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Immune checkpoint inhibitors (ICIs) are the current standard of care for non-small-cell lung cancer (NSCLC). Myocarditis is a rare but serious immune-related adverse event (irAE) associated with ICI therapy. We present a patient who received a single dose of pembrolizumab for NSCLC and developed ICI-associated pneumonia. Although pneumonia improved with corticosteroid therapy, the patient subsequently developed ICI-associated fulminant myocarditis. Despite high-dose corticosteroid therapy, the patient died on day 30 after pembrolizumab initiation. Even if an observed irAE was effectively treated, clinicians should remain vigilant for other irAEs, especially those that are difficult to control with low-dose corticosteroids.
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Background: In its normal anatomical relationship, the inferior vena cava is located on the right side of the abdominal aorta. Iliac vein compression syndrome (IVCS) is a pathological condition in which a blood clot is formed due to blood flow obstruction when the left common iliac vein is compressed between the right common iliac artery and the vertebral body. Therefore, right-sided IVCS (RIVCS) is rare. The effectiveness of treatment for RIVCS has not been sufficiently investigated. Case summary: A 51-year-old man developed deep vein thrombosis in the right lower extremity and non-massive pulmonary embolism during steroid treatment for IgA nephropathy. Magnetic resonance angiography (MRA) suggested iliac compression syndrome. Symptoms improved with the use of direct oral anticoagulants and compression stockings. At the 8-month follow-up, the clinical course was uneventful. Discussion: The causes of RIVCS in this case are believed to be the effects of steroids, prolonged sitting, and compression of the right external iliac vein. However, considering that deep vein thrombosis did not form in the left lower limb where there was no venous compression, it can be considered that the compression of the right external iliac vein had a significant impact. This case has been followed up for 8 months with anticoagulants and is progressing well. This is the first case to report the course of RIVCS treated conservatively with anticoagulant therapy for 8 months. This case suggested that conservative treatment is effective for RIVCS.
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We herein report a 49-year-old woman who developed "happy heart syndrome" while watching a family theater performance. She was followed up with cardiac magnetic resonance imaging (CMR). The time course of the CMR findings was similar to that previously reported for Takotsubo cardiomyopathy (TTC), including the form of "broken heart syndrome." CMR findings for "happy heart syndrome" have not been sufficiently investigated. However, the CMR findings in this case suggest that "happy heart syndrome" and other conventional TTC including "broken heart syndrome" are clinically a single disease, at least from an imaging aspect.
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Corazón , Cardiomiopatía de Takotsubo , Femenino , Humanos , Persona de Mediana Edad , Cardiomiopatía de Takotsubo/diagnóstico por imagen , Imagen por Resonancia Magnética , SíndromeRESUMEN
Osteocytes form a cellular network by gap junctions between their cell processes. This network is important since intercellular communication via the network is essential for bone metabolism. However, the factors that influence the formation of this osteocyte network remain unknown. As the early stage of osteocyte network formation occurs on the bone surface, we observed a newly formed trabecular bone surface by orthogonal focused ion beam-scanning electron microscopy. The embedding late osteoblast processes tended to avoid bundled collagen fibrils and elongate into sparse collagen fibrils. Then, we examined whether the inhibition of bundling of collagen fibrils using a potent lysyl oxidase inhibitor, ß-aminopropionitrile (BAPN) changed the cellular network of the chick calvaria. The osteocyte shape of the control group was spindle-shape, while that of the BAPN group was sphere-shaped. In addition, the osteocyte processes of the control group were elongated vertically to the long axis of the cell body, whereas the osteocyte processes of the BAPN group were elongated radially. Therefore, it was suggested that the bundling of collagen fibrils influences normal osteocyte network formation during bone modeling.
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Aminopropionitrilo , Osteocitos , Osteocitos/metabolismo , Matriz Extracelular/metabolismo , Cráneo/metabolismo , Colágeno/metabolismoRESUMEN
A machine-learning-based beam optimizer has been implemented to maximize the spectral brightness of the X-ray free-electron laser (XFEL) pulses of SACLA. A new high-resolution single-shot inline spectrometer capable of resolving features of the order of a few electronvolts was employed to measure and evaluate XFEL pulse spectra. Compared with a simple pulse-energy-based optimization, the spectral width was narrowed by half and the spectral brightness was improved by a factor of 1.7. The optimizer significantly contributes to efficient machine tuning and improvement of XFEL performance at SACLA.
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BACKGROUND: The Cockcroft-Gault formula is commonly used as a substitute for glomerular filtration rate (GFR) in Calvert's formula for carboplatin dosing, where adjusting serum creatinine measured using the enzymatic method with 0.2 mg/dL has been suggested in Japan. However, the effects of these adjustments on efficacy in patients with non-small-cell lung cancer remain unknown. METHODS: We conducted a post hoc analysis of the PREDICT1 study (CJLSG1201), a multicenter prospective observational trial of carboplatin-pemetrexed. Glomerular filtration rate values in Calvert's formula were back-calculated from the administered dosages of carboplatin and the reported value of the target area under the curve. We estimated the serum creatinine adjustments and divided the patients into crude and adjusted groups. RESULTS: Patients in the crude group (N = 169) demonstrated similar efficacy to those in the adjusted group (N = 104) in progression-free survival (PFS) and overall survival (OS) (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.76-1.35; p = 0.916 vs. HR, 0.87; 95% CI, 0.65-1.17; p = 0.363), with higher grade 3-4 hematologic toxicity. Among patients aged ≥75 years, the crude group (N = 47) showed superior efficacy compared with the adjusted group (N = 17) in PFS and OS (HR, 0.37; 95% CI, 0.20-0.69; p = 0.002 vs. HR, 0.43; 95% CI, 0.23-0.82; p = 0.010). CONCLUSIONS: Serum creatinine adjustment may be associated with similar efficacy compared to the crude serum creatinine value. In older patients, the adjustment should be cautiously applied owing to the potential for reduced efficacy.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Anciano , Carboplatino , Neoplasias Pulmonares/tratamiento farmacológico , Creatinina/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resultado del Tratamiento , Tasa de Filtración GlomerularRESUMEN
Calcium phosphate forms particles under excessive urinary excretion of phosphate in the kidney. While the formation of calcium phosphate particles (CaPs) has been implicated in the damage to renal tubular cells and renal dysfunction, clarifying the ultrastructural information and the elemental composition of the small CaPs in the wide areas of kidney tissue has been technically difficult. This study introduces correlative and sequential light as well as electron microscopic CaP observation in the kidney tissue by combining fluorescent staining for CaPs and energy-dispersive X-ray spectroscopy (EDS) in scanning electron microscopy (SEM) on resin sections prepared using high-pressure freezing and freeze substitution. CaPs formed in mouse kidneys under long-term feeding of a high-phosphate diet were clearly visualized on resin sections by fluorescence-conjugated alendronate derivatives and toluidine blue metachromasia. These CaPs were verified by correlative observation with EDS. Furthermore, small CaPs formed in the kidney under short-term feeding were detected using fluorescent probes. The elemental composition of the particles, including calcium and magnesium, was identified following EDS analyses. These results suggest that the correlative microscopy approach is helpful for observing in situ distribution and elemental composition of CaPs in the kidney and contributing to studies regarding CaP formation-associated pathophysiology.
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Fosfatos de Calcio , Electrones , Ratones , Animales , Microscopía Electrónica de Rastreo , Fosfatos , Riñón , DietaRESUMEN
Crizotinib shows antitumor activity against C-ros oncogene 1-rearranged non-small-cell lung cancer (NSCLC). While corrected QT interval (QTc) prolongation and bradycardia are known as cardiac adverse effects, little is known about crizotinib-related heart failure. Our patient with C-ros oncogene 1-rearranged NSCLC on a reduced dose of crizotinib (200 mg twice daily) after initially experiencing bradycardia and QTc prolongation developed crizotinib-induced heart failure. With further dose reduction (250 mg once daily), there was no recurrence of any cardiac adverse effects, and the patient achieved a long-term response. Although crizotinib can cause heart failure, continuation of crizotinib at a low dose may be an effective treatment option.
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Carcinoma de Pulmón de Células no Pequeñas , Insuficiencia Cardíaca , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Crizotinib/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas Tirosina Quinasas , Bradicardia/inducido químicamente , Especies Reactivas de Oxígeno/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Reordenamiento Génico , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
X-ray free-electron lasers (XFELs) provide intense pulses that can generate stimulated X-ray emission, a phenomenon that has been observed and studied in materials ranging from neon to copper. Two schemes have been employed: amplified spontaneous emission (ASE) and seeded stimulated emission (SSE), where a second color XFEL pulse provides the seed. Both phenomena are currently explored for coherent X-ray laser sources and spectroscopy. Here, we report measurements of ASE and SSE of the 5.9 keV Mn Kα1 fluorescence line from a 3.9 molar NaMnO4 solution, pumped with 7 femtosecond FWHM XFEL pulses at 6.6 keV. We observed ASE at a pump pulse intensity of 1.7 × 1019 W/cm2, consistent with earlier findings. We observed SSE at dramatically reduced pump pulse intensities down to 1.1 × 1017 W/cm2. These intensities are well within the range of many existing XFEL instruments, which supports the experimental feasibility of SSE as a tool to generate coherent X-ray pulses, spectroscopic studies of transition metal complexes, and other applications.
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Transient structural changes of Al_{2}O_{3} on subatomic length scales following irradiation with an intense x-ray laser pulse (photon energy: 8.70 keV; pulse duration: 6 fs; fluence: 8×10^{2} J/cm^{2}) have been investigated by using an x-ray pump x-ray probe technique. The measurement reveals that aluminum and oxygen atoms remain in their original positions by â¼20 fs after the intensity maximum of the pump pulse, followed by directional atomic displacements at the fixed unit cell parameters. By comparing the experimental results and theoretical simulations, we interpret that electron excitation and relaxation triggered by the pump pulse modify the potential energy surface and drives the directional atomic displacements. Our results indicate that high-resolution x-ray structural analysis with the accuracy of 0.01 Å is feasible even with intense x-ray pulses by making the pulse duration shorter than the timescale needed to complete electron excitation and relaxation processes, which usually take up to a few tens of femtoseconds.
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The antagonism between global energy needs and the obligation to slow global warming is a current challenge. In order to ensure sufficient thermal comfort, the automotive, housing and agricultural building sectors are major energy consumers. Solar control materials and more particularly, selective glazing are part of the solutions proposed to reduce global energy consumption and tackle global warming. In this context, these works are focused on developing new highly ultraviolet (UV) and near-infrared (NIR) absorbent nanocomposite coatings based on K4[{Nb6-xTaxXi12}Xa6]. (X = Cl, Br, 0 ≤ x ≤ 6) transition metal cluster compounds. These compounds contain cluster-based active species that are characterized by their strong absorption of UV and NIR radiations as well as their good transparency in the visible range, which makes them particularly attractive for window applications. Their integration, by solution processes, into a silica-polyethylene glycol or polyvinylpyrrolidone matrices is discussed. Of particular interest is the control and the tuning of their optical properties during the integration and shaping processes. The properties of the solutions and films were investigated by complementary techniques (UV-Vis-NIR spectrometry, ESI-MS, SEM, HRTEM, etc.). Results of these works have led to the development of versatile solar control coatings whose optical properties are competitive with commercialized material.
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A simple spectrometer using diffraction from diamond microcrystals has been developed to diagnose single-shot spectra of X-ray free-electron laser (XFEL) pulses. The large grain size and uniform lattice constant of the adopted crystals enable characterizing the XFEL spectrum at a resolution of a few eV from the peak shape of the powder diffraction profile. This single-shot spectrometer has been installed at beamline 3 of SACLA and is used for daily machine tuning.
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INTRODUCTION: Osteocytes play a role as mechanosensory cells by sensing flow-induced mechanical stimuli applied on their cell processes. High-resolution imaging of osteocyte processes and the canalicular wall are necessary for the analysis of this mechanosensing mechanism. Focused ion beam-scanning electron microscopy (FIB-SEM) enabled the visualization of the structure at the nanometer scale with thousands of serial-section SEM images. We applied machine learning for the automatic semantic segmentation of osteocyte processes and canalicular wall and performed a morphometric analysis using three-dimensionally reconstructed images. MATERIALS AND METHODS: Six-week-old-mice femur were used. Osteocyte processes and canaliculi were observed at a resolution of 2 nm/voxel in a 4 × 4 µm region with 2000 serial-section SEM images. Machine learning was used for automatic semantic segmentation of the osteocyte processes and canaliculi from serial-section SEM images. The results of semantic segmentation were evaluated using the dice similarity coefficient (DSC). The segmented data were reconstructed to create three-dimensional images and a morphological analysis was performed. RESULTS: The DSC was > 83%. Using the segmented data, a three-dimensional image of approximately 3.5 µm in length was reconstructed. The morphometric analysis revealed that the median osteocyte process diameter was 73.8 ± 18.0 nm, and the median pericellular fluid space around the osteocyte process was 40.0 ± 17.5 nm. CONCLUSION: We used machine learning for the semantic segmentation of osteocyte processes and canalicular wall for the first time, and performed a morphological analysis using three-dimensionally reconstructed images.
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Imagenología Tridimensional , Aprendizaje Automático , Osteocitos , Animales , Fémur/diagnóstico por imagen , Ratones , SemánticaRESUMEN
The exoskeleton of the pinching side of claws with denticles and of the outer side without them on the coconut crab, Birgus latro, which is a rare organism, were studied using a materials science approach. The mechanical resistance of three claws of different sizes was investigated along the exoskeleton thickness from the outer surface to the inner surface, and the results were compared, including the contribution of the microstructure and chemical compositions. Mechanical properties, hardness (H) and stiffness (Er), were probed through nanoindentation tests. The results showed the H, Er, microstructures, and chemical components of the exocuticle and endocuticle layers were almost the same, in a BW range of 300 g to 1650 g. At the same time, the H and Er near the surface of the denticles of a small coconut crab of 300 g were lower than those of other large coconut crabs. The microstructure of the denticles was clearly different from that of the exocuticle, but the maximum mechanical properties near their surface indicated almost the same values, Hmax = 4 GPa and Er(max) = 70 GPa, regardless of being on the pinching side or the outer side. A denticle can be regarded as a bulge of the cuticle without phosphorus and with high magnesium. The results provided novel information that expanded our knowledge about the claw microstructure of coconut crabs with different body sizes, and may be used in further studies.
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The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.
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Fosfatos de Calcio/metabolismo , Túbulos Renales/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Líquidos Corporales/química , Fosfatos de Calcio/química , Línea Celular , Cristalización , Dieta Occidental/efectos adversos , Progresión de la Enfermedad , Endocitosis , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Homeostasis , Humanos , Túbulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfatos/administración & dosificación , Fosfatos/efectos adversos , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/patología , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
BACKGROUND: Enterococcus casseliflavus is rarely isolated from human specimens. To the best of our knowledge, there are no reports on its detailed treatment course and prognosis. Here, we present the first known case of E. casseliflavus endocarditis with a detailed treatment course. CASE PRESENTATION: An 86-year-old Japanese woman was transferred to the emergency department with dyspnoea, wheezing, and lumbago. Her medical history included hypertension, chronic kidney disease, idiopathic interstitial pneumonia, and rectal carcinoma. Physical examination revealed expiratory wheezes and a diastolic murmur (Levine 2/6) at the 4th right sternal border. Chest radiography revealed bilateral interstitial opacities and slight cardiac dilatation. Transthoracic echocardiography demonstrated the presence of mobile vegetation with perforation, prolapse, and regurgitation of the aortic valve. With a suspicion of infective endocarditis, we started administering intravenous ampicillin/sulbactam. Thereafter, blood cultures identified E. casseliflavus through matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry. The antimicrobial treatment was then switched to ampicillin plus gentamicin. The patient underwent aortic valve replacement on the thirteenth hospital day. She was administered intravenous ampicillin and gentamicin for 6 weeks. The patient was discharged 8 weeks after admission. CONCLUSIONS: Our case demonstrated that E. casseliflavus could cause infective endocarditis, which can be successfully treated with a 6-week regimen of ampicillin and gentamicin in combination with proper surgical treatment.
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Endocarditis Bacteriana/diagnóstico , Enterococcus/aislamiento & purificación , Anciano de 80 o más Años , Ampicilina/uso terapéutico , Antibacterianos/uso terapéutico , Válvula Aórtica/patología , Quimioterapia Combinada , Ecocardiografía , Endocarditis Bacteriana/microbiología , Femenino , Gentamicinas/uso terapéutico , Prótesis Valvulares Cardíacas/efectos adversos , Humanos , Tórax/diagnóstico por imagenRESUMEN
Ultrafast changes of charge density distribution in diamond after irradiation with an intense x-ray pulse (photon energy, 7.8 keV; pulse duration, 6 fs; intensity, 3×10^{19} W/cm^{2}) have been visualized with the x-ray pump-x-ray probe technique. The measurement reveals that covalent bonds in diamond are broken and the electron distribution around each atom becomes almost isotropic within â¼5 fs after the intensity maximum of the x-ray pump pulse. The 15 fs time delay observed between the bond breaking and atomic disordering indicates nonisothermality of electron and lattice subsystems on this timescale. From these observations and simulation results, we interpret that the x-ray-induced change of the interatomic potential drives the ultrafast atomic disordering underway to the following nonthermal melting.
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A superconducting joint of unreacted monofilament internal magnesium diffusion-processed magnesium diboride (MgB2) wires was fabricated by exploiting the phenomenon of magnesium diffusion into the boron layer inside the superconducting joint. Unprecedentedly, the joint was able to carry an almost identical transport current compared to the bare wire in a 2-7 T magnetic field at 20 K. The joint also exhibited very low joint resistance of 2.01 × 10-13 Ω in self-field at 20 K. Among commercially available superconductors, this work is the first to successfully realize a superconducting joint that is capable of transferring current from one conductor to another without any notable degradation under strong magnetic fields. This work demonstrates great potential to apply MgB2 in a range of practical applications, where superconducting joints are essential.
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Carbon monoxide diffusion capacity (DLCO) is impaired in heart failure patients; however, its clinical impact has not been well investigated in the left ventricular assist device (LVAD) population. We explored the predictive value of preoperative DLCO in the survival and cardiac readmission rates after LVAD implantation. Seventy-six patients who received continuous-flow LVAD as bridge-to-transplant therapy from November 2007 to September 2018 and underwent pulmonary function test before LVAD implantation were included. The primary study endpoints were death and readmission for heart failure or arrhythmia (cardiac readmission). Patients were stratified into two groups according to the percent of predicted DLCO (%DLCO). Pulmonary vascular resistance (PVR) was equivocal between the groups preoperatively, whereas the low DLCO group (%DLCO < 80%) showed significantly high PVR postoperatively. The mortality rate was not different between the groups. The 2 year cardiac readmission rate was 33.5% in the low DLCO group and 8.7% in the high DLCO group (%DLCO ≥ 80%) (P = 0.028). The %DLCO was associated with cardiac readmission in univariate and multivariate analyses (hazard ratio: 4.32; 95% CI: 1.50-15.9; P = 0.005). Low %DLCO was associated with high PVR postoperatively and was a risk factor for cardiac readmission after LVAD implantation.
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Insuficiencia Cardíaca , Corazón Auxiliar , Monóxido de Carbono , Insuficiencia Cardíaca/cirugía , Corazón Auxiliar/efectos adversos , Humanos , Japón/epidemiología , Readmisión del Paciente , Pruebas de Función Respiratoria , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
A simple scheme is proposed and experimentally confirmed to generate X-ray free-electron lasers (XFELs) consisting of broadband and narrowband beams with a controllable intensity ratio and a large photon-energy separation. This unique two-color XFEL beam will open new opportunities for investigation of nonlinear interactions between intense X-rays and matter.