Emergent elastic fields induced by topological phase transitions: Impact of molecular chirality and steric anisotropy.

SignificanceChirality, the property of an object that cannot be superimposed on its mirror image, plays an essential role in condensed matter, such as magnetic, electronic, and liquid crystal systems. Topological phases emerge in such chiral materials, wherein helical and vortex-like structures-called skyrmions-are observed. However, the role of elastic fields in these topological phases remains unexplored. Here, we construct a molecular model of two-dimensional crystals incorporating steric anisotropy and chiral interactions to elucidate this problem. The coupling between the elastic fields and phase transitions between uniform, helical, and half-skyrmion phases can be utilized to switch these topological phases by external forces. Our results provide a fundamental physical principle for designing topological materials using chiral molecular and colloidal crystals.

Functional roles of CD26/DPP4 in lipopolysaccharide-induced lung injury.

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells. In LPS-induced lung injury, inflammatory responses [bronchoalveolar lavage fluid (BALF) neutrophil numbers and several proinflammatory cytokine levels] were attenuated in Dpp4 knockout (Dpp4 KO) mice. However, multiple assays of alveolar capillary permeability were similar between the Dpp4 KO and wild-type mice. TNF-α and IL-6 production was suppressed in alveolar macrophages isolated from Dpp4 KO mice. In contrast, in cultured mouse lung microvascular endothelial cells (MLMVECs), reduction in CD26/DPP4 expression by siRNA resulted in greater ICAM-1 and IL-6 expression after LPS stimulation. Moreover, the LPS-induced vascular monolayer permeability in vitro was higher in MLMVECs treated with Dpp4 siRNA, suggesting that CD26/DPP4 plays a protective role in endothelial barrier function. In summary, this study demonstrated that genetic deficiency of Dpp4 attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential functional roles of CD26/DPP4 expression in resident cellular components of the lung. CD26/DPP4 may be a potential therapeutic target for ARDS and warrants further exploration to precisely identify the multiple functional effects of CD26/DPP4 in ARDS pathophysiology.NEW & NOTEWORTHY We aimed to clarify the functional roles of CD26/DPP4 in ARDS pathophysiology using Dpp4-deficient mice and siRNA reduction techniques in cultured lung cells. Our results suggest that CD26/DPP4 expression plays a proinflammatory role in alveolar macrophages while also playing a protective role in the endothelial barrier. Dpp4 genetic deficiency attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential roles of CD26/DPP4 expression in the resident cellular components of the lung.

Scale Separation of Shear-Induced Criticality in Glasses.

In a sheared steady state, glasses reach a nonequilibrium criticality called yielding criticality. We report that the qualitative nature of this nonequilibrium critical phenomenon depends on the details of the system and that responses and fluctuations are governed by different critical correlation lengths in specific situations. This scale separation of critical lengths arises when the screening of elastic propagation of mechanical signals is not negligible. We also discuss the determinant of the impact of screening effects from the viewpoint of the microscopic dissipation mechanism.

Franseen needle in endobronchial ultrasound-guided transbronchial needle aspiration: a phase II prospective study.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been used to diagnose and stage lung cancer. Acquire™ Pulmonary and Expect™ Pulmonary dedicated EBUS-TBNA needles were introduced as the Franseen and Lancet needles, respectively. It is still unclear whether the Franseen or Lancet needles yield a higher quality specimen especially focusing on next-generation sequencing-based molecular testing. METHODS: A single-center, prospective study performed at the Chiba University Hospital randomly assigned patients to two groups: Group A, wherein the first and second EBUS-TBNA were performed using Lancet and Franseen needles, respectively, and Group B, wherein the first and second EBUS-TBNA were performed using Franseen and Lancet needles, respectively. Each specimen was compared and analyzed pathologically. The primary outcome was the histological tissue area except blood clot and the cellularity of each sample. We also examined the success rate of molecular testing. RESULTS: Twelve patients who underwent EBUS-TBNA between November 2022 and February 2023 were enrolled in this study. The tissue area of the specimens obtained by the Franseen and Lancet needles was 13.3 ± 6.4 mm2 and 10.6 ± 6.3 mm2, respectively (P = .355). The tumor cellularity in the specimens obtained using the Franseen and Lancet needles was 54.0 ± 30.3 and 46.2 ± 36.3%, respectively (P = .608). The success rate of molecular testing using the single-pass sample by Franseen needle was 85.7 and 57.1% by Lancet needle. No serious complications were reported. CONCLUSIONS: The Franseen needle tended to show a greater amount of specimen with higher tumor cellularity than the Lancet needle which may contribute higher success rate of molecular testing. Further studies must be conducted to validate the results of this study. KEY FINDINGS: What is known and what is new?  What is the implication, and what should change now?

Utility of interferon-gamma releasing assay for the diagnosis of active tuberculosis in children: A systematic review and meta-analysis.

INTRODUCTION: The accurate diagnosis of tuberculosis (TB) in children is essential for its effective management and control. Reliable diagnostic tools that are currently available for identifying TB infection include the in vivo tuberculosis skin test (TST) and ex vivo interferon-gamma release assays (IGRAs). This systematic review and meta-analysis aimed to evaluate the diagnostic accuracy of IGRAs in children. METHODS: Of the 768 screened studies, 47 met the eligibility criteria. Data from 9065 patients, including 1086 (12.0 %) with confirmed TB, were included in the analysis. The overall quality of the included studies, assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, was unclear. RESULTS: The calculated pooled sensitivity and specificity of IGRAs in children were 0.85 (95 % confidence interval [CI]: 0.79-0.89) and 0.94 (95 % CI: 0.88-0.97), respectively. Subpopulation analysis revealed that the sensitivities and specificities were as follows: QuantiFERON tests: 0.83 (95 % CI: 0.74-0.89) and 0.93 (95 % CI: 0.87-0.96), T-SPOT: 0.87 (95 % CI: 0.79-0.91) and 0.99 (95 % CI: 0.85-1.00), IGRAs in children under 15 years: 0.77 (95 % CI: 0.43-0.94) and 0.96 (95 % CI: 0.84-0.97), and IGRAs in children under 5 years: 0.85 (95 % CI: 0.52-0.97) and 0.94 (95 % CI: 0.90-0.99), respectively. CONCLUSIONS: This study demonstrated that the sensitivity and specificity of the IGRAs in children were moderate and high, respectively. Therefore, the IGRAs may be useful for detecting TB infection in children. CLINICAL TRIAL REGISTRATION: The review protocol was prospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000046737).

Effects of Anti-Fibrotic Drugs on Transcriptome of Peripheral Blood Mononuclear Cells in Idiopathic Pulmonary Fibrosis.

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between "patients with IPF and healthy controls" and "before and after anti-fibrotic treatment" were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-ß/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.

Functional Roles of CD26/DPP4 in Bleomycin-Induced Pulmonary Hypertension Associated with Interstitial Lung Disease.

Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). Dpp4 knockout (Dpp4KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in Dpp4KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in Dpp4KO mice was milder than that in WT mice. The viability of TGFß-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the DPP4 knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFß treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, DPP4 knockdown in hPASMCs inhibited the pathways upregulated by TGFß treatment. These results suggest that genetic deficiency of Dpp4 protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFß-related pathways in PASMCs.

Different Transcriptome Features of Peripheral Blood Mononuclear Cells in Non-Emphysematous Chronic Obstructive Pulmonary Disease.

Non-emphysematous chronic obstructive pulmonary disease (COPD), which is defined based on chest computed tomography findings, presented different transcriptome features of peripheral blood mononuclear cells (PBMCs) compared with emphysematous COPD. Enrichment analysis of transcriptomic data in COPD demonstrated that the "Hematopoietic cell lineage" pathway in Kyoto Encyclopedia of Genes and Genomes pathway analysis was highly upregulated, suggesting that cellular dynamic dysregulation in COPD lungs is affected by pathologically modified PBMCs. The differentially expressed genes (DEGs) upregulated in PBMCs reflected the disease state of non-emphysematous COPD. Upregulated DEGs such as XCL1, PRKCZ, TMEM102, CD200R1, and AQP1 activate T lymphocytes and eosinophils. Upregulating keratan sulfate biosynthesis and metabolic processes is associated with protection against the destruction of the distal airways. ITGA3 upregulation augments interactions with extracellular matrix proteins, and COL6A1 augments the profibrotic mast cell phenotype during alveolar collagen VI deposition. Upregulating HSPG2, PDGFRB, and PAK4 contributes to the thickening of the airway wall, and upregulating SERPINF1 expression explains the better-preserved vascular bed. Therefore, gene expression and pathway analysis in PBMCs in patients with non-emphysematous COPD represented type 2 immune responses and airway remodeling features. Therefore, these patients have asthmatic potential despite no clinical signs of asthma, in contrast to those with emphysematous COPD.

Physicochemical properties of wooden breast-extracted myosin and rheological properties of its heat-induced gel.

BACKGROUND: It is reported that broilers with 'wooden breast' have poor processing properties, such as low binding and water-holding capacities. However, the reason for the poor functional characteristics has not been clarified. In this study, myosin was extracted from a wooden breast. Its physicochemical properties were investigated to clarify the relationship between the structure and physicochemical properties of the heating gel of myosin obtained from the wooden breast. RESULTS: The turbidity of myosin solution extracted from wooden breast increased with increase in the heat treatment to a higher value than that from the normal breast meat myosin. The solubility of myosin collected from a wooden breast after heating decreased like normal breast muscle myosin. The surface hydrophobicity of myosin removed from wooden breast increased continually above 60 °C, unlike the change in surface hydrophobicity of normal breast myosin. The free thiol group of myosin extracted from the wooden breast was higher than normal breast myosin before and after heating. The apparent elasticity of heat-induced gels and chicken meat sausages was significantly lower in sausages and gel with wooden breast than normal ones (P < 0.05). The microstructure of the heated gel of normal myosin showed a fine network structure. In contrast, the heat-induced gel of wooden breast-extracted myosin showed a structure with loosely connected aggregates and many gaps. CONCLUSION: The coarseness of the internal gel structure of myosin extracted from wooden breast was shown to affect the apparent elasticity of the gel and sausages made from the chicken meat. © 2023 Society of Chemical Industry.

Aging or DEAD: Origin of the non-monotonic response to weak self-propulsion in active glasses.

Among amorphous states, glass is defined by relaxation times longer than the observation time. This nonergodic nature makes the understanding of glassy systems an involved topic, with complex aging effects or responses to further out-of-equilibrium external drivings. In this respect, active glasses made of self-propelled particles have recently emerged as a stimulating systems, which broadens and challenges our current understanding of glasses by considering novel internal out-of-equilibrium degrees of freedom. In previous experimental studies we have shown that in the ergodicity broken phase, the dynamics of dense passive particles first slows down as particles are made slightly active, before speeding up at larger activity. Here, we show that this nonmonotonic behavior also emerges in simulations of soft active Brownian particles and explore its cause. We refute that the deadlock by emergence of active directionality model we proposed earlier describes our data. However, we demonstrate that the nonmonotonic response is due to activity enhanced aging and thus confirm the link with ergodicity breaking. Beyond self-propelled systems, our results suggest that aging in active glasses is not fully understood.

Adverse events during intrahospital transport of critically ill patients: A systematic review and meta-analysis.

INTRODUCTION: Intrahospital transport of critically ill patients is often necessary for diagnostic procedures, therapeutic procedures, or admission to the intensive care unit. The aim of this study was to investigate and describe safety and adverse events during intrahospital transport of critically ill patients. MATERIAL AND METHODS: A systematic search was performed of MEDLINE and the Cochrane Central Register of Controlled Trials for studies published up to June 3, 2020, and of the International Clinical Trials Platform Search Portal and ClinicalTrials.gov for ongoing trials. We selected prospective and retrospective cohort studies published in English on intrahospital transport of critically ill patients, and then performed a meta-analysis. The primary outcome was the incidence of all adverse events that occurred during intrahospital transport. The secondary outcomes were death due to intrahospital transport or life-threatening adverse events, minor events in vital signs, adverse events related to equipment, durations of ICU and hospital stay, and costs. RESULTS: A total of 12,313 intrahospital transports and 1898 patients from 24 studies were included in the meta-analysis. Among 24 studies that evaluated the primary outcome, the pooled frequency of all adverse events was 26.2% (95% CI: 15.0-39.2) and the heterogeneity among these studies was high (I2 = 99.5%). The pooled frequency of death due to intrahospital transport and life-threatening adverse events was 0% and 1.47% each, but heterogeneity was also high. CONCLUSIONS: Our findings suggest that adverse events can occur during intrahospital transport of critically ill patients, and that the frequency of critical adverse events is relatively low. The results of this meta-analysis could assist in risk-benefit analysis of diagnostic or therapeutic procedures requiring intrahospital transport of critically ill patients. TRIAL REGISTRATION: UMIN000040963.

Mitochondrial characteristics of chicken breast muscle affected by wooden breast.

The growth rate of broiler chickens has increased by 400% over the past 50 years, and breast yields continue to increase. This has led to an increase in thoracic muscle abnormalities in broilers, with wooden breast becoming a major issue worldwide. The etiology and the mechanism underlying the etiology of wooden breasts have not yet been elucidated; however, it occurs due to oxidative stress. Reactive oxygen species, which cause oxidative stress, are mainly produced in mitochondria. Thus, in this study, we investigated the relationship between the severity of wooden breast in broilers and the characteristics of mitochondria as the source of reactive oxygen species. Sampling of the pectoralis major muscle at the ventral cranial position was conducted in 50-day-old broilers. The severity of wooden breast was classified into three groups based on the muscle fiber roundness and wing-wing contact test, with highest severity in severe wooden breast and lowest severity in normal breast. Nicotinamide adenine dinucleotide tetrazolium reductase staining revealed an increase in darkly stained muscle fibers, indicating high severity of wooden breast. The mitochondria were swollen in severe wooden breast cases, with highest swelling in severe wooden breast and lowest swelling in normal breast. The expression levels of the mitochondrial antioxidant enzyme genes superoxide dismutase 1 and superoxide dismutase 2 were significantly lower in wooden breast-severe tissue than in normal tissue. These results suggest that when the levels of reactive oxygen species in muscle fibers, which should be constant, are increased, mitochondrial homeostasis is not maintained and the damage levels increase in various membranes of the cell, leading to the disruption of normal physiological functions.

Geometrical properties of mechanically annealed systems near the jamming transition.

Geometrical properties of two-dimensional mixtures near the jamming transition point are numerically investigated using harmonic particles under mechanical training. The configurations generated by the quasi-static compression and oscillatory shear deformations exhibit anomalous suppression of the density fluctuations, known as hyperuniformity, below and above the jamming transition. For the jammed system trained by compression above the transition point, the hyperuniformity exponent increases. For the system below the transition point under oscillatory shear, the hyperuniformity exponent also increases until the shear amplitude reaches the threshold value. The threshold value matches with the transition point from the point-reversible phase where the particles experience no collision to the loop-reversible phase where the particles' displacements are non-affine during a shear cycle before coming back to an original position. The results demonstrated in this paper are explained in terms of neither of universal criticality of the jamming transition nor the nonequilibrium phase transitions.

Modified albumin-bilirubin grade to predict eligibility for second-line therapies at progression on sorafenib therapy in hepatocellular carcinoma patients.

BACKGROUND: Our aim is to evaluate the utility of liver function measured by modified albumin-bilirubin (mALBI) grade to predict eligibility for second-line therapies, including regorafenib and ramucirumab therapy, at initiation of sorafenib therapy for patients with hepatocellular carcinoma (HCC). METHODS: Participants in this retrospective, single-center study comprised 197 patients with sorafenib-treated HCC, Child-Pugh scores (CPs) 5-7 and performance status 0-1 treated between October 2009 and June 2019. The factors at initiation of sorafenib therapy, including mALBI grade and CPs, were analyzed with regard to second-line eligibility, regorafenib eligibility and ramucirumab eligibility, respectively. RESULTS: Proportions of eligibility for second-line therapies, regorafenib therapy and ramucirumab therapy were 48.7%, 35.5% and 18.3%. Modified ALBI grades 1 and 2a were contributing factors for second-line eligibility (odd ratios [OR] 16.7 and 5.6; 95% CI 6.5-43.3 and 2.6-12.2), regorafenib therapy (OR 13.9 and 6.9; 95% CI 5.6-34.4 and 2.9-16.2), and ramucirumab therapy (OR 9.5 and 4.8; 95% CI 2.9-30.8 and 1.6-14.4), with grade 2b defined as reference. Patients with mALBI grade 1 and CPs 5 exhibited especially high proportion of eligibility for regorafenib therapy (70.5%). In patients with mALBI grade 2b, those with CPs 5 displayed higher proportion of eligibility for second-line therapy and ramucirumab therapy (100% and 50%) than those with CPs 6 (31.8% and 11.4%). CONCLUSIONS: Modified ALBI grade in combination with CPs at the initiation of sorafenib therapy would be useful to predict eligibility for second-line therapies.

Real-time 400 Gbps/carrier WDM transmission over 2,000†km of field-installed G.654.E fiber.

We combine erbium-doped fiber amplifier (EDFA) and backward distributed Raman amplifier (DRA) to achieve the real-time wavelength division multiplexing (WDM) transmission of 400 Gbps/carrier polarization division multiplexing (PDM) 16 quadrature amplitude modulation (QAM) signals over 2,000 km of terrestrial field-deployed cut-off shifted fiber (CSF) compliant with ITU-T G.654.E. This paper compares the transmission performance of 400 Gbps/carrier signals achieved in CSF and standard single-mode fiber (SMF). This transmission distance, 2,019 km, is, to the best of our knowledge, the longest in 400 Gbps/carrier WDM transmission field experiments using digital signal processing (DSP) application specific integrated circuit (ASIC) integrated real-time optical transponders with the technologies to compensate device imperfections; the backward DRA used is fully compliant with laser power safety requirements.

Degradation of group V secretory phospholipase A2 in lung endothelium is mediated by autophagy.

Group V secretory phospholipase A2 (gVPLA2) is a potent inflammatory mediator in mammalian tissues that hydrolyzes phospholipids and initiates eicosanoid biosynthesis. Previous work has demonstrated that multiple inflammatory stimuli induce its expression and secretion in several cell types, including the lung endothelium. However, little is known about the mechanism(s) by which gVPLA2 inflammatory signaling is subsequently downregulated. Therefore, in this study we characterized potential clearance mechanisms for gVPLA2 in lung endothelial cells (EC). We observed that exogenous gVPLA2 is taken up rapidly by nutrient-starved human pulmonary artery EC (HPAEC) in vitro, and its cellular expression subsequently is reduced over several hours. In parallel experiments performed in pulmonary vascular EC isolated from mice genetically deficient in gVPLA2, the degradation of exogenously applied gVPLA2 occurs in a qualitatively similar fashion. This degradation is significantly attenuated in EC treated with ammonium chloride or chloroquine, which are lysosomal inhibitors that block autophagic flux. In contrast, the proteasomal inhibitor MG132 fails to prevent the clearance of gVPLA2. Both immunofluorescence microscopy and proximity ligation assay demonstrate the co-localization of LC3 and gVPLA2 during this process, indicating the association of gVPLA2 with autophagosomes. Nutrient starvation, a known inducer of autophagy, is sufficient to stimulate gVPLA2 degradation. These results suggest that a lysosome-mediated autophagy pathway contributes to gVPLA2 clearance from lung EC. These novel observations advance our understanding of the mechanism by which this key inflammatory enzyme is downregulated in the lung vasculature.

Universal Relaxation Dynamics of Sphere Packings below Jamming.

We show that non-Brownian suspensions of repulsive spheres below jamming display a slow relaxational dynamics with a characteristic timescale that diverges at jamming. This slow timescale is fully encoded in the structure of the unjammed packing and can be readily measured via the vibrational density of states. We show that the corresponding dynamic critical exponent is the same for randomly generated and sheared packings. Our results show that a wide variety of physical situations, from suspension rheology to algorithmic studies of the jamming transition are controlled by a unique diverging timescale, with a universal critical exponent.

Glass Stability Changes the Nature of Yielding under Oscillatory Shear.

We perform molecular dynamics simulations to investigate the effect of a glass preparation on its yielding transition under oscillatory shear. We use swap Monte Carlo to investigate a broad range of glass stabilities from poorly annealed to highly stable systems. We observe a qualitative change in the nature of yielding, which evolves from ductile to brittle as glass stability increases. Our results disentangle the relative role of mechanical and thermal annealing on the mechanical properties of amorphous solids, which is relevant for various experimental situations from the rheology of soft materials to fatigue failure in metallic glasses.

Tolerability of nintedanib-related diarrhea in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Nintedanib is an important drug for the treatment of idiopathic pulmonary fibrosis (IPF). However, the drug is discontinued in some patients who present with diarrhea. In this study, we aimed to assess the drug continuation rate in patients who developed diarrhea during nintedanib therapy and to evaluate if antidiarrheal drugs or nintedanib dose reductions improved clinical tolerability and efficacy. METHODS: Eighty-six patients with IPF were treated in our institution between December 2015 and March 2018. Among them, 50 patients who experienced nintedanib-related diarrhea were analyzed regarding tolerability and persistence rate. RESULTS: In 50 patients who experienced nintedanib-related diarrhea, 26 (n = 11, without reduction and n = 15, with reduction) continuously received nintedanib. Meanwhile, the drug was discontinued in 24 patients (n = 13, without reduction and n = 11, with reduction). In 9 of 24 patients, the drug was discontinued due to diarrhea. The annual rate of decline in forced vital capacity and the duration of nintedanib administration were not significantly different between groups with and without dosage reduction. Moreover, 23, 13, 8, and 2 patients received 1, 2, 3, and 4 agents, respectively. Clostridium butyricum is a probiotic bacterium most commonly used as an antidiarrheal agent. In this study, it was used in 28 of 46 patients. The total durations of nintedanib administration differed significantly according to the number of antidiarrheal drugs taken: 853 ± 221 days, more than three agents; 424 ± 365 days, without an agent (p = 0.043); and 460 ± 142, one agent (p = 0.0003). CONCLUSIONS: When diarrhea occurs within a year after using nintedanib, the dose reduction may be acceptable without affecting pulmonary function. Moreover, treatment with multiple antidiarrheals may be a practical option to maintain the use of nintedanib therapy compared with monotherapy and no therapy.

Acoustic resonance in periodically sheared glass: damping due to plastic events.

Using molecular dynamics simulation, we study acoustic resonance in a low-temperature model glass by applying a small periodic shear at a boundary wall. Shear wave resonance occurs as the frequency ω approaches ωl = πc⊥l/L (l = 1, 2…). Here, c⊥ is the transverse sound speed and L is the cell width. At resonance, large-amplitude sound waves appear after many cycles even if the applied strain γ0 is very small. They then induce plastic events, which are heterogeneous on the mesoscopic scale and intermittent on timescales longer than the oscillation period tp = 2π/ω. We visualize them together with the extended elastic strains around them. These plastic events serve to damp sounds. We obtain the nonlinear damping Q-1 = tan δ due to the plastic events near the first resonance at ω ≅ ω1, which is linear in γ0 and independent of ω. After many resonant cycles, we observe an increase in the shear modulus (measured after switching-off the oscillation). We also observe catastrophic plastic events after a very long time (∼103tp), which induce system-size elastic strains and cause a transition from resonant to off-resonant states. At resonance, stroboscopic diffusion becomes detectable.