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This post-marketing surveillance (PMS) was initiated in Japan to identify factors affecting the safety and effectiveness of pembrolizumab monotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death ligand-1 (PD-L1) expression. This PMS was conducted from December 2016 to June 2019 at 717 centers across Japan. Patients with unresectable advanced/recurrent NSCLC who received pembrolizumab monotherapy as first-line (1L) treatment for PD-L1-expressing tumors (Tumor Proportion Score [TPS] ≥ 50%) or second-line or later (2L+) treatment for tumors with PD-L1 TPS ≥ 1% were enrolled and followed up for 1 year. Of 2805 registered patients, 2740 and 2400 comprised the safety and effectiveness analysis sets, respectively. The median age (range) was 69 (27-92) years; 55.7% and 29.2% of patients experienced treatment-related adverse events and adverse events of special interest (AEOSIs), respectively. More common AEOSIs included interstitial lung disease, endocrine disorders, liver dysfunction, colitis/severe diarrhea, infusion reactions, and severe skin disorders. The frequency of experiencing ≥2 AEOSIs was low (1L, 6.5%; 2L+, 2.8%). Most AEOSIs occurred within 150 days after initiation of pembrolizumab monotherapy. At 1-year follow-up, the objective response rate was 39.2% (1L, 51.5%; 2L+, 30.0%). In conclusion, the 1-year safety and effectiveness of pembrolizumab monotherapy in patients with unresectable advanced/recurrent NSCLC as 1L treatment for tumors with PD-L1 TPS ≥ 50% and 2L+ treatment for tumors with PD-L1 TPS ≥ 1% were similar to those reported in phase 2/3 trials.

Cutaneous electrogastrography (EGG) is used in clinical and physiological fields to noninvasively measure the electrical activity of the stomach and intestines. Dipole models that mathematically express the electrical field characteristics generated by the stomach and intestines have been developed to investigate the relationship between the electrical control activity (ECA) (slow waves) shown in EGG and the internal gastric electrical activity. However, these models require a mathematical description of the movement of an annular band of dipoles, which limits the shape that can be modeled. In this study, we propose a novel polygonally meshed dipole model to conveniently reproduce ECA based on the movement of the annular band in complex shapes, such as the shape of the stomach and intestines, constructed in three-dimensional (3D) space. We show that the proposed model can reproduce ECA simulation results similar to those obtained using conventional models. Moreover, we show that the proposed model can reproduce the ECA produced by a complex geometrical shape, such as the shape of the intestines. The study results indicate that ECA simulations can be conducted based on structures that more closely resemble real organs than those used in conventional dipole models, with which, because of their intrinsic construction, it would be difficult to include realistic complex shapes, using the mathematical description of the movement of an annular band of dipoles. Our findings provide a powerful new approach for computer simulations based on the electric dipole model.

The multistate redox-active/multi-interactive ligand 5,5',8,8'-tetra(4-pyridyl)-2,2'-(1,4-phenylene)bis-1H-perimidine (H2 TPP) was designed and synthesized. H2 TPP undergoes four one-electron oxidation steps, and was used for the preparation of a multistate redox-active coordination network in a solid-liquid interface reaction using molten Cd2+ salts. The multiple redox states of H2 TPP were confirmed spectroscopically by stepwise four-electron oxidation. Spectroscopic analysis indicated that the mixed-valence states of the ligand are class II on the UV/Vis/NIR timescale and borderline class II/class III on the ESR timescale.

Rational engineering and assimilation of diverse chemo- and biocatalytic functionalities in a single nanostructure is highly desired for efficient multistep chemical reactions but has so far remained elusive. Here, we design and synthesize multimodal catalytic nanoreactors (MCNRs) based on a mesoporous metal-organic framework (MOF). The MCNRs consist of customizable metal nanocrystals and stably anchored enzymes in the mesopores, as well as coordinatively unsaturated cationic metal MOF nodes, all within a single nanoreactor space. The highly intimate and diverse catalytic mesoporous microenvironments and facile accessibility to the active site in the MCNR enables the cooperative and synergistic participation from different chemo- and biocatalytic components. This was shown by one-pot multistep cascade reactions involving a heterogeneous catalytic nitroaldol reaction followed by a [Pd/lipase]-catalyzed chemoenzymatic dynamic kinetic resolution to yield optically pure (>99 % ee) nitroalcohol derivatives in quantitative yields.

A neutral mononuclear Fe(III) complex [Fe(III) (H-5-Br-thsa-Me)(5-Br-thsa-Me)]⋅H2 O (1; H2 -5-Br-thsa-Me=5-bromosalicylaldehyde methylthiosemicarbazone) was prepared that exhibited a three-step spin-crossover (SCO) with symmetry breaking and a 14 K hysteresis loop owing to strong cooperativity. Two ordered intermediate states of 1 were observed, 4HS-2LS and 2HS-4LS, which exhibited reentrant phase-transition behavior. This study provides a new platform for examining multistability in SCO complexes.

A [2+2] cycloaddition reaction has been observed in a number of solids. The cyclobutane ring in a photodimerized material can be cleaved into olefins by UV light and heat. The high thermal stability of the metal-organic salt K2SDC (H2SDC = 4,4'-stilbenedicarboxylic acid) has been successfully utilized to investigate the reversible cleavage of a cyclobutane ring. The two polymorphs of K2SDC undergo reversible cyclobutane formation by UV light and cleavage by heat in cycles. Of these, one polymorph retains its single-crystal nature during the reversible processes. Polymorphs are known to show different physical properties and chemical reactivities. This work reveals that the retention of single-crystal nature is strongly associated with the packing of molecules, which is controlled by kinetics and thermodynamics. The photoemissive nature of the products makes this as a promising material for photoswitches and optical data storage devices.

A net gain: A kinetically assembled, but thermally stable network is obtained using the labile metal species [Cu4 I4 (PPh3 )4 ]. The network uniquely adsorbs I2 by chemisorption through I3 (-) formation. The chemisorbed I2 readily desorbs above 380 K owing to the dynamic motion of the framework. A thermodynamically assembled network physisorbs I2 , which is an exact fit for the channel.

This study was undertaken to determine the educational benefits of mannequin simulation for performance of tube thoracostomy in a porcine model by medical students. Thirty medical students were randomized into two groups; the first performed tube thoracostomy on a mannequin simulator and then a porcine model; the second used only the porcine model. Performance measures included completion of subtasks, time to perform the procedure, a global score assigned by faculty raters, and a self-evaluation survey. Subtask completion rate was similar in both groups ( P > 0.05). Mean time to perform the procedure was 9.8 minutes (±0.9, simulator), and 9.3 minutes (± 1.0, nonsimulator, P > 0.05). Global scores were 12.3 (±1.3, simulator) and 11.0 (±1.4, non-simulator, P > 0.05). Self-evaluation of confidence (1= “very”, 7= “not at all”) showed the simulator group was significantly more confident (3.4 ± 0.42) than the nonsimulator group (4.7 ± 0.49, P < 0.05). All students met basic competencies to perform tube thoracostomy. The simulator group felt significantly more confident to subsequently perform the procedure on a patient, whereas performance was not statistically significantly different for the two groups. Further trials may be needed to delineate the optimal role for these simulators in teaching tube thoracostomy.

Introduction Aromatic stacking of π-conjugated planar molecules leads to the exhibition of unique chemical and physical properties. Discotic liquid crystals are, for example, columnar assembly of aromatic compounds with long alkyl chains. Organic electroconductive materials involve alternative charge-transfer stacking of electron-donating and -accepting π-conjugated compounds. Whereas such infinite assemblies have been thoroughly studied, precisely controlled discrete assemblies composed of more than two π-conjugated molecules are much less explored. Here we report the self-assembly of a metalhinged organic-pillared cage 1 with a large cavity which can accommodate two large π-conjugated molecules. The cage consists of two large organic panels 2, three rod-like pillars 3, and six metal-hinges 4 (Figure1a). The large box-shaped cavity accommodates π-conjugated molecules in limited numbers.

慢性閉塞性肺疾患急性増悪の治療法には,薬物療法,酸素療法,侵襲的人工呼吸療法及び非侵襲的人工呼吸療法がある.その中で,非侵襲的人工呼吸療法の非侵襲的陽圧換気法(NIPPV: noninvasive positive pressure ventilation)は,気管内挿管を行わずに陽圧換気が可能であり,近年世界的に普及してきている.このNIPPVの適応と注意点,及び具体的施行手順について解説した.

Recent molecular studies on the Rh blood group system have shown that the Rh locus of each haploid RhD-positive chromosome is composed of two structural genes: RHD and RHCE, whereas the locus is made of a single gene (RHCE) on each haploid RhD-negative chromosome. We analyzed the presence or absence of the RHD gene in 130 Japanese RhD-negative donors using the PCR method. The RhD-negative phenotypes consisted of 34 ccEe, 27 ccee, 17 ccEE, 26 Ccee, 19 CcEe, 1 CcEE, and 6 CCee. Among them, 36 (27.7%) donors demonstrated the presence of the RHD gene. Others showed gross or partial deletions of the RHD gene. These results were confirmed by Southern blot analysis. Additionally, the RHD gene detected in the RhD-negative donors seemed to be intact through sequencing of the RhD polypeptide cDNA and the promoter region of RHD gene. The phenotypes of these donors with the RHD gene were CC or Cc, but not cc. It suggested that there is some relationship between the RHD gene and the RhC phenotypes in RhD-negative individuals. In Caucasian RhD-negative individuals, the RHD gene has not been found outside of the report of Hyland et al. (Hyland, C.A., L.C. Wolter, and A. Saul. 1994. Blood. 84:321-324). The discrepant data on the RHD gene in RhD-negative donors between Japanese and Caucasians appear to be derived from the difference of the frequency of RhD-negative and RhC-positive phenotypes. Careful attention is necessary for clinicians in applying RhD genotyping to clinical medicine.

Porous coordination networks are materials that maintain their crystal structure as molecular "guests" enter and exit their pores. They are of great research interest with applications in areas such as catalysis, gas adsorption, proton conductivity, and drug release. As with zeolite preparation, the kinetic states in coordination network preparation play a crucial role in determining the final products. Controlling the kinetic state during self-assembly of coordination networks is a fundamental aspect of developing further functionalization of this class of materials. However, unlike for zeolites, there are few structural studies reporting the kinetic products made during self-assembly of coordination networks. Synthetic routes that produce the necessary selectivity are complex. The structural knowledge obtained from X-ray crystallography has been crucial for developing rational strategies for design of organic-inorganic hybrid networks. However, despite the explosive progress in the solid-state study of coordination networks during the last 15 years, researchers still do not understand many chemical reaction processes because of the difficulties in growing single crystals suitable for X-ray diffraction: Fast precipitation can lead to kinetic (metastable) products, but in microcrystalline form, unsuitable for single crystal X-ray analysis. X-ray powder diffraction (XRPD) routinely is used to check phase purity, crystallinity, and to monitor the stability of frameworks upon guest removal/inclusion under various conditions, but rarely is used for structure elucidation. Recent advances in structure determination of microcrystalline solids from ab initio XRPD have allowed three-dimensional structure determination when single crystals are not available. Thus, ab initio XRPD structure determination is becoming a powerful method for structure determination of microcrystalline solids, including porous coordination networks. Because of the great interest across scientific disciplines in coordination networks, especially porous coordination networks, the ability to determine crystal structures when the crystals are not suitable for single crystal X-ray analysis is of paramount importance. In this Account, we report the potential of kinetic control to synthesize new coordination networks and we describe ab initio XRPD structure determination to characterize these networks' crystal structures. We describe our recent work on selective instant synthesis to yield kinetically controlled porous coordination networks. We demonstrate that instant synthesis can selectively produce metastable networks that are not possible to synthesize by conventional solution chemistry. Using kinetic products, we provide mechanistic insights into thermally induced (573-723 K) (i.e., annealing method) structural transformations in porous coordination networks as well as examples of guest exchange/inclusion reactions. Finally, we describe a memory effect that allows the transfer of structural information from kinetic precursor structures to thermally stable structures through amorphous intermediate phases. We believe that ab initio XRPD structure determination will soon be used to investigate chemical processes that lead intrinsically to microcrystalline solids, which up to now have not been fully understood due to the unavailability of single crystals. For example, only recently have researchers used single-crystal X-ray diffraction to elucidate crystal-to-crystal chemical reactions taking place in the crystalline scaffold of coordination networks. The potential of ab initio X-ray powder diffraction analysis goes beyond single-crystal-to-single-crystal processes, potentially allowing members of this field to study intriguing in situ reactions, such as reactions within pores.

Crystalline networks containing empty cavities can host a variety of molecules but also promote reactions between guests. Through robust crystallinity and a pseudo-solution state (dynamic movements) within their pores, these crystalline molecular flasks enable the direct observation of species — including unstable intermediates — during a reaction by in situ X-ray diffraction.

Many crystal structures of porous coordination networks have been solved by single-crystal X-ray crystallography, providing detailed molecular structural information on framework, guest arrangement, and even reactive intermediates generated in situ. Such detailed structural analysis facilitated the explosive development of porous coordination networks in the last 15 years. On the other hand, although there are many examples of ab initio powder X-ray diffraction (PXRD) analysis of inorganic materials, organic solids, nonporous coordination networks, and discrete small molecules, there are only few reports of ab initio PXRD analysis of porous coordination networks describing guest behavior (guest exchange, gas adsorption, etc.). This is because ab initio PXRD analysis is considerably more challenging than singlecrystal structure determination. Porous coordination networks usually have large unit cells and often low symmetry that contribute to severe peak overlap which hampers accurate structure determination. By using high-resolution synchrotron PXRD and the simulating annealing method, we have now succeeded in solving the crystal structure of a biporous coordination network having an unprecedented arrangement of tetrathiafulvalene (TTF) molecules and a unit cell larger than 15000 . The PXRD analysis revealed very short intermolecular S···S contacts between TTF molecules (3.370 ) that have a nonplanar shape indicating a neutral form. Those findings agree with solid-state spectroscopic features. A key issue in inducing intriguing physical properties in TTF is how to arrange the molecules. We tried to achieve a unique arrangement of TTF molecules by using the pores of a porous coordination network. We used the previously reported network [(ZnI2)3(1)2(2)]n·xC6H5NO2·yCH3OH (3, where 1 is 2,4,6-tris(4-pyridyl)-1,3,5-triazine (TPT) and 2 is triphenylene; x 4 and y 2) and prepared new isostructural ZnBr2 network 4 (Scheme 1) by instant synthesis. [3b]

Seven crystal structures of arylazides, 2-azidobiphenyl (2), 4-(4-azidophenyl)butanoic acid (3), 3-azidobenzoic acid (4), N-(4-azidophenyl)acetamide (5), 2,4,6-trichlorophenyl azide (6), 2,5-dibromophenyl azide (7) and 2,4,6-tribromophenyl azide (8), have been analyzed by X-rays. When the crystals were irradiated with UV light at ≃ 80 K, only 2-azidobiphenyl gradually changed its cell dimensions with the retention of the single-crystal form. The crystal structure after photo-irradiation was analyzed by X-rays under the same conditions as those before photo-irradiation. Approximately 20% of the 2-azidobiphenyl molecule was converted to the triplet 2-biphenylnitrene and dinitrogen molecules. The existence of the triplet nitrene was confirmed by ESR and IR measurements. Although the structure of dinitrogen was clearly determined, the nitrene structure was obscure because the nitrene produced was almost superimposed on the original 2-azidobiphenyl. The other six crystals were non-reactive or easily broken when they were exposed to UV light. The different reactivity between 2-azidobiphenyl and the other compounds was successfully explained by the reaction cavity of the azido group.

1The pore channels facilitate increased mobility and rapid diffusion of included guest molecules. Large organic molecules can readily enter into the pores via guest exchange. In this sense, the pore interior is a pseudo-solution state where chemical reactions may proceed as in a solution, yet can be directly analyzed by crystallography. Here, we show that single-crystal-tosingle-crystal chemical reactions with large, common reagents proceed quite smoothly inside the pores of the network. Taking advantage of the network’s robust crystallinity, we succeeded in the acylation and ureidation of aromatic amines and imine formation from aromatic aldehydes within a single crystal. The pores of the network complexes thus serve as “single crystalline molecular flasks”. 2 In related studies, we have reported the preliminary results of the diffusion of aldehydes into the pores of porous networks to form imine. 3

Introduction Long alkyl chains have a tendency to aggregate and form localized hydrophobic environments in polar solvent. This tendency has been exploited to prepare a variety of artificial structures, such as micelles, vesicles, core-shell structured polymers, and dendrimers, where the localized hydrophobic environments show interesting properties. These artificial long alkyl chain assemblies, as well as biomembranes, are typically structurally dispersed. The structural disparities result in a distribution of properties. Here we report discrete and well-defined assemblies of alkyl chains confined in a 5 nm spherical coordination shell (Fig. 1). The shell framework quantitatively assembles from 12 Pd ions and 24 bent ligands and sharply defines the boundary of the interior hydrophobic phase of long alkyl chains. Furthermore, the nature of hydrophobic interior can be easily tuned by varying length of the alkyl chains.

The intermolecular exchange coupling 2J for the light-induced radical pair in a crystal of 2,2'-di(ortho-chlorophenyl)-4,4',5,5'-tetraphenylbiimidazole (o-Cl-HABI) was measured for the first time on the basis of Curie analyses of the EPR spectral intensities. The coupling constant evaluated from density functional theory calculations compares well with the experimental value. The picture shows the distribution of spin density for the radical pair.