by a group classification. Therefore, we reviewed the clinical characteristics of classic ReA, poststreptococcal ReA, Poncet's disease, and iBCG-induced ReA. Considering the diversity in triggering microbes, infection sites, and frequency of HLA-B27, these are different disorders. However, the clinical symptoms and intracellular parasitism pathogenic mechanism among classic ReA and infection-related arthritis entities are similar. Therefore, poststreptococcal ReA, Poncet's disease, and iBCG-induced ReA could be included in the expanding spectrum of ReA, especially based on the pathogenic mechanism.
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http://dx.doi.org/10.1007/s00296-021-04879-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091991PMC
August 2021

Structural and mechanical characteristics of exosomes from osteosarcoma cells explored by 3D-atomic force microscopy.

Nanoscale 2021 Apr 29;13(13):6661-6677. Epub 2021 Mar 29.

WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.

Exosomes have recently gained interest as mediators of cell-to-cell communication and as potential biomarkers for cancer and other diseases. They also have potential as nanocarriers for drug delivery systems. Therefore, detailed structural, molecular, and biomechanical characterization of exosomes is of great importance for developing methods to detect and identify the changes associated with the presence of cancer and other diseases. Here, we employed three-dimensional atomic force microscopy (3D-AFM) to reveal the structural and nanomechanical properties of exosomes at high spatial resolution in physiologically relevant conditions. The substructural details of exosomes released from three different cell types were determined based on 3D-AFM force mapping. The resulting analysis revealed the presence of distinct local domains bulging out from the exosome surfaces, which were associated with the exosomal membrane proteins present on the outer surface. The nanomechanical properties of individual exosomes were determined from the 3D-force maps. We found a considerably high elastic modulus, ranging from 50 to 350 MPa, as compared to that obtained for synthetic liposomes. Moreover, malignancy-dependent changes in the exosome mechanical properties were revealed by comparing metastatic and nonmetastatic tumor cell-derived exosomes. We found a clear difference in their Young's modulus values, suggesting differences in their protein profiles and other exosomal contents. Exosomes derived from a highly aggressive and metastatic k-ras-activated human osteosarcoma (OS) cell line (143B) showed a higher Young's modulus than that derived from a nonaggressive and nonmetastatic k-ras-wildtype human OS cell line (HOS). The increased elastic modulus of the 143B cell-derived exosomes was ascribed to the presence of abundant specific proteins responsible for elastic fiber formation as determined by mass spectroscopy and confirmed by western blotting and ELISA. Therefore, we conclude that exosomes derived from metastatic tumor cells carry an exclusive protein content that differs from their nonmetastatic counterparts, and thus they exhibit different mechanical characteristics. Discrimination between metastatic and nonmetastatic malignant cell-derived exosomes would be of great importance for studying exosome biological functions and using them as diagnostic biomarkers for various tumor types. Our findings further suggest that metastatic tumor cells release exosomes that express increased levels of elastic fiber-associated proteins to preserve their softness.
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http://dx.doi.org/10.1039/d0nr09178bDOI Listing
April 2021

Increased Serum Alkaline Phosphatase and Functional Outcome in Patients with Acute Ischemic Stroke Presenting a Low Ankle-Brachial Index.

J Atheroscler Thromb 2021 Mar 30. Epub 2021 Mar 30.

Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences.

Aims: Elevated serum alkaline phosphatase (ALP) levels are associated with an increased risk of cerebrocardiovascular diseases. However, the associations of ALP with peripheral arterial disease (PAD) and outcomes in patients with acute ischemic stroke (AIS) are not well-known.

Methods: We examined the association between ALP levels and the ankle-brachial index (ABI) in 2111 consecutive patients with AIS. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-6 at 3 months after stroke. A low ABI was defined as a value of ≤ 0.9.

Results: Of the total cohort, 482 patients (22.8%) had a low ABI. ALP levels were higher in patients with a low ABI than in those without (p<0.001). The multivariable logistic analysis revealed that quartiles of ALP levels were significantly associated with a low ABI (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.08-1.33). Of the 1322 patients with a premorbid mRS score of 0-2, 434 patients (32.8%) had a poor outcome. The multivariable analysis revealed that elevated serum ALP levels and a low ABI were independently associated with poor stroke outcomes after adjustment for baseline characteristics (OR: 1.21, 95% CI: 1.07-1.38, and OR: 2.00, 95% CI: 1.40-2.84, respectively).

Conclusions: Increased serum ALP levels are significantly associated with a low ABI. These indicators are independent prognostic factors for poor stroke outcomes at 3 months.
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http://dx.doi.org/10.5551/jat.62795DOI Listing
March 2021

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway.

Cell Death Dis 2021 03 26;12(4):322. Epub 2021 Mar 26.

Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain largely unknown. We observed that during hematopoietic stem cell transplantation (HSCT) in mouse myeloid leukemia models, double-stranded (ds)DNAs were constitutively secreted in the form of extracellular vesicles (EVs) from myeloid leukemia cells and were transferred to the donor cells to dampen their hematopoietic capabilities. Subsequent analysis of cytoplasmic DNA dynamics in leukemia cells revealed that autophagy regulated cytoplasmic dsDNA accumulation and subsequent redistribution into EVs. Moreover, accumulated cytoplasmic dsDNAs activated STING pathway, thereby reducing leukemia cell viability through reactive oxygen species (ROS) generation. Pharmaceutical inhibition of autophagosome formation induced cytoplasmic DNA accumulation, eventually triggering cytoplasmic DNA sensing pathways to exert cytotoxicity, preferentially in leukemia cells. Thus, manipulation of cytoplasmic dsDNA dynamics can be a novel and potent therapeutic strategy for myeloid leukemias.
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http://dx.doi.org/10.1038/s41419-021-03587-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997981PMC
March 2021

Oesophageal pressure as a surrogate of pleural pressure in mechanically ventilated patients.

ERJ Open Res 2021 Jan 8;7(1). Epub 2021 Mar 8.

Médecine Intensive Réanimation, Hôpital Nord, AP-HM, Marseille, France.

Background: Oesophageal pressure ( ) is used to approximate pleural pressure ( ) and therefore to estimate transpulmonary pressure ( ). We aimed to compare oesophageal and regional pleural pressures and to calculate transpulmonary pressures in a prospective physiological study on lung transplant recipients during their stay in the intensive care unit of a tertiary university hospital.

Methods: Lung transplant recipients receiving invasive mechanical ventilation and monitored by oesophageal manometry and dependent and nondependent pleural catheters were investigated during the post-operative period. We performed simultaneous short-time measurements and recordings of oesophageal manometry and pleural pressures. Expiratory and inspiratory were computed by subtracting regional or from airway pressure; inspiratory was also calculated with the elastance ratio method.

Results: 16 patients were included. Among them, 14 were analysed. Oesophageal pressures correlated with dependent and nondependent pleural pressures during expiration (R=0.71, p=0.005 and R=0.77, p=0.001, respectively) and during inspiration (R=0.66 for both, p=0.01 and p=0.014, respectively). values calculated using were close to those obtained from the dependent pleural catheter but higher than those obtained from the nondependent pleural catheter both during expiration and inspiration.

Conclusions: In ventilated lung transplant recipients, oesophageal manometry is well correlated with pleural pressure. The absolute value of is higher than of nondependent lung regions and could therefore underestimate the highest level of lung stress in those at high risk of overinflation.
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http://dx.doi.org/10.1183/23120541.00646-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938048PMC
January 2021

ASSOCIATION BETWEEN DOME-SHAPED MACULA AND POSTERIOR STAPHYLOMA IN HIGHLY MYOPIC EYES INVESTIGATED BY ULTRA-WIDEFIELD OPTICAL COHERENCE TOMOGRAPHY.

Retina 2021 Mar;41(3):646-652

Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan.

Purpose: To investigate the relationship between dome-shaped maculas (DSMs) and posterior staphylomas in highly myopic eyes.

Methods: Five hundred and eleven eyes of 291 patients with high myopia (refractive error ≤-8.0 diopters or axial length ≥26.5 mm) were examined by ultra-widefield swept-source optical coherence tomography (UWF-OCT). Posterior staphylomas were identified by detecting the staphyloma edges in the UWF-OCT images.

Results: Eighty-two eyes of the 511 highly myopic eyes had a DSM, and a posterior staphyloma was observed in 45 of 82 eyes with a DSM (54.9%) and in 301 of 429 eyes (70.2%) without a DSM. The incidence of staphylomas was significantly lower in eyes with a DSM than those without a DSM (P = 0.007). The wide macular type of staphyloma was the predominant type in eyes with a DSM (31/45 eyes; 68.9%), whereas the narrow macular type and wide macular type of staphylomas were present almost equally in the eyes without a DSM.

Conclusion: The lack of staphylomas in 45% of eyes with a DSM suggests that DSMs form independently from posterior staphylomas. Dome-shaped maculas tend to occur in eyes with a large expansion of the posterior fundus and should be considered a posterior scleral curvature abnormality.
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http://dx.doi.org/10.1097/IAE.0000000000002889DOI Listing
March 2021

Secondary aorto-esophageal fistula treated by covered esophageal stent and muscle wrapping.

Ann Thorac Surg 2021 Feb 4. Epub 2021 Feb 4.

Cardiovascular Surgery Department, Matsubara Tokushukai Hospital, 7-13-26 Amamihigashi, Matusbara, Osaka, Japan.

Secondary aorto-esophageal fistula is rare, but associated with serious complications and high mortality. We devised a treatment strategy involving a covered esophageal stent, instead of esophageal resection, and placing the latissimus dorsi muscle around the infected aorta without removing the aorta and the stent graft. A 72-year-old man with a history of total arch replacement with a frozen elephant trunk for a thoracic dissecting aneurysm developed aorto-esophageal fistula and underwent surgical treatment using our strategy. He recovered well, and there is no evidence of re-infection 6 months after surgery. This strategy may be a less invasive surgical option.
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http://dx.doi.org/10.1016/j.athoracsur.2021.01.044DOI Listing
February 2021

Complex hereditary spastic paraplegia associated with episodic visual loss caused by ACO2 variants.

Hum Genome Var 2021 Jan 26;8(1). Epub 2021 Jan 26.

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

Most patients with homozygous or compound heterozygous pathogenic ACO2 variants present with muscular hypotonia features, namely, infantile cerebellar-retinal degeneration. Recently, two studies reported rare familial cases of ACO2 variants presenting as complex hereditary spastic paraplegia (HSP) with broad clinical spectra. Here, we report the case of a 20-year-old Japanese woman with complex HSP caused by compound heterozygous ACO2 variants, revealing a new phenotype of episodic visual loss during febrile illness.
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http://dx.doi.org/10.1038/s41439-021-00136-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838304PMC
January 2021

Clinical practice guidelines for high-resolution breast PET, 2019 edition.

Ann Nucl Med 2021 Mar 25;35(3):406-414. Epub 2021 Jan 25.

Health Insurance Committee, Japanese Society of Nuclear Medicine, Tokyo, Japan.

Breast positron emission tomography (PET) has had insurance coverage when performed with conventional whole-body PET in Japan since 2013. Together with whole-body PET, accurate examination of breast cancer and diagnosis of metastatic disease are possible, and are expected to contribute significantly to its treatment planning. To facilitate a safer, smoother, and more appropriate examination, the Japanese Society of Nuclear Medicine published the first edition of practice guidelines for high-resolution breast PET in 2013. Subsequently, new types of breast PET have been developed and their clinical usefulness clarified. Therefore, the guidelines for breast PET were revised in 2019. This article updates readers as to what is new in the second edition. This edition supports two different types of breast PET depending on the placement of the detector: the opposite-type (positron emission mammography; PEM) and the ring-shaped type (dedicated breast PET; dbPET), providing an overview of these scanners and appropriate imaging methods, their clinical applications, and future prospects. The name "dedicated breast PET" from the first edition is widely used to refer to ring-shaped type breast PET. In this edition, "breast PET" has been defined as a term that refers to both opposite- and ring-shaped devices. Up-to-date breast PET practice guidelines would help provide useful information for evidence-based breast imaging.
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http://dx.doi.org/10.1007/s12149-021-01582-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902575PMC
March 2021

Surgical Treatment for Primary Mycotic Aneurysms Using Endovascular Therapy, Focusing on Patient Selection: Single-Center Experience.

Surg Infect (Larchmt) 2021 Jan 12. Epub 2021 Jan 12.

Cardiovascular Surgery Department. Yao Tokushukai General Hospital, Yao, Osaka, Japan.

Mycotic aneurysms (MAs) are relatively rare but life-threatening. Some recent reports have described the use of endovascular therapy for their treatment; however, this still is a controversial treatment, and a definite target population has not been determined. We performed surgery on 34 patients with MAs from March 2005 to March 2019. Twenty patients who underwent open surgery (OS) first comprised the OS group, and 14 patients who underwent endovascular therapy first comprised the stent-graft (SG) group. We analyzed between-group differences, long-term outcomes, and risk factors for death retrospectively. Patients in the OS group had a higher initial white blood cell count than those in the SG group (p = 0.047). The SG group had more patients with a low albumin concentration (≤2.0 mg/dL) than did the OS group (p = 0.026). There were no significant differences in the operative mortality rates between the groups (p = 0.773). Additional procedures were required more often in the SG than the OS group (p = 0.0013). The overall survival rate as estimated by the Kaplan-Meier method was 88% at 1 month, 67% at 1 year, 57% at 3 years, and 45% at 10 years. In the univariable analysis, chronic obstructive pulmonary disease (COPD) was a risk factor for death (p = 0.003). Endovascular therapy for MAs produced reasonable outcomes when patient selection was based on the activity level, nutritional condition, and degree of inflammation. Endovascular therapy may become an option for patients with a low albumin concentration or COPD despite the fact that additional procedures may be needed.
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http://dx.doi.org/10.1089/sur.2020.363DOI Listing
January 2021

Positive End-Expiratory Pressure, Pleural Pressure, and Regional Compliance during Pronation: An Experimental Study.

Am J Respir Crit Care Med 2021 05;203(10):1266-1274

Interdepartmental Division of Critical Care Medicine.

The physiological basis of lung protection and the impact of positive end-expiratory pressure (PEEP) during pronation in acute respiratory distress syndrome are not fully elucidated. To compare pleural pressure (Ppl) gradient, ventilation distribution, and regional compliance between dependent and nondependent lungs, and investigate the effect of PEEP during supination and pronation. We used a two-hit model of lung injury (saline lavage and high-volume ventilation) in 14 mechanically ventilated pigs and studied supine and prone positions. Global and regional lung mechanics including Ppl and distribution of ventilation (electrical impedance tomography) were analyzed across PEEP steps from 20 to 3 cm HO. Two pigs underwent computed tomography scans: tidal recruitment and hyperinflation were calculated. Pronation improved oxygenation, increased Ppl, thus decreasing transpulmonary pressure for any PEEP, and reduced the dorsal-ventral pleural pressure gradient at PEEP < 10 cm HO. The distribution of ventilation was homogenized between dependent and nondependent while prone and was less dependent on the PEEP level than while supine. The highest regional compliance was achieved at different PEEP levels in dependent and nondependent regions in supine position (15 and 8 cm HO), but for similar values in prone position (13 and 12 cm HO). Tidal recruitment was more evenly distributed (dependent and nondependent), hyperinflation lower, and lungs cephalocaudally longer in the prone position. In this lung injury model, pronation reduces the vertical pleural pressure gradient and homogenizes regional ventilation and compliance between the dependent and nondependent regions. Homogenization is much less dependent on the PEEP level in prone than in supine positon.
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http://dx.doi.org/10.1164/rccm.202007-2957OCDOI Listing
May 2021

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

Oncologist 2021 04 6;26(4):e588-e596. Epub 2021 Jan 6.

Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.

Background: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors.

Materials And Methods: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan.

Results: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy.

Conclusion: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs.

Implications For Practice: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
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http://dx.doi.org/10.1002/onco.13639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018334PMC
April 2021

Diagnostic usefulness of denervation edema in the multifidus muscles using 3-Tesla magnetic resonance imaging in cervical radiculopathy.

Muscle Nerve 2021 03 26;63(3):365-370. Epub 2020 Dec 26.

Department of Neurology, Kanazawa Medical University, Uchinada, Japan.

Background: Diagnosing cervical radiculopathy (CR) can be difficult because of symptomatic overlap with peripheral neuropathies. In this retrospective observational study, we aimed to determine whether short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) sequences are useful for detecting signs of denervation in the multifidus muscles in patients with CR.

Methods: We analyzed the data of 18 patients with CR who developed arm weakness within 1 year. We also included 10 patients with sensorimotor symptoms involving the upper extremities who did not have intervertebral foraminal stenosis on MRI as controls. For each patient with CR, the signal intensity (SI) of the affected multifidus muscles was measured and compared to that on the contralateral side (signal intensity ratio: SIR).

Results: Control patients without CR did not exhibit STIR signal abnormalities in the multifidus muscles. Most of the 18 patients with CR were male (83.3%), and the mean age was 59.4 years. Thirteen of 18 CR patients (72.2%) were determined to have STIR signal abnormalities by a radiologist. The mean SIR in the 13 patients with increased SI was significantly higher than that in the five patients without signal abnormalities (1.23 vs 0.97, P = .004), supporting the radiologist's diagnosis. The distribution of signal abnormalities closely followed those identified via clinical and electrophysiological tests, especially severe weakness (P = .044).

Conclusions: Denervation edema of the multifidus muscles can be detected in CR and correlates with clinical/electrophysiological tests and weakness severity, which may aid in CR diagnostics.
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http://dx.doi.org/10.1002/mus.27142DOI Listing
March 2021

Prognostic Factors for Axial Length Elongation and Posterior Staphyloma in Adults With High Myopia: A Japanese Observational Study.

Am J Ophthalmol 2021 05 9;225:76-85. Epub 2020 Dec 9.

Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan.

Purpose: To identify prognostic factors for axial length (AL) elongation and incidence of posterior staphyloma (PS) in adult Japanese patients with high myopia.

Design: Retrospective, observational cohort study.

Methods: Six-year follow-up data for 345 patients (620 eyes with AL ≥ 26.5 mm and spherical equivalent [SE] ≤- 8.00 diopters) admitted to the Tokyo Medical and Dental University Hospital from 2007 to 2017 were analyzed retrospectively. Main outcome measures were change in AL from baseline, factors associated with AL, categorization of eyes with high myopia, factors associated with incidence of PS, and impact of PS on myopic maculopathy and visual function.

Results: The mean annual increase in AL was 0.03 mm. Presence of optic nerve disc conus (P = .025), steeper corneal curvature, lower SE, and decreased choroidal thickness (CT) (all P < .001) were associated with increased AL in univariate and multivariate analyses. Younger age (P = .003) and no use of intraocular pressure-lowering medications (P = .046) were associated with increased AL. Eyes with high myopia were categorized using factor analysis as associated with glaucoma, severe pathologic myopia, and mild-to-moderate pathologic myopia. Older age, increased AL, glaucoma, and choroidal thinning (all P ≤ .001) were identified as significant risk factors for the incidence of PS in univariate and/or multivariate analyses. Incidence of PS was a precursor for myopic maculopathy and visual field defects.

Conclusions: Optic nerve disc conus, steeper corneal curvature, lower SE, decreased CT, and no use of intraocular pressure-lowering medications were prognostic factors for increased AL. Older age, increased AL, glaucoma, and decreased CT were prognostic factors for PS.
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http://dx.doi.org/10.1016/j.ajo.2020.11.023DOI Listing
May 2021

Predictors of Stroke Outcome Extracted from Multivariate Linear Discriminant Analysis or Neural Network Analysis.

J Atheroscler Thromb 2020 Dec 9. Epub 2020 Dec 9.

Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences.

Aim: The prediction of functional outcome is essential in the management of acute ischemic stroke patients. We aimed to explore the various prognostic factors with multivariate linear discriminant analysis or neural network analysis and evaluate the associations between candidate factors, baseline characteristics, and outcome.

Methods: Acute ischemic stroke patients (n=1,916) with premorbid modified Rankin Scale (mRS) scores of 0-2 were analyzed. The prediction models with multivariate linear discriminant analysis (quantification theory type II) and neural network analysis (log-linearized Gaussian mixture network) were used to predict poor functional outcome (mRS 3-6 at 3 months) with various prognostic factors added to age, sex, and initial neurological severity at admission.

Results: Both models revealed that several nutritional statuses and serum alkaline phosphatase (ALP) levels at admission improved the predictive ability. Of the 1,484 patients without missing data, 560 patients (37.7%) had poor outcomes. The patients with poor outcomes had higher ALP levels than those without (294.3±259.5 vs. 246.3±92.5 U/l, P<0.001). Multivariable logistic analyses revealed that higher ALP levels (1-SD increase) were independently associated with poor stroke outcomes after adjusting for several confounding factors, including the neurological severity, malnutrition status, and inflammation (odds ratio 1.21, 95% confidence interval 1.02- 1.49). Several nutritional indicators extracted from prediction models were also associated with poor outcome.

Conclusion: Both the multivariate linear discriminant and neural network analyses identified the same indicators, such as nutritional status and serum ALP levels. These indicators were independently associated with functional stroke outcome.
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http://dx.doi.org/10.5551/jat.59642DOI Listing
December 2020

Monitoring the patient for a safe-assisted ventilation.

Curr Opin Crit Care 2021 02;27(1):1-5

Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

Purpose Of Review: A growing evidence shows that injurious spontaneous breathing, either too weak or too strong, may injure lung and diaphragm. The purpose of review is to understand why we need monitoring for safe spontaneous breathing, and to know the target value of each monitoring to preserve safe spontaneous breathing during assisted ventilation.

Recent Findings: Lung protection sometimes goes counter to diaphragm protection. For instance, silence of respiratory muscle activity is necessary to minimize lung injury from vigorous spontaneous effort in acute respiratory distress syndrome, but it may also have a risk of diaphragm atrophy. Thus, our current goal is to preserve spontaneous breathing activity at modest level during assisted ventilation. To achieve this goal, several monitoring/techniques are now available at the bedside (e.g., plateau pressure measurement, airway occlusion pressure, end-expiratory airway occlusion, esophageal balloon manometry, electrical impedance tomography). The target value of each monitoring is vigorously being investigated, facilitating 'safe' spontaneous breathing effort from the perspective of lung and diaphragm protection.

Summary: We summarize why we need monitoring for safe spontaneous breathing during assisted ventilation and what the target value of each monitoring is to facilitate 'safe' spontaneous breathing during assisted ventilation.
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http://dx.doi.org/10.1097/MCC.0000000000000788DOI Listing
February 2021

Tumor-secreted proliferin-1 regulates adipogenesis and lipolysis in cachexia.

Int J Cancer 2021 04 28;148(8):1982-1992. Epub 2020 Dec 28.

Department of Immunology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.

Cancer-associated cachexia (CAC) is a common syndrome in cancer patients and is characterized by loss of body weight accompanied by the atrophy of fat and skeletal muscle. Metabolic changes are a critical factor in CAC; however, the mechanisms through which tumors inhibit adipogenesis and promote lipolysis are poorly understood. To clarify these mechanisms, we investigated adipogenesis-limiting factors released by tumors in a cell culture system. We identified proliferin-1 (PLF-1), a member of the growth hormone/prolactin gene family, as a key factor secreted from certain tumors that inhibited preadipocyte maturation and promoted the lipolysis of mature adipocytes. Importantly, mice transplanted with PLF-1-depleted tumor cells were protected from fat loss due to CAC. These data show that tumor-secreted PLF-1 plays an essential role in impaired adipogenesis and accelerated lipolysis and is a potential therapeutic target against CAC.
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http://dx.doi.org/10.1002/ijc.33418DOI Listing
April 2021

Myorelaxants in ARDS patients.

Intensive Care Med 2020 12 7;46(12):2357-2372. Epub 2020 Nov 7.

Assistance Publique - Hôpitaux de Marseille, Hôpital Nord, Médecine Intensive Réanimation, 13015, Marseille, France.

Neuromuscular blocking agents (NMBAs) inhibit patient-initiated active breath and the risk of high tidal volumes and consequent high transpulmonary pressure swings, and minimize patient/ ventilator asynchrony in acute respiratory distress syndrome (ARDS). Minimization of volutrauma and ventilator-induced lung injury (VILI) results in a lower incidence of barotrauma, improved oxygenation and a decrease in circulating proinflammatory markers. Recent randomized clinical trials did not reveal harmful muscular effects during a short course of NMBAs. The use of NMBAs should be considered during the early phase of severe ARDS for patients to facilitate lung protective ventilation or prone positioning only after optimising mechanical ventilation and sedation. The use of NMBAs should be integrated in a global strategy including the reduction of tidal volume, the rational use of PEEP, prone positioning and the use of a ventilatory mode allowing spontaneous ventilation as soon as possible. Partial neuromuscular blockade should be evaluated in future trials.
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http://dx.doi.org/10.1007/s00134-020-06297-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648542PMC
December 2020

Current and evolving standards of care for patients with ARDS.

Intensive Care Med 2020 12 6;46(12):2157-2167. Epub 2020 Nov 6.

Interdepartmental Division of Critical Care Medicine, Departments of Medicine and Physiology, Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.

Care for patients with acute respiratory distress syndrome (ARDS) has changed considerably over the 50 years since its original description. Indeed, standards of care continue to evolve as does how this clinical entity is defined and how patients are grouped and treated in clinical practice. In this narrative review we discuss current standards - treatments that have a solid evidence base and are well established as targets for usual care - and also evolving standards - treatments that have promise and may become widely adopted in the future. We focus on three broad domains of ventilatory management, ventilation adjuncts, and pharmacotherapy. Current standards for ventilatory management include limitation of tidal volume and airway pressure and standard approaches to setting PEEP, while evolving standards might focus on limitation of driving pressure or mechanical power, individual titration of PEEP, and monitoring efforts during spontaneous breathing. Current standards in ventilation adjuncts include prone positioning in moderate-severe ARDS and veno-venous extracorporeal life support after prone positioning in patients with severe hypoxemia or who are difficult to ventilate. Pharmacotherapy current standards include corticosteroids for patients with ARDS due to COVID-19 and employing a conservative fluid strategy for patients not in shock; evolving standards may include steroids for ARDS not related to COVID-19, or specific biological agents being tested in appropriate sub-phenotypes of ARDS. While much progress has been made, certainly significant work remains to be done and we look forward to these future developments.
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http://dx.doi.org/10.1007/s00134-020-06299-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646492PMC
December 2020

Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort.

Intensive Care Med 2020 12 2;46(12):2314-2326. Epub 2020 Nov 2.

Department of Intensive Care, Amsterdam UMC, Location VUmc, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.

Mechanical ventilation may have adverse effects on both the lung and the diaphragm. Injury to the lung is mediated by excessive mechanical stress and strain, whereas the diaphragm develops atrophy as a consequence of low respiratory effort and injury in case of excessive effort. The lung and diaphragm-protective mechanical ventilation approach aims to protect both organs simultaneously whenever possible. This review summarizes practical strategies for achieving lung and diaphragm-protective targets at the bedside, focusing on inspiratory and expiratory ventilator settings, monitoring of inspiratory effort or respiratory drive, management of dyssynchrony, and sedation considerations. A number of potential future adjunctive strategies including extracorporeal CO removal, partial neuromuscular blockade, and neuromuscular stimulation are also discussed. While clinical trials to confirm the benefit of these approaches are awaited, clinicians should become familiar with assessing and managing patients' respiratory effort, based on existing physiological principles. To protect the lung and the diaphragm, ventilation and sedation might be applied to avoid excessively weak or very strong respiratory efforts and patient-ventilator dysynchrony.
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http://dx.doi.org/10.1007/s00134-020-06288-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605467PMC
December 2020

Role of Positive End-Expiratory Pressure and Regional Transpulmonary Pressure in Asymmetrical Lung Injury.

Am J Respir Crit Care Med 2021 04;203(8):969-976

Interdepartmental Division of Critical Care Medicine.

Asymmetrical lung injury is a frequent clinical presentation. Regional distribution of Vt and positive end-expiratory pressure (PEEP) could result in hyperinflation of the less-injured lung. The validity of esophageal pressure (Pes) is unknown. To compare, in asymmetrical lung injury, Pes with directly measured pleural pressures (Ppl) of both sides and investigate how PEEP impacts ventilation distribution and the regional driving transpulmonary pressure (inspiratory - expiratory). Fourteen mechanically ventilated pigs with lung injury were studied. One lung was blocked while the contralateral one underwent surfactant lavage and injurious ventilation. Airway pressure and Pes were measured, as was Ppl in the dorsal and ventral pleural space adjacent to each lung. Distribution of ventilation was assessed by electrical impedance tomography. PEEP was studied through decremental steps. Ventral and dorsal Ppl were similar between the injured and the noninjured lung across all PEEP levels. Dorsal Ppl and Pes were similar. The driving transpulmonary pressure was similar in the two lungs. Vt distribution between lungs was different at zero end-expiratory pressure (≈70% of Vt going in noninjured lung) owing to different respiratory system compliance (8.3 ml/cm HO noninjured lung vs. 3.7 ml/cm HO injured lung). PEEP at 10 cm HO with transpulmonary pressure around zero homogenized Vt distribution opening the lungs. PEEP ≥16 cm HO equalized distribution of Vt but with overdistension for both lungs. Despite asymmetrical lung injury, Ppl between injured and noninjured lungs is equalized and esophageal pressure is a reliable estimate of dorsal Ppl. Driving transpulmonary pressure is similar for both lungs. Vt distribution results from regional respiratory system compliance. Moderate PEEP homogenizes Vt distribution between lungs without generating hyperinflation.
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http://dx.doi.org/10.1164/rccm.202005-1556OCDOI Listing
April 2021