Search

Background: Anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD) may occur without myositis. Although a recent Japanese guide proposed a watch-and-wait approach for chronic ASS-ILD without obvious progression, the natural history of this subgroup and the appropriateness of the watch-and-wait approach remain unclear. We aimed to describe the natural history of ASS-ILD, that is sufficiently indolent to be a candidate for the watch-and-wait approach., Methods: Among consecutive patients with ASS-ILD, we retrospectively identified those without myositis, acute/subacute onset, and significant lung function impairment, which qualified them as indolent-ASS-ILD cases, and described their natural course. Additionally, we evaluated the risk factors for fibrosis progression on computed tomography (CT) using the Cox proportional hazards model., Results: Among 80 patients with ASS-ILD, we identified 33 with indolent-ASS-ILD, all of whom were initially followed up with a watch-and-wait approach. Among 30 patients with sufficient follow-up data, 27 (90%) showed a stable course without treatment over 24 months. Subsequently, four patients experienced ≥10% relative forced vital capacity (FVC) decline without treatment during a median follow-up duration of 81 months. Seven patients showed fibrosis progression with >10% increase in the total lung area on CT. Higher levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) were associated with fibrosis progression on CT., Conclusion: Most patients with indolent-ASS-ILD did not experience ≥10% relative FVC decline over five years without treatment. However, fibrosis progression on CT, which seemed to precede significant FVC decline, occurred more frequently, especially in patients with higher KL-6 and SP-D levels., Competing Interests: Declaration of competing interest Mitsuhiro Moda has no conflict of interest; Hiromitsu Sumikawa has no conflict of interest; Ryota Shintani has no conflict of interest; Naoko Takeuchi has no conflict of interest; Tomoko Kagawa has no conflict of interest; Takayuki Takimoto has no conflict of interest; Toru Arai received lecture fees from Boehringer Ingelheim and Shionogi for activities not connected to the submitted work., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Polymers possessing saturated fused polycycles in the main chain repeating unit have been underexplored despite their potential utility based on their expected properties such as high rigidity, chemical resistance, transparency, and thermal stability. In this regard, herein, we developed a radical stitching polymerization of styryl vinyl ketones for the synthesis of polyketones possessing saturated fused bicyclic repeating units. The polymerization proceeded smoothly with a high degree of stitching efficiency in a chain-growth manner under free radical conditions. This method was further extended to the alternating copolymerization of styryl vinyl ketones and 1-styryl-2-vinylbenzenes, representing the first alternating stitching copolymerization of two different monomers. The obtained polymers were found to show promising thermal properties and high transparency in the visible light region.

A KO t Bu-catalyzed ring-opening gem -silylborylation of cyclopropenes with silylboronates has been developed for the synthesis of (1-silyl)allylboronates, a useful class of compounds in organic synthesis. The reaction proceeds with high selectivity under mild conditions, and the reaction mechanism has been theoretically investigated using DFT calculations.

Dearomative photocycloaddition of monocyclic arenes is an appealing strategy for comprehending the concept of "escape from flatland". This brings the replacement of readily available planar aromatic hydrocarbon units with a 3D fused bicyclic core with sp 3 -enriched carbon units. Herein, we outline an intermolecular approach for the dearomative photocycloaddition of phenols. In order to circumvent the ground-state aromaticity and to construct conformationally restrained building blocks, bicyclo[1.1.0]butanes were chosen as coupling partners. This dearomative approach renders straightforward access to a bicyclo[2.1.1]hexane unit fused to a cyclic enone moiety, which further contributed as a synthetic linchpin for postmodifications. Mechanistic experiment advocates for a plausible onset from both the reactants, depending on the redox potential.

A palladium-catalyzed skeletal rearrangement of 2-(2-allylarylsilyl)aryl triflates has been developed to give highly fused tetrahydrophenanthrosilole derivatives via unprecedented 1,5-C-Pd/C-Si bond exchange. The reaction pathways can be switched toward 4-membered ring-forming C(sp 2 )-H alkylation by tuning the reaction conditions to give completely different products, fused dihydrodibenzosilepin derivatives, from the same starting materials. The inspection of the reaction conditions revealed the importance of carboxylates in promoting the C-Pd/C-Si bond exchange., (© 2023 Wiley-VCH GmbH.)

Catalytic reactions involving 1, n -metal migration from carbon to carbon enable a nonclassical way of constructing organic molecular skeletons, rapidly providing complex molecules from relatively simple precursors. By utilization of this attractive feature, a new and efficient synthesis of alkenylsilylmethylboronates has been developed by formal hydro(borylmethylsilyl)ation of unsymmetric internal alkynes with silylboronates under copper catalysis. The reaction proceeds regioselectively and involves an unprecedented alkenyl-to-alkyl 1,4-copper migration. The reaction mechanism has been investigated by a series of kinetic, NMR, and deuterium-labeling experiments.

Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction owing to the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. A 77-year-old man with APAP was referred to our hospital for whole-lung lavage (WLL) due to oxygenation exacerbation and pulmonary shadows. The patient had had coronavirus disease 2019 (COVID-19) during the APAP evaluation before WLL. About three months after COVID-19 resolved, his oxygenation and shadow reflecting APAP had obviously improved, thus avoiding the need for WLL. We suspected that the improvement in APAP was due to various immunological reactions induced by COVID-19.

Background: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance., Research Question: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression?, Methods: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52., Results: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019)., Interpretation: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time., Trial Registration Number: UMIN000026376., Competing Interests: Competing interests: The following authors received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events outside the submitted work: KK and ON (Nippon Boehringer Ingerheim); TaO (Nippon Boehringer Ingerheim; Shionogi; Eisai; Astellas Pharma; Bristol-Myers Squibb; Taiho Pharmaceutical); TT and HT (Nippon Boehringer Ingerheim; KYORIN Pharmaceutical; AstraZeneca K.K.; Teijin Pharma Limited), KT (Nippon Boehringer Ingerheim; Teijin Pharma); HIs, KI and HaS (Nippon Boehringer Ingerheim); YK (Nippon Boehringer Ingerheim; Asahi Kasei Pharma Corp.; Shionogi; Janssen Pharmaceutical K.K.; Healios K.K.; Taiho Pharmaceutical; AstraZeneca K.K.; Eisai; KYORIN Pharmaceutical; Mitsubishi Tanabe Pharma; Novartis Pharma K.K.)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

A palladium-catalyzed synthesis of benzosilacyclobutenes has been developed via position-selective C(sp 3 )-H bond activation, including those having substituents at the methylene carbon on the 4-membered silacycle. The obtained products could be engaged in the palladium- or nickel-catalyzed ring-expansion reactions to give compounds possessing 6-membered silacycles.

A kinetically-stabilized nitrogen-doped triangulene cation derivative has been synthesized and isolated as the stable diradical with a triplet ground state that exhibits near-infrared emission. As was the case for a triangulene derivative we previously synthesized, the triplet ground state with a large singlet-triplet energy gap was experimentally confirmed by magnetic measurements. In contrast to the triangulene derivative, the nitrogen-doped triangulene cation derivative is highly stable even in solution under air and exhibits near-infrared absorption and emission because the alternancy symmetry of triangulene is broken by the nitrogen cation. Breaking the alternancy symmetry of triplet alternant hydrocarbon diradicals by a nitrogen cation would therefore be an effective strategy to create stable diradicals possessing magnetic properties similar to the parent hydrocarbons but with different electrochemical and photophysical properties., (© 2023 Wiley-VCH GmbH.)

A copper-catalyzed disilylative cyclization of silicon-containing internal alkynes with silylboronates has been developed for the synthesis of 3-silyl-1-silacyclopent-2-enes. The reaction proceeded regio- and anti -selectively under simple and mild conditions by employing a combination of nucleophilic silicon donors and electrophilic silicon acceptors. The reaction could also be extended to the synthesis of a 1-germacyclopent-2-ene and a silicon-centered spirocyclic compound by using appropriate alkyne substrates.

Abnormal peripheral perfusion (PP) worsens the prognosis of patients with septic shock. Polymyxin B-direct hemoperfusion (PMX-DHP) increases blood pressure and reduces vasopressor doses. However, the modification of PP following administration of PMX-DHP in patients with vasopressor-dependent septic shock have not yet been elucidated. A retrospective exploratory observational study was conducted in patients with septic shock treated with PMX-DHP. Pulse-amplitude index (PAI), vasoactive inotropic score (VIS), and cumulative fluid balance data were extracted at PMX-DHP initiation (T0) and after 24 (T24) and 48 (T48) h. Changes in these data were analyzed in all patients and two subgroups (abnormal PP [PAI < 1] and normal PP [PAI ≥ 1]) based on the PAI at PMX-DHP initiation. Overall, 122 patients (abnormal PP group, n = 67; normal PP group, n = 55) were evaluated. Overall and in the abnormal PP group, PAI increased significantly at T24 and T48 compared with that at T0, with a significant decrease in VIS. Cumulative 24-h fluid balance after PMX-DHP initiation was significantly higher in the abnormal PP group. PMX-DHP may be an effective intervention to improve PP in patients with abnormal PP; however, caution should be exercised as fluid requirements may differ from that of patients with normal PP., (© 2023. The Author(s).)

A palladium-catalyzed synthesis of 4-sila-4 H -benzo[ d ][1,3]oxazines, silicon-switched analogs of biologically relevant 4 H -benzo[ d ][1,3]oxazines, was developed by the intramolecular Hiyama coupling of 3-amido-2-(arylsilyl)aryl triflates. The present reaction is an unusual way of utilizing the Hiyama coupling, enabling the synthesis of value-added organosilanes as the main products. The intramolecular nature of transmetalation with inversion of the stereochemistry at the silicon center was revealed by the mechanistic investigation, and an asymmetric variant of this process was also demonstrated to give silicon-stereogenic 4-sila-4 H -benzo[ d ][1,3]oxazines with relatively high enantioselectivity., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Poly(arylenevinylene)s constitute an important class of π-conjugated polymers for their potential utility as optoelectronic materials. Herein, we developed a sequence of rhodium-catalyzed stitching polymerization of 1,2-dialkynyl(hetero)arenes and aromatization-driven alkene isomerization for the synthesis of new poly(arylenevinylene)s. The polymerization and subsequent alkene isomerization proceeded smoothly with high degree of stitching efficiency by employing a Rh/tfb complex as the catalyst, and not only diynes but also triynes and tetraynes could be polymerized to give poly(arylenevinylene)s that are not easily accessible by existing synthetic methods. The polymers obtained by the present method were thermally stable, and their optical properties could be varied depending on the repeating unit structure.

Design, synthesis, and isolation of a Kekulé hydrocarbon with a triplet ground state is described. Its triplet ground state was unambiguously confirmed by ESR experiments, and the structure and fundamental physical properties were also revealed. The key feature of the molecular design is the decrease in the bonding interaction in the singlet state by aromatic stabilization of benzene rings and the increase of the exchange interaction of unpaired electrons which are favorable for the triplet state. These results contribute to the development of hydrocarbon-based organic magnetic materials., (© 2022 Wiley-VCH GmbH.)

A 58-year-old man was diagnosed with stage IVB lung adenocarcinoma in the right upper lobe and underwent systemic chemotherapy. Seven months after the diagnosis, large left pleural and pericardial effusion was detected. The patient developed both chylothorax and chylopericardium following superior vena cava (SVC) obstruction with mediastinal lymphadenopathy caused by lung carcinoma. Since conservative treatment of the chyle leakage was ineffective, we administered radiotherapy to treat the SVC obstruction and mediastinal lymphadenopathy. After radiotherapy, the chylothorax and chylopericardium gradually resolved, and no further chyle leaks were identified on follow-up computed tomography. This case indicates that radiotherapy can be used to ameliorate lung cancer-related chylothorax and chylopericardium.

Introduction: A subgroup analysis of the CAPACITY and ASCEND trials showed that pirfenidone use beyond disease progression reduced the risk of subsequent forced vital capacity (FVC) decline and death. Our study aimed to compare the efficacy and safety of nintedanib with or without pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) who experienced disease progression during previous pirfenidone therapy., Methods: In this randomized, open-label, selection design phase II trial, patients with IPF and a ≥5% relative decline in FVC within 6 months of the pirfenidone administration period were randomly assigned to nintedanib (switch group) or nintedanib plus pirfenidone (combination group). The primary endpoint was the incidence of a ≥5% relative decline in FVC or death during the first 6 months., Results: Only 7 patients were enrolled (4 in the switch group and 3 in the combination group). Although the switch group continued with nintedanib for 1 year or more, 2 patients (66.7%) in the combination group discontinued nintedanib within 6 months due to severe adverse events. Given the slow case registration and safety concerns in the combination group, the trial was terminated without extending the registration. The incidence of a ≥5% relative decline in FVC during the first 6 months was 50.0% in the switch group and 66.7% in the combination group. There were no deaths during the observation period., Conclusions: Clinical trials verifying the use of pirfenidone after disease progression in IPF may be difficult to enroll patients. Definitive conclusions on both safety and efficacy cannot be drawn from the results of this study alone., Trial Registration: UMIN Clinical Trial Registry; registration number, UMIN000019436; date of first registration, 21/10/2015; https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000022471., Competing Interests: S Ikeda, T Baba, and T Kato received an honorarium from Boehringer Ingelheim Co., Ltd. T Ogura received an honorarium from Boehringer Ingelheim Co., Ltd and Shionogi and Co., Ltd. A Sekine, T Katano, E Tabata, R Shintani, H Yamakawa, T Oda, R Okuda, H Kitamura, T Iwasawa, and T Takemura declare that there are no potential conflicts of interest with any companies/organisations whose products or services might be discussed in this article., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Anionic stitching polymerization of styryl(vinyl)silanes has been developed for the synthesis of a new type of silicon- and carbon-containing polymer possessing fused sila-bicyclic structures in the main chain. The obtained polymers were found to be thermally stable with relatively high glass-transition temperatures and highly transparent in the visible light region.

Polymers possessing a silicon-bridged π-conjugated repeating unit constitute an important class of compounds for their potential utility as optoelectronic materials. Herein we developed a rhodium-catalyzed stitching polymerization of nonconjugated and readily prepared alkynylsilylacetylenes for the synthesis of new π-conjugated polymers with ladder-type silicon-bridged repeating units. The polymerization proceeded smoothly by employing a Rh/tfb complex as the catalyst, and not only diynes but also triynes and tetraynes could be polymerized in a stitching manner to give polymers that are inaccessible by existing methods. The solubility of the polymers in different types of solvents could be controlled by introducing appropriate functional groups on the silicon atoms, and sequence-controlled functionalized polyacetylenes could be accessed by protodesilylation of the stitched polymers. Physical properties of the obtained polymers were also investigated to understand their characteristic features.

The synthesis and isolation of hydrocarbons with a triplet ground state in crystalline forms have been sought in materials science. Triangulene is one of the most famous triplet-ground-state benzenoid hydrocarbons. Its unique electronic structure and highly symmetric structure have prompted many scientists to synthesize and isolate triangulene and its derivatives, but all attempts so far to isolate them as crystals have been unsuccessful. Herein we report the synthesis and isolation of a kinetically stabilized crystalline triangulene for the first time. The key to success is the introduction of bulky substituents onto the reactive zigzag edges. Its highly symmetric structure was confirmed by X-ray crystallography, and its fundamental properties, including the triplet ground state, were revealed. The achievement here will open the door for the synthesis and isolation of other hydrocarbons with higher spin multiplicity.

Background: Unilateral upper-lung field pulmonary fibrosis (upper-PF), which is radiologically consistent with pleuroparenchymal fibroelastosis, develops after thoracic surgery. In most patients with unilateral upper-PF, aberrant intra-/extra thoracic air commonly emerges and an autopsy shows chronic pleuritis, which indicates that pleural involvement is associated with upper-PF development. If so, there may be patients with unilateral upper-PF who have a history of pleural involvement, including tuberculous pleurisy (TP) or asbestos exposure (AE). This study aimed to examine this supposition., Methods: We examined the radiological reports of all consecutive patients from 2012 to 2018 to investigate whether there were patients having unilateral upper-PF and a history of TP or AE., Results: Eight patients were included in the study. Five patients had a history of TP, and the remaining three had that of AE. All patients were men and had respiratory symptoms, and seven patients presented with restrictive ventilatory impairment. The interval between TP or last AE and upper-PF development was long, with a median of over 20 years. The upper-PF lesion was commonly located in the right lung, and aberrant intrathoracic air was observed in five patients during their clinical course. Additionally, the upper-PF lesion transformed into a cystic lesion in six patients, which resulted in Aspergillus infection in two patients. The prognosis was poor, with a median overall survival of 38 months., Conclusions: Unilateral upper-PF developed even in patients with a history of pleural involvement. Our results indicate that pleural involvement plays an important role in the development of unilateral upper-PF., Competing Interests: Conflict of Interest All authors have no conflict of interest related to this study to declare., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The serum Krebs von den Lungen-6 (KL-6) level is a predictive factor for acute respiratory distress syndrome (ARDS). The development of ARDS has been reported in patients with coronavirus disease 2019 (COVID-19). This study aimed to determine whether serum KL-6 levels are associated with mortality and severity in patients with COVID-19., Methods: Among 361 Japanese patients with COVID-19 who were hospitalized at Kanagawa Cardiovascular and Respiratory Center between February 2020 and December 2020, 356 patients with data on serum KL-6 levels were enrolled and their medical records were retrospectively analyzed., Results: A negative correlation was observed between KL-6 levels and the ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen on admission. The KL-6 levels on admission and the maximal KL-6 levels were higher in patients with severe disease (n = 60) than in those with nonsevere disease (n = 296). Furthermore, the maximal KL-6 levels were higher in nonsurvivors (n = 6) than in survivors (n = 350). In nonsurvivors, the KL-6 levels increased as the disease progressed. The optimal cutoff value of the maximal KL-6 level for discriminating between survivors and nonsurvivors was 684 U/mL, with a sensitivity of 83.3%, a specificity of 90.5%, and an area under the curve of 0.89., Conclusions: The serum KL-6 level was associated with disease severity. Patients with KL-6 levels ≥684 U/mL had a significantly poorer outcome than those with KL-6 levels <684 U/mL., Competing Interests: Conflict of Interest The authors declare no conflicts of interest, (Copyright © 2021. Published by Elsevier B.V.)

Spontaneous regression (SR) is defined as a complete or partial, temporary or permanent disappearance of a tumor without anticancer treatment, which potentially develops after surgery or biopsy for primary and metastatic tumors despite unknown incidence rate. Here, we report the incidence rate of SR after endobronchial ultrasound-guided transbronchial nodal needle aspiration (EBUS-TBNA) in lung cancer patients. Among 96 patients evaluable with chest CT before and after EBUS-TBNA, SR was found in three patients (3.1%). With regards to patient characteristics, two patients had small cell lung cancer (SCLC), and one patient had adenocarcinoma. All patients had stage 3 disease with a bulky N2 stage and a history of smoking. Two patients also had interstitial lung disease. Notably, SR was observed not only at the biopsied site, but also at the non-biopsied site. Our results indicate that SR can develop following EBUS-TBNA in a substantial proportion of lung cancer patients., Competing Interests: Conflict of Interest All authors have no financial disclosure to declare., (Copyright © 2021. Published by Elsevier B.V.)

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.

Introduction: Although several reports on the risk factors for severe disease of COVID-19 already exist, reports on effective early indicators are still limited, especially from Japan. This study was conducted to clarify the patient's characteristics whose disease progressed to severe status., Methods: The medical records of all consecutive 300 Japanese patients hospitalized at our institution between February and November 2020 were retrospectively reviewed. The clinical characteristics were evaluated to compare between mild (no oxygen needed), moderate (oxygen needs of 1-4 L/min), and severe diseases (oxygen needs of 5 L/min or more)., Results: The median age was 68 years old, with 123 (41.0%) males and 177 (59.0%) females. Of these, 199 patients (66.3%), 55 patients (18.3%), 46 patients (15.3%) patients were in the mild disease, moderate disease, severe disease groups, respectively. Patients with severe disease were more likely to be older, have more comorbidities, and tended to have higher body mass index. In laboratory data, lymphocyte count, levels of C-reactive protein (CRP), LDH, and AST on admission were significantly associated with the severity. In multivariate analysis, age and CRP were the independent risk factors for severe disease (OR = 1.050, 1.130, respectively). The optimal cut-off value for age was 74 years old and that for CRP was 3.15 mg/dL., Conclusions: Age and CRP were independently associated with disease severity of COVID-19 in multivariate analysis. Additionally, the numbers of underlying disease, lymphocyte count, and inflammatory markers such as LDH and D-dimer may also be related to disease severity., Competing Interests: Declaration of competing interest All of the authors report they have no conflict of interest to disclose., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

As a new and complementary method for the synthesis of structurally defined tetrasubstituted alkenes, a copper-catalyzed regio- and anti-selective addition of silylboronates to unsymmetric internal alkynes has been developed. A variety of unactivated alkynes can be employed with high selectivity under simple and mild conditions, and the resulting products have been further functionalized by utilizing silyl and boryl groups on the alkene., (© 2021 Wiley-VCH GmbH.)

A 42-year-old man with a history of surgery for tongue cancer was referred to our hospital due to an abnormal chest shadow. High-resolution computed tomography showed lower lobe reticulation. A physical examination revealed nail dystrophy, oral leukoplakia, and reticulated hypopigmentation. Lung biopsy revealed subpleural and perilobular fibrosis, suggestive of usual interstitial pneumonia. However, multiple pathological findings, including homogenous fibrosis and cell infiltration in the centrilobular region, which were compatible with nonspecific interstitial pneumonia, and bronchiolitis were also seen. Genetic testing showed a hemizygous missense mutation in the DKC1 gene, and the patient was diagnosed with dyskeratosis congenita. Although anti-fibrotic therapy was initiated, the patient's respiratory function has continued to decrease.

Catalytic reactions involving 1, n -metal migration represent a powerful method for the synthesis of complex molecules from simple precursors through the activation of C-H bonds. By utilizing this attractive feature, herein we devised a palladium-catalyzed synthesis of new members of 5 H -dibenzo[ b , f ]silepins, a class of underexplored but potentially useful silicon-bridged π-conjugated compounds. The reaction sequence is composed of 1, n -palladium migrations and unusual anti -carbopalladation of alkynes, which was realized by the proper choice of ligand for palladium. A series of deuterium-labeling experiments were conducted toward an understanding of the reaction mechanism to propose plausible catalytic cycles. The newly obtained 5 H -dibenzo[ b , f ]silepins exhibited tunable optical and electronic properties, demonstrating the power and importance of developing a new synthetic method based on 1, n -metal migration processes.

The effect of ginkgo fruit addition on methane production potential of cattle feces and slurry was assessed in relation to other fermentation products and the microbial community. Holstein cattle fresh feces and slurry were left at 30°C for 0, 30, 60, 90, and 180 days with/without ginkgo fruit to monitor the effect on fermentation potential. With the addition of ginkgo fruit, methane production potential of feces was reduced on Day 30 and thereafter, and that of slurry was consistently reduced over the experimental period. As a general trend, ginkgo fruit addition resulted in decreased acetate and increased propionate in feces and acetate accumulation in slurry. With ginkgo fruit addition, MiSeq analyses indicated decreases in methanogen (in particular Methanocorpusculum), Ruminococcaceae, and Clostridiaceae populations and increases in Bacteroidaceae and Porphyromonadaceae populations, which essentially agreed with quantitative real-time polymerase chain reaction (qPCR) assay results. These data indicate that direct addition of ginkgo fruit to cattle excreta is useful for reducing methane emissions by altering the microbial community structure. The application of ginkgo fruit to lower methane emissions from cattle excreta is, therefore, useful in cases in which the excreta is left without special management for a long period of time., (© 2021 Japanese Society of Animal Science.)

Although the use of corticosteroids is not recommended in the World Health Organization statement for the treatment of coronavirus disease 2019 (COVID-19), steroid therapy may be indicated for critical cases in specific situations. Here, we report the successful treatment of 11 cases of severe COVID-19 pneumonia with favipiravir and methylprednisolone. All cases were severe and patients required oxygen administration or had a blood oxygen saturation ≤93% on room air. All were treated with favipiravir and methylprednisolone, and 10 of 11 patients responded well and required no further oxygen supplementation or ventilator management. This study shows the importance of the early-stage use of a combination of favipiravir and methylprednisolone in severe cases to achieve a favorable clinical outcome., Competing Interests: Conflict of Interest None of the authors have any real or perceived conflicts of interest to declare regarding the subject of this manuscript., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by deteriorated exocrine gland function with associated lymphocytic infiltration. However, there are few pathological studies on bronchial glands in SS. In this study, we aimed to clarify pathological features of bronchial glands in SS., Methods: We retrospectively evaluated infiltration of lymphocytes in the bronchial glands incidentally collected by transbronchial lung cryobiopsy (TBLC), which were performed for the diagnosis of diffuse lung diseases. The degrees of lymphocyte infiltration in the bronchial glands were classified into four grades (grade 0-3). We compared the degrees of infiltration of SS with those of other diffuse lung diseases., Results: TBLC for diagnosis of diffuse lung diseases were performed on 432 cases during the study period. The samples of 50 cases included bronchial glands. Of those, 20 cases were excluded due to insufficient size or influence of therapy. The remaining 30 cases included 17 of idiopathic interstitial pneumonias, 5 of chronic hypersensitivity pneumonia, 6 of connective tissue disease (SS; n = 4, systemic sclerosis; n = 1, dermatomyositis; n = 1) and 2 of other diseases. In SS, infiltration of lymphocytes was observed in all cases; grade 1 in one, grade 2 in one, and grade 3 in two cases. In contrast, 11 of 26 in other diseases showed no lymphocytes infiltration, with the remaining 15 of grade 1 infiltration. Grade 2 or more infiltration were found only in SS but not in other diseases., Conclusion: Our results suggested that high-grade lymphocytic infiltration of bronchial glands is a distinct characteristics in SS.

A new cyclopropanation reaction of allyl phosphates with lithium phosphides has been developed to give cyclopropylphosphines through the formation of both a C-P bond and a cyclopropane ring at the same time, and high selectivity toward cyclopropanation over allylic substitution has been realized by conducting the reaction in the presence of HMPA.

A three-component synthesis of multisubstituted fluorene derivatives has been developed by devising a rhodium-catalyzed stitching reaction/remote nucleophilic substitution sequence. A variety of nucleophiles can be installed in the second step including both heteroatom and carbon nucleophiles. An efficient synthesis of 5 H -benzo[ a ]fluoren-5-ones has also been realized using N -(2-alkynyl)benzoylpyrrole as the reaction partner through a new reaction pathway.

A new and efficient synthesis of 8H-benzo[e]phenanthro[1,10-bc]silines from 2-((2-(arylethynyl)aryl)silyl)aryl triflates under palladium catalysis has been developed. The reaction mechanism was experimentally investigated and a catalytic cycle involving C-H/C-H coupling through a new mode of 1,4-palladium migration with concomitant alkene stereoisomerization is proposed., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A convergent synthetic method for the synthesis of fluorene derivatives has been developed by devising a rhodium-catalyzed stitching reaction/alkene isomerization sequence. The reactions proceed smoothly under mild conditions for a variety of substrate combinations, and extended π-conjugation systems are also readily accessible by utilizing this synthetic method. Optical properties of the obtained fluorene derivatives have also been examined., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A polycyclic zwitterion, azoniadibenzo[a,j]phenalenide, having a singlet biradical character, was synthesized and isolated for the first time. The negative charge was found to be delocalized over the periphery of the main core of the zwitterion and the positive charge was localized near the nitrogen atom. Its singlet biradical character was confirmed by a small HOMO-LUMO energy gap with their spatial overlap, and observation of thermally excited triplet species together with DFT calculations., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new mode of polymerization, rhodium-catalyzed stitching polymerization, has been developed for the synthesis of π-conjugated polymers with bridged repeating units from nonconjugated 1,5-hexadiynes containing both terminal and internal alkyne moieties as monomers. The polymerization proceeded smoothly with a high degree of stitching efficiency under mild conditions, and 1,5,9-decatriyne and 1,5,9,13-tetradecatetrayne monomers could also be employed. The present polymerization strategy would be particularly beneficial for the synthesis of polymers consisting of a repeating unit that is difficult to prepare as a stable monomer because it does not require the use of a preformed bridged π-conjugated monomer., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Current clinical practice guidelines for idiopathic pulmonary fibrosis (IPF) conditionally recommend use of pirfenidone and nintedanib. However, an optimal treatment sequence has not been established, and the data of treatment sequence from pirfenidone to nintedanib are limited. This study aimed to evaluate safety, tolerability and efficacy of nintedanib switched from pirfenidone in patients with IPF., Methods: Thirty consecutive IPF cases, which discontinued pirfenidone because of a decline in forced vital capacity (FVC) or intolerable adverse event (AE), and newly started nintedanib (150 mg twice daily) from September 2015 to August 2017 (switch-group) were retrospectively reviewed. Subsequently, we compared the characteristics, treatment status, and AEs between the switch-group and other 64 IPF patients newly started nintedanib during the same period without any prior anti-fibrotic treatment (pirfenidone-naïve group)., Results: In the switch group, median age, body weight, body mass index (BMI), and %FVC were 72 years old, 54.9 kg, 21.0 kg/m 2 , and 52.9%, respectively. Most common AE of nintedanib was aspartate aminotransferase/alanine aminotransferase elevation (71.9%), followed by anorexia (46.7%) and diarrhea (46.7%); whereas, anorexia (63.3%) and ≥ 5% weight loss from baseline (56.7%) were common during pirfenidone administration. Sixteen patients (53.3%) discontinued nintedanib within 6 months (early termination). Multivariate logistic regression analysis revealed a significant association between low BMI and early nintedanib termination in the switch-group (p = 0.0239). Nintedanib suppressed FVC decline as compared with that during administration period of pirfenidone in 70% of the patients who could undergo lung function before and after switching to nintedanib. The incidence of early termination of nintedanib was higher in the switch-group than in the pirfenidone-naïve group, whereas body-weight, BMI, absolute FVC values, and %FVC were significantly lower in the switch-group (just before nintedanib initiation) than in the pirfenidone-naïve group. Nintedanib-induced anorexia was more frequent and severer in the switch-group than in the pirfenidone-naïve group, but no significant differences were observed in terms of other AEs., Conclusions: A high incidence of early termination of nintedanib was noted when patients were switched from pirfenidone. Anorexia and weight loss during prior pirfenidone administration may increase the rate of the early termination of subsequent nintedanib treatment.

An efficient synthesis of 1,3-dialkylidene-2,3-dihydro-1 H-benzo[ c]siloles, a new type of silicon-bridged π-conjugated compounds, was developed from a simple substrate combination of dialkynylsilanes and arylboronic acids under rhodium catalysis through the use of 1,4-rhodium migration. The reaction pathway was probed by deuterium-labeling experiments, and the use of o-tolylboronic acids led to the formation of 6-membered silacycles via 1,5-rhodium migration.

Various carbonyl-bridged dibenzofulvalenes were synthesized by a sequence of rhodium-catalyzed stitching reaction and post-functionalization, and their optical and electronic properties could be tuned by changing the terminal substituents. The present stitching reaction also allowed for facile synthesis of dibenzofulvalenes having C, Si, Ge, S, and P as the bridging elements.

Theoretical investigations were carried out to elucidate the origin of chemoselectivity in the palladium-catalyzed reactions of 2-(dimethylphenylsilyl)phenyl triflates with or without an amino group at the 3-position. The selective formation of a 5,10-dihydrophenazasiline rather than a dibenzosilole from the substrate with an amino group at the 3-position could be successfully explained by proposing a new 1,5-palladium migration pathway that involves a neutral diorganopalladium(II) intermediate along with the subsequent formation of a low-energy amine-coordinated palladacycle intermediate prior to the C-N bond-forming process., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Little has been reported on long-term pulmonary function trends among patients with interstitial lung disease associated with anti-aminoacyl-tRNA synthetase antibodies (ARS-ILD)., Objectives: To clarify the factors predictive of progression in ARS-ILD based on patients' initial clinical and radiological features., Methods: The clinical courses of 88 patients with > 1 year of follow-up data on pulmonary function tests (PFTs) were retrospectively analyzed. Disease behavior was categorized into three groups: (1) improved or (2) worsened (defined as increases or decreases, respectively, of > 10% in forced vital capacity and > 15% in %diffusing capacity of lung carbon monoxide) or (3) stable based on PFT changes compared between 1-year results as the initial data and results at 3 years to assess the long-term course., Results: In the initial course of 75 patients with ARS-ILD who received anti-inflammatory therapy within 6 months after diagnosis, 48 patients (64.0%) improved and 6 patients (8.0%) worsened. The radiological patterns in the patients with ARS-ILD included nonspecific interstitial pneumonia (NSIP) in 46.7% and NSIP with organizing pneumonia overlap in 52.0% of the cases. One-third of the initially improved patients who worsened over the long-term course were assigned to the unstable group. By multivariate logistic analysis, middle lobe traction bronchiectasis was a significant predictive factor for the patients in the unstable group., Conclusions: Most patients with ARS-ILD receiving anti-inflammatory therapy had improved or remained stable in the first year. However, over the long-term course, some patients worsened despite their initial improvement. Even though the extent of the disease is limited, middle lobe traction bronchiectasis in ARS-ILD may be a useful predictor of poor long-term disease behavior., (© 2018 S. Karger AG, Basel.)

A palladium-catalyzed asymmetric synthesis of silicon-stereogenic 5,10-dihydrophenazasilines was developed that proceeds via an unprecedented enantioselective 1,5-palladium migration. High enantioselectivity was achieved by employing 4,4'-bis(trimethylsilyl) (R)-Binap as the chiral ligand, and a series of mechanistic investigations were carried out to probe the catalytic cycle of this process., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

New quinoidal fused oligosiloles containing an even number of silole units have been synthesized by a rhodium-catalyzed stitching reaction. Employing [RhCl(tfb)] 2 as the catalyst significantly improved the stitching efficiency, and up to six siloles could be fused in quinoidal form. A systematic comparison of the physical properties of Si1-Si6' confirmed the unique trend in their LUMO levels, which become higher with longer π conjugation. To understand the origin of this unusual trend, theoretical calculations were also carried out using various model compounds, and the results indicated that the terminal indenylidene (cyclopentadienylidene) moieties in Si1-Si6 (Si1a-Si6a) are primarily responsible for this phenomenon through their frontier orbital correlations with the HOMO of the central polyene unit, which becomes higher in energy with longer π conjugation.

A convergent and regioselective synthesis of silicon-bridged 4-arylpyridines has been developed through a rhodium-catalyzed [2+2+2] cycloaddition of silicon-containing diynes with nitriles. The absorption and emission properties of these compounds have been examined and could be tuned by varying the substituent on the benzene ring, as well as through the protonation or alkylation of the nitrogen atom on the pyridine ring. A catalytic asymmetric synthesis of silicon-centered axially chiral spirocyclic derivatives has also been achieved with high enantioselectivity by using a newly modified MeO-MOP (MeO-MOP=2-(diphenylphosphino)-2'-methoxy-1,1'-binaphthyl) derivative as the chiral ligand. These spirocyclic compounds were found to be CPL-active (CPL=circularly polarized luminescence), representing the first CPL-active compounds based on the chirality at silicon., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A rhodium-catalysed stitching reaction between 2-(silylethynyl)arylboronates and 2-(silylethynyl)aryl bromides has been developed for the synthesis of unsymmetric dibenzo[ a , e ]pentalenes. The introduction of appropriately sized silyl groups on the starting substrates led to a high crossover selectivity without using an excess amount of either substrate. The present stitching reaction could produce a variety of unsymmetric dibenzo[ a , e ]pentalene derivatives, including those with electronically different substituents on the fused benzene rings as well as heteroarene fused compounds. Desilylative halogenation was also demonstrated to synthesise the corresponding halogenated dibenzo[ a , e ]pentalenes, which can be used as building blocks for further chemical transformations.