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Abstract Background Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. Case presentation A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid–Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte–macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. Conclusions This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.

Background: Human norovirus is a predominant etiological agent responsible for acute gastroenteritis across all age groups. Recently, norovirus recombinant strains have been reported as the cause of norovirus outbreaks in several settings and the strains that cause outbreaks mostly belong to the norovirus GII. However, yet, the norovirus GI recombinant strains have never been reported previously in Thailand. The aims of this study were to investigate the genetic recombination and genotype diversity of norovirus GI strains in children hospitalized with acute gastroenteritis in Chiang Mai, Thailand during a period of seven years from 2015 to 2021. Methods: A total of 2829 stool specimens were screened for norovirus GI by real-time PCR, and the polymerase and capsid genes were sequenced and analyzed. Results: Of 2829 specimens tested, 12 (0.4%) were positive for norovirus GI. Of these, 7 out of 12 (58.3%) strains were identified as norovirus GI recombinant strains. Among 7 norovirus GI recombinant strains, 3, 3, and 1 were identified as GI.3[P13], GI.5[P4], and GI.6[P11], respectively. The remaining five strains were identified as non-recombinant strains of the GI.4[P4], GI.5[P5], and GI.6[P6] genotypes. Conclusions: The findings highlight the genetic diversity and multiple intergenotype recombinant strains of norovirus GI circulating in children with acute gastroenteritis in Chiang Mai, Thailand from 2015 to 2021. The detection of multiple intergenotype norovirus GI recombinant strains further underscore the complexity of norovirus GI strains circulating in this region.

ABSTRACT Background Although transbronchial lung cryobiopsy (TBLC) is widely used in diagnostic algorithms for various interstitial lung diseases (ILDs), its real‐world utility in the therapeutic decision‐making strategy for ILD patients remains unclear, in particular, when judging the time to start antifibrotic agents. Methods We analyzed medical records of 40 consecutive patients with idiopathic or fibrotic hypersensitivity pneumonitis who underwent TBLC. A TBLC‐based usual interstitial pneumonia (UIP) score was used to assess three morphologic descriptors: patchy fibrosis, fibroblastic foci, and honeycombing. Results In our 40 patients with ILD, the most frequent radiological feature was indeterminate for UIP (45.0%). Final diagnosis included idiopathic pulmonary fibrosis (22.5%), fibrotic nonspecific interstitial pneumonia (5.0%), fibrotic hypersensitivity pneumonitis (35.0%), and unclassifiable ILD (37.5%). Linear mixed‐effects analysis showed that declines in the slopes of %FVC and %DLCO in patients with TBLC‐based UIP “Score ≥ 2” were significantly steeper than those of patients with “Score ≤ 1.” During follow‐up of patients with Score ≥ 2 (n = 24), more than half of them (n = 17) received an antifibrotic agent, with most patients (n = 13) receiving early administration of the antifibrotic agent within 6 months after the TBLC procedure. Conclusions TBLC‐based UIP Score ≥ 2 indicated the increased possibility of a progressive fibrosis course that may prove helpful in predicting progressive pulmonary fibrosis/progressive fibrosing ILD even if disease is temporarily stabilized due to anti‐inflammatory agents. Patients may benefit from early introduction of antifibrotic agents by treating clinicians.

This paper proposes a novel proper orthogonal decomposition method for constructing a reduced-order model. This model effectively computes solutions for various initial conditions in time-dependent partial differential equations. The mode obtained from the proposed proper orthogonal decomposition captures both the fluctuating component and the mean-field of the time-dependent solution. In this mode, the eigenvalues representing the mean-field, are significantly larger than those representing the fluctuating component. Consequently, determining the number of modes required for representing a solution cannot rely solely on the cumulative contribution rate. Therefore, the proposed method gives a scalar weight to the mean-field and controls the magnitude of the mean-field energy. We propose a method that considers the magnitude of the scaler weight alongside the cumulative contribution ratio for determining the number of modes. This method was evaluated using the time-dependent Burgers equation with parametric initial values. Our proposed method selects the appropriate mode to represent the given dataset, unlike the conventional method. A reduced-order model based on the proposed method effectively computes the time evolutions of the solutions using datasets for several parameters by imposing a condition that the cumulative contribution ratio exceeds 98%.

Abstract Background Although vaccination is recommended for protection against invasive pneumococcal disease, the frequency of pneumococcal pneumonia is still high worldwide. In fact, no vaccines are effective for all pneumococcal serotypes. Fusion pneumococcal surface protein A (PspA) has been shown to induce a broad range of cross-reactivity with clinical isolates and afford cross-protection against pneumococcal challenge in mice. Furthermore, we developed prime-boost-type mucosal vaccines that induce both antigen-specific IgG in serum and antigen-specific IgA in targeted mucosal organs in previous studies. We investigated whether our prime-boost-type immunization with a fusion PspA was effective against pneumococcal infection in mice and cynomolgus macaques. Methods C57BL/6 mice were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan. Six weeks later, PspA was administered intranasally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some mice were given intranasal Streptococcus pneumoniae and the severity of infection was analyzed. Macaques were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan at week 0 and week 4. Then, 13 or 41 weeks later, PspA was administered intratracheally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some macaques were intranasally administered S. pneumoniae and analyzed for the severity of pneumonia. Results Serum samples from mice and macaques injected with antigens in combination with CpG oligodeoxynucleotides and/or curdlan contained antigen-specific IgG. Bronchial samples contained antigen-specific IgA after the fusion PspA boosting. This immunization regimen effectively prevented S. pneumoniae infection. Conclusions Prime-boost-type immunization with a fusion PspA prevented S. pneumoniae infection in mice and macaques.

Abstract Background Para‐tracheal or para‐carinal air cysts (PACs) are often asymptomatic and usually detected incidentally by methods such as computed tomography. Their clinical significance is unclear in patients with pleuroparenchymal fibroelastosis (PPFE). Methods We evaluated the clinical significance of PACs in PPFE and their relationship with pneumomediastinum or pneumothorax. Results In total, 50 patients had PPFE and 34 (68%) had PACs. Most PACs were para‐carinal (n = 30). A para‐tracheal air cyst was detected in only nine patients, which included five patients having both para‐carinal and para‐tracheal air cysts. Overall median survival was 24.7 months. Survival was not significantly different between the patients with [PACs(+)] and without PACs (P = 0.268). A high frequency (64%) of the complication of pneumomediastinum or pneumothorax occurred in the overall population during follow‐up. Pneumomediastinum/pneumothorax occurred significantly more frequently in patients with PACs(+) than in those without (76.5% vs. 37.5%; P = 0.012). PACs(+) was the only significant risk factor for pneumomediastinum/pneumothorax. Conclusions Our data showed that PACs commonly occur in patients with PPFE, and most PACs were para‐carinal air cysts. Additionally, PACs(+) was a significant risk factor for pneumomediastinum/pneumothorax; therefore, clinicians should be more aware of these complications during follow‐up examination, particular in PACs(+) patients with PPFE.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe acute respiratory symptoms in humans. Controlling the coronavirus disease pandemic is a worldwide priority. The number of SARS-CoV-2 studies has dramatically increased, and the requirement for analytical tools is higher than ever. Here, we propose monolayered-intestinal epithelial cells (IECs) derived from human induced pluripotent stem cells (iPSCs) instead of three-dimensional cultured intestinal organoids as a suitable tool to study SARS-CoV-2 infection. Differentiated IEC monolayers express high levels of angiotensin-converting enzyme 2 and transmembrane protease serine 2 (TMPRSS2), host factors essential for SARS-CoV-2 infection. SARS-CoV-2 efficiently grows in IEC monolayers. Using this propagation system, we confirm that TMPRSS2 inhibition blocked SARS-CoV-2 infection in IECs. Hence, our iPSC-derived IEC monolayers are suitable for SARS-CoV-2 research under physiologically relevant conditions.

Abstract Background Some patients with connective tissue disease (CTD)-associated interstitial lung disease (ILD) progress to pulmonary fibrosis over their disease course despite initial improvement, potentially indicating a poor prognosis. Transbronchial lung cryobiopsy (TBLC) is a new bioptic approach used in diffuse parenchymal lung diseases. This study of CTD-ILD assessed the utility of TBLC in determining therapeutic decision-making strategies. Methods We analyzed medical records of 31 consecutive CTD-ILD patients who underwent TBLC focusing on radio-pathological correlation and disease course. A TBLC-based usual interstitial pneumonia (UIP) score was used that assessed three morphologic descriptors: i) patchy fibrosis, ii) fibroblastic foci, and iii) honeycombing. Results Among the patients with CTD-ILD, 3 had rheumatoid arthritis, 2 systemic sclerosis, 5 polymyositis/dermatomyositis, 8 anti-synthetase syndrome, 6 Sjögren’s syndrome, and 5 had microscopic polyangiitis. Pulmonary function test results showed a mean %FVC of 82.4% and %DLCO of 67.7%. Among the 10 CTD patients and TBLC-proven pathological UIP, 3 patients had prominent inflammatory cells in addition to a framework of UIP, and pulmonary function of most patients improved with anti-inflammatory agents. Six (40%) of 15 patients with TBLC-based UIP score ≥ 1 had a progressive disease course during follow-up, of whom 4 patients received anti-fibrotic agents. Conclusions TBLC in patients with CTD-ILD can help determine an appropriate medication strategy, particularly when UIP-like lesions are present. TBLC may be useful when judging which agents to prioritize, anti-inflammatory or anti-fibrotic, is difficult. Moreover, additional information from TBLC may be beneficial when considering early intervention with anti-fibrotic agents in clinical practice.

Abstract Organoids are regarded as physiologically relevant cell models and useful for compound screening for drug development; however, their applications are currently limited because of the high cost of their culture. We previously succeeded in reducing the cost of human intestinal organoid culture using conditioned medium (CM) of L cells co-expressing Wnt3a, R-spondin1, and Noggin. Here, we further reduced the cost by replacing recombinant hepatocyte growth factor with CM. Moreover, we showed that embedding organoids in collagen gel, a more inexpensive matrix than Matrigel, maintains organoid proliferation and marker gene expression similarly when using Matrigel. The combination of these replacements also enabled the organoid-oriented monolayer cell culture. Furthermore, screening thousands of compounds using organoids expanded with the refined method identified several compounds with more selective cytotoxicity against organoid-derived cells than Caco-2 cells. The mechanism of action of one of these compounds, YC-1, was further elucidated. We showed that YC-1 induces apoptosis through the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, the mechanism of which was distinct from cell death caused by other hit compounds. Our cost-cutting methodology enables large-scale intestinal organoid culture and subsequent compound screening, which could expand the application of intestinal organoids in various research fields.

Quantum computers are expected to drastically accelerate certain computing tasks versus classical computers. Noisy intermediate-scale quantum (NISQ) devices, which have tens to hundreds of noisy physical qubits, are gradually becoming available, but it is still challenging to achieve useful quantum advantages in meaningful tasks. On the other hand, full fault-tolerant quantum computing (FTQC) based on quantum error correction code remains far beyond realization due to its extremely large requirement of high-precision physical qubits. In this study, we propose a quantum computing architecture to close the gap between NISQ and FTQC architectures. Our architecture is based on erroneous arbitrary rotation gates and error-corrected Clifford gates implemented by lattice surgery. We omit the typical distillation protocol to achieve direct analog rotations and small qubit requirements, and minimize the remnant errors of the rotations by a carefully designed state injection protocol. Our estimation based on numerical simulations shows that for early-FTQC devices that consist of 10^{4} physical qubits with physical error probability p=10^{−4}, we can perform roughly 1.72×10^{7} Clifford operations and 3.75×10^{4} arbitrary rotations on 64 logical qubits. Such computations cannot be realized by the existing NISQ and FTQC architectures on the same device, as well as classical computers. We hope that our proposal and the corresponding development of quantum algorithms based on it will bring new insights into the realization of practical quantum computers in the future.

Peyer’s patches (PPs) are specialized gut-associated lymphoid tissues that initiate follicular helper T (Tfh)-mediated immunoglobulin A (IgA) response to luminal antigens derived from commensal symbionts, pathobionts, and dietary sources. IgA-producing B cells migrate from PPs to the small intestinal lamina propria and secrete IgA across the epithelium, modulating the ecological balance of the commensal microbiota and neutralizing pathogenic microorganisms. α-glucosidase inhibitors (α-GIs) are antidiabetic drugs that inhibit carbohydrate digestion in the small intestinal epithelium, leading to alterations in the commensal microbiota composition and metabolic activity. The commensal microbiota and IgA responses exhibit bidirectional interactions that modulate intestinal homeostasis and immunity. However, the effect of α-GIs on the intestinal IgA response remains unclear. We investigated whether α-GIs affect IgA responses by administering voglibose and acarbose to mice via drinking water. We analyzed Tfh cells, germinal center (GC) B cells, and IgA-producing B cells in PPs by flow cytometry. We also assessed pathogen-specific IgA responses. We discovered that voglibose and acarbose induced Tfh cells, GCB cells, and IgA-producing B cells in the PPs of the proximal small intestine in mice. This effect was attributed to the modification of the microbiota rather than a shortage of monosaccharides. Furthermore, voglibose enhanced secretory IgA (S-IgA) production against attenuated Salmonella Typhimurium. Our findings reveal a novel mechanism by which α-GIs augment antigen-specific IgA responses by stimulating Tfh-GCB responses in PPs, and suggest a potential therapeutic application as an adjuvant for augmenting mucosal vaccines.

The current study proposes a multidimensional student athlete well-being framework (SAWBF). The authors used 12 items to capture SAWBF comprised of four well-being dimensions (i.e., physical, hedonic, psychological, and social well-being). To empirically assess the reliability and validity of the framework, data from elite collegiate student athletes in Japan (N = 546) were procured. The results indicated sufficient convergent and discriminant validities of SAWBF. The authors also assessed predictive validity correlations of the framework by focusing on the oft-supported well-being outcome–organizational citizenship behavior, which were also found to be associated with SAWBF. The findings indicated the usefulness of SAWBF; and coaches and staff members can utilize the framework to multi-dimensionally understand well-being status of their student athletes, potentially boosting adaptive behaviors.

Highly accurate quantum state transfer and remote entanglement between superconducting fixed-frequency qubits have not yet been realized. In this study, we calculate the characteristics of a transmission path with a 1- or 0.25 m superconducting coaxial cable and use the characteristics to perform time evolution simulations of quantum state transfer and remote entanglement between superconducting fixed-frequency qubits. We find that remote entanglement, or half-quantum state transfer, can achieve a high fidelity ${>}99\% $ even in the presence of a qubit frequency detuning caused by manufacturing fluctuations, while a small qubit frequency detuning substantially reduces the efficiency of quantum state transfer. Quantum circuit simulations modeling proposed remote entanglement demonstrate that teleportation of a logical qubit with a $3\; \times \;3$ surface code, as an example of computation using remote entanglement, attains nearly the same fidelity as in-node computation for both 1- and 0.25 m cable lengths.

Efficient decoding to estimate error locations from outcomes of syndrome measurements is the prerequisite for quantum error correction. Decoding in the presence of circuit-level noise including measurement errors should be considered in case of actual quantum computing devices. In this paper, we develop a decoder for circuit-level noise that solves the error estimation problems as Ising-type optimization problems. We confirm that the threshold theorem in the surface code under circuit-level noise is reproduced with an error threshold of approximately 0.4%. We also demonstrate the advantage of the decoder through which the Y error detection rate can be improved compared with other matching-based decoders. Our results reveal that a lower logical error rate can be obtained using our algorithm compared with that of the minimum-weight perfect matching algorithm.

Abstract The best available evidence and the predictive value of computed tomography (CT) findings for prognosis in patients with acute respiratory distress syndrome (ARDS) are unknown. We systematically searched three electronic databases (MEDLINE, CENTRAL, and ClinicalTrials.gov). A total of 410 patients from six observational studies were included in this systematic review. Of these, 143 patients (34.9%) died due to ARDS in short-term. As for CT grade, the CTs used ranged from 4- to 320-row. The index test included diffuse attenuations in one study, affected lung in one study, well-aerated lung region/predicted total lung capacity in one study, CT score in one study and high-resolution CT score in two studies. Considering the CT findings, pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 62% (95% confidence interval [CI] 30–88%), 76% (95% CI 57–89%), 2.58 (95% CI 2.05–2.73), 0.50 (95% CI 0.21–0.79), and 5.16 (95% CI 2.59–3.46), respectively. This systematic review revealed that there were major differences in the definitions of CT findings, and that the integration of CT findings might not be adequate for predicting short-term mortality in ARDS. Standardisation of CT findings and accumulation of further studies by CT with unified standards are warranted.

We propose a quantum error mitigation strategy for the variational quantum eigensolver (VQE) algorithm. We find, via numerical simulation, that very small amounts of coherent noise in VQE can cause substantially large errors that are difficult to suppress by conventional mitigation methods, and yet our proposed mitigation strategy is able to significantly reduce these errors. The proposed strategy is a combination of previously reported techniques, namely randomized compiling (RC) and zero-noise extrapolation (ZNE). Intuitively, randomized compiling turns coherent errors in the circuit into stochastic Pauli errors, which facilitates extrapolation to the zero-noise limit when evaluating the cost function. Our numerical simulation of VQE for small molecules shows that the proposed strategy can mitigate energy errors induced by various types of coherent noise by up to two orders of magnitude.

Sapoviruses, like noroviruses, are single-stranded positive-sense RNA viruses classified in the family Caliciviridae and are recognized as a causative pathogen of diarrhea in infants and the elderly. Like human norovirus, human sapovirus (HuSaV) has long been difficult to replicate in vitro. Recently, it has been reported that HuSaV can be replicated in vitro by using intestinal epithelial cells (IECs) derived from human tissues and cell lines derived from testicular and duodenal cancers. In this study, we report that multiple genotypes of HuSaV can sufficiently infect and replicate in human-induced pluripotent stem cell-derived IECs. We also show that this HuSaV replication system can be used to investigate the conditions for inactivation of HuSaV by heat and alcohol, and the effects of virus neutralization of antisera obtained by immunization with vaccine antigens, under conditions closer to the living environment. The results of this study confirm that HuSaV can also infect and replicate in human normal IECs regardless of their origin and are expected to contribute to future virological studies.

Abstract Background Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is often positive in patients with interstitial lung disease (ILD), which is also often present in patients with microscopic polyangiitis (MPA). A possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. The objective of this study was to determine whether high-resolution computed tomography (HRCT) classification based on recent idiopathic pulmonary fibrosis guideline and specific CT findings can obtain new knowledge of prognostic factors in all MPO-ANCA-positive patients with ILD including both idiopathic ILD and MPA-ILD. Methods We analyzed 101 consecutive MPO-ANCA-positive patients with respiratory disease. We assessed the diagnostic accuracy of CT findings, HRCT pattern, and specific radiological signs. Prognostic predictors were determined using Cox regression models. Results Subjects with chronic ILD included 22 patients with MPA-ILD and 39 patients with ILD but without MPA. A quarter of the patients were radiological indeterminate for usual interstitial pneumonia (UIP) pattern, which resulted in a better prognosis than that for UIP pattern. “Increased attenuation around honeycomb and traction bronchiectasis” and “anterior upper lobe honeycomb-like lesion” were found to be highly frequent radiological findings (39% and 30%, respectively). In addition, the latter finding was a significant negative prognostic factor. Conclusions Radiological indeterminate for UIP was a useful HRCT classification in MPO-ANCA-positive patients with ILD. In addition, anterior upper lobe honeycomb-like lesion was found to be specific radiological finding that was a significant prognostic factor. The present results might aid in the assessment of appropriate strategies of diagnosis in these patients.

Several bacteria in the gut microbiota have been associated with colorectal cancer (CRC) but it is not completely clear whether they have a role in tumourigenesis. Here, the authors show enrichment of 12 bacterial taxa in two cohorts of CRC patients and that two Porphyromonas species accelerate CRC onset through butyrate secretion.

Computation of the Green's function is crucial to study the properties of quantum many-body systems such as strongly correlated systems. Although the high-precision calculation of the Green's function is a notoriously challenging task on classical computers, the development of quantum computers may enable us to compute the Green's function with high accuracy even for classically-intractable large-scale systems. Here, we propose an efficient method to compute the real-time Green's function based on the local variational quantum compilation (LVQC) algorithm, which simulates the time evolution of a large-scale quantum system using a low-depth quantum circuit constructed through optimization on a smaller-size subsystem. Our method requires shallow quantum circuits to calculate the Green's function and can be utilized on both near-term noisy intermediate-scale and long-term fault-tolerant quantum computers depending on the computational resources we have. We perform a numerical simulation of the Green's function for the one- and two-dimensional Fermi-Hubbard model up to 4×4 sites lattice (32 qubits) and demonstrate the validity of our protocol compared to a standard method based on the Trotter decomposition. We finally present a detailed estimation of the gate count for the large-scale Fermi-Hubbard model, which also illustrates the advantage of our method over the Trotter decomposition.

The world engaged in online sport watching during COVID-19. Fortunately, in Taiwan, the pandemic was stably controlled in 2020, allowing for the continuation of the Chinese Professional Baseball League (CPBL); this attracted international attention and encouraged relevant discussions on social media in Taiwan. In the present study, through text mining, we analyzed user content (e.g., the concepts of sports service quality and social identity) on the Professional Technology Temple (PTT) baseball board—the largest online bulletin board system in Taiwan. A predictive model was constructed to assess PTT users’ COVID-19-related comments in 2020. A total of 422 articles and 21,167 comments were retrieved. PTT users interacted more frequently during the closed-door period, particularly during the beginning of the CPBL in April. Effective pandemic prevention, which garnered global attention to the league, generated a sense of national identity among the users, which was strengthened with the development of peripheral products, such as English broadcasting and live broadcasting on Twitch. We used machine learning to develop a chatbot for predicting the attributes of users’ comments; this chatbot may improve CPBL teams’ understanding of public opinion trends. Our findings may help stakeholders develop tailored programs for online spectators of sports during pandemic situations.

Previous studies of animal behavioural sleep is mainly divided into two study types, observation by video recording or counts by sensor, both of which require a complex environment and procedure. An actigraph unit is a commercially available product which can provide non-invasive monitoring human rest/activity cycles. The goal of this study was to evaluate whether actigraphy can be applied for analysing behavioural sleep in rats, since no reports have described utilization of the actigraphy unit for monitoring sleep of small animals. The actigraph unit was held on the chest of eight male rats by a loose elastic belt. The rats spent two days in a normal condition, followed by two days of sleep deprivation. Total counts measured by the actigraph could be clearly divided into two phases, sleep phase and awake phase, when the rats were kept in the normal cage. Next, the rats were moved into the sleep-deviation cage, and the total counts were significantly higher during daytime, indicating the successful induction of sleep deprivation. These results showed that the actigraphy unit monitored rest/activity cycles of rats, which will contribute to making sleep behaviour experiments easier.

How can sport community involvement influence life satisfaction during a pandemic? Self-expansion theory posits that individuals seek to gain resources such as positive interpersonal relationships for growth and achievement. By considering psychological capital (PsyCap) as a dispositional resource intervening between sport community involvement and life satisfaction, we examined an empirical model to test the chain of effects. Based on the stress process model, distress and generational group (Generation Z vs. others) were tested as moderators. Participants (N = 233) responded to the scale item questionnaire for model assessment. Supporting the hypothesized relationships, the model was supported with a significant moderated-moderated mediation. The mediation effect of PsyCap was stronger when distress level was lower and such interaction effect was amplified for Generation Z (Gen Z). Whereas the global sport communities and Gen Z were found to be more particularly vulnerable to COVID-19, our findings suggest that there are psychological pathways for fans to maintain their resilience. It is foremost imperative to lower the stress level of sport fans for their community involvement to positively affect life satisfaction. Gen Z were more stressed during the pandemic but individuals who managed to cope with stress were able to leverage community involvement to boost positive psychological resources. Acknowledgment of these effects brings implications for better management strategies and provides avenues for new research.

Armchair-edged graphene nanoribbons, characterized by width-dependent bandgaps, may become prominent in future semiconductor devices. Here, a small bandgap of 0.19 eV is achieved in 17-atom-wide nanoribbons, promising better transport characteristics in field-effect transistors.

Abstract Background Interstitial lung disease (ILD) is the most common and important pulmonary manifestation of rheumatoid arthritis (RA). A radiological honeycomb pattern has been described in diverse forms of ILD that can impact survival. However, the clinical course and sequential radiological changes in the formation of the honeycomb pattern in patients with RA-ILD is not fully understood. Methods We evaluated the sequential changes in computed tomography findings in 40 patients with chronic forms of RA-ILD without the honeycomb pattern at initial diagnosis. We classified the patients into the Non-honeycomb group and Honeycomb group, and then analyzed the characteristics and prognosis of the two groups. The term “honeycomb formation” indicated a positive finding of honeycombing on any available follow-up CT. Results Our RA-ILD cohort included patients with probable usual interstitial pneumonia (UIP) (35%), nonspecific interstitial pneumonia (NSIP) (20%), and mixed NSIP/UIP (45%). Among all RA-ILD patients, 16 (40%) showed honeycomb formation on follow-up CT (median time between initial and last follow-up CT was 4.7 years). Patient characteristics and prognosis were not significantly different between the Non-honeycomb and Honeycomb groups. However, Kaplan-Meier survival curve for the time from the date of honeycomb formation to death showed a poor median survival time of 3.2 years. Conclusions A certain number of patients with RA-ILD developed a honeycomb pattern during long-term follow-up, regardless of whether they had UIP or NSIP. Prognosis in the patients with characteristics of both progressive ILD and honeycomb formation could be poor. Although radiological findings over the disease course and clinical disease behavior in RA-ILD are heterogenous, clinicians should be alert to the possibility of progressive disease and poor prognosis in patients with RA-ILD who form a honeycomb pattern during follow-up observation.

Microfold cells (M cells) sit at the gut epithelial surface to sample antigens and maintain local immune homeostasis. Here the authors show that M cells are feedback-regulated by M cell-originated osteoprotegerin (OPG) to suppress RNAKL-induced M cell differentiation, and that OPG deficiency alters both gut colitis and infection phenotypes.

Epithelioid hemangioendothelioma (EHE) affects many organs, particularly lung and liver, and typically presents as multiple lesions. Treatment for EHE is not yet standardized, but surgery is appropriate when lesions are resectable. In our patient, radiography revealed multiple bilateral pulmonary nodules, and CT showed several liver tumors. The liver masses and those in the right lung were removed during the initial surgery; pathology of hepatic specimens confirmed the diagnosis of EHE. During the second operation, the left lung nodules were excised, and all were EHEs. Surgical removal of multiorgan multinodular EHE is a viable treatment option, especially for young patients.

Passive administration of neutralizing antibodies (Abs) is an attractive strategy for the control of gastrointestinal infections. However, an unanswered practical concern is the need to assure the stability of sufficient amounts of orally administered neutralizing Abs against intestinal pathogens (e.g., norovirus) in the harsh environment of the gastrointestinal tract. To this end, we expressed a single-domain Ab (VHH, nanobody) against norovirus on the cell surface of Lactobacillus, a natural and beneficial commensal component of the gut microbiome. First, we used intestinal epithelial cells generated from human induced pluripotent stem cells to confirm that VHH 1E4 showed neutralizing activity against GII.17 norovirus. We then expressed VHH 1E4 as a cell-wall–anchored form in Lactobacillus paracasei BL23. Flow cytometry confirmed the expression of VHH 1E4 on the surface of lactobacilli, and L. paracasei that expressed VHH 1E4 inhibited the replication of GII.17 norovirus in vitro. We then orally administered VHH 1E4-expressing L. paracasei BL23 to germ-free BALB/c mice and confirmed the presence of lactobacilli with neutralizing activity in the intestine for at least 10 days after administration. Thus, cell-wall-anchored VHH-displaying lactobacilli are attractive oral nanobody deliver vectors for passive immunization against norovirus infection.

Quantum error correction is one of the most important milestones for the realization of large-scale quantum computation. To achieve this, it is essential not only to integrate a large number of qubits with high fidelity but also to build a scalable classical system that can perform error correction. Here, we propose an efficient and scalable decoder for quantum error correction using “Fujitsu Digital Annealer” (DA). Specifically, the error correction problem of stabilizer codes is mapped into an Ising-type optimization problem, so-called quadratic unconstrained binary optimization (QUBO) problem, which is solved by DA. In particular, we implement the proposed DA decoder for the surface code and perform detailed numerical experiments for various code distances to see its performance and scalability. We observe that computational scaling for the DA decoder has a lower order of polynomials than the decoding methods using simulated annealing (SA) and minimum-weight perfect matching (MWPM) algorithm under all tested conditions. It is also shown that the DA decoder has advantages over the Union-Find (UF) decoder from a variety of perspectives including hardware implementation. Furthermore, the threshold behavior of the logical error probability for the DA decoder is analyzed and the resultant threshold lies between 9.4% and 9.8%, which is very close to that obtained by the MWPM decoder. This result clearly shows the high potential of the DA decoder for quantum error correction.

The low-voltage operation of a dielectric-barrier-discharge (DBD) plasma actuator with a simple electric circuit has the potential to put it into industrial applications. However, there is an issue that the efficiency of the low-voltage operated DBD plasma actuator is lower than that of the high-voltage operated one. In this study, the characteristics of silicon carbide (SiC) metal-oxide-semiconductor field-effect transistors (MOSFETs), which are used in the electric circuit, are investigated with a focus on the on-state resistance. The on-state resistance of the SiC-MOSFET affects the rise time of the applied voltage in our experimental condition. The energy consumption by applying a pulse voltage to the DBD plasma actuator increases with increasing the on-state resistance. Flow visualization with particle image velocimetry measurement reveals that a DBD plasma actuator with the SiC-MOSFET whose on-state resistance is the lowest induces the highest velocity of the ionic wind. Also, low on-state resistance is preferable in terms of the thrust-to-power ratio. These findings contribute to the development of an optimal power supply for DBD plasma actuators for industrial applications.

Previous research in evolutionary psychology has highlighted the potential role of facial structures in explaining human behavior. The facial width-to-height ratio (fWHR) was found to be associated with testosterone-driven behavioral tendencies like achievement drive, aggression, and sporting success. The current study aimed to replicate such relationships using real-world data (i.e., professional basketball players; N = 482). Achievement drive, aggression, and sporting success were operationalized as field-goal attempts (FGA), the number of fouls committed (Foul), and player performance rating (EFF), respectively. The results indicated that fWHR was significantly associated with FGA and EFF, controlling for minutes of play and body-mass-index. The same results were obtained for separate analyses focusing on outsider players. However, analyses of inside players demonstrated that fWHR was associated only with EFF. The current research further provides empirical evidence supporting the effects of fWHR on achievement drive and sporting successes, although the effect sizes are notably small.

Abstract Lung or head and neck cancer have been indicated as solid cancers associated with invasive pulmonary aspergillosis (IPA), but the relationship with hepatocellular carcinoma (HCC) is unknown. We report a case of HCC in which the presence of cirrhosis and corticosteroid administration may have caused the development of IPA.

Abstract Background Nintedanib is a tyrosine kinase inhibitor that efficiently slows the progression of idiopathic pulmonary fibrosis (IPF) and has an acceptable tolerability profile. In contrast, immune checkpoint inhibitors (ICIs) such as programmed death 1 and programmed death ligand 1 inhibitors have shown clinical activity and marked efficacy in the treatment of non-small cell lung cancer. However, it is unclear whether nintedanib reduces the risk of ICI-induced pneumonitis in IPF. Case presentation A 78-year-old man with squamous cell lung carcinoma in IPF underwent second-line treatment with pembrolizumab. He was diagnosed as having pembrolizumab-induced pneumonitis after two cycles. He was administered prednisolone (PSL) and then improved immediately. Thereafter, his lung cancer lesion enlarged despite treatment with TS-1. Atezolizumab was then administered as 4th-line chemotherapy, but he immediately developed atezolizumab-induced pneumonitis after 1 cycle. The re-escalated dosage of PSL improved the pneumonitis, and then nintedanib was started as additional therapy. Under careful observation with nintedanib, atezolizumab was re-administered on day 1 of an every-21-day cycle. After three cycles, it remained stable without exacerbation of drug-induced pneumonitis. Conclusion This case indicates the possibility that the addition of nintedanib to ICI therapy might prevent drug-induced pneumonitis or acute exacerbation of IPF. However, whether anti-fibrotic agents such as nintedanib are actually effective in preventing ICI-induced pneumonitis in ILD remains unknown and additional research is greatly needed to identify effective therapies for ILD combined with lung cancer.

We provide a pure state formulation for hydrodynamics of isolated quantum many-body systems. A pure state describing quantum systems in local thermal equilibrium is constructed, which we call a local thermal pure quantum (ℓTPQ) state. We show that the thermodynamic functional and the expectation values of local operators (including a real-time correlation function) calculated from the ℓTPQ state converge to those from a local Gibbs ensemble in the large fluid-cell limit. As a numerical demonstration, we investigate a one-dimensional spin chain and observe the hydrodynamic relaxation obeying Fourier's law. We further prove the second law of thermodynamics and the quantum fluctuation theorem, which are also validated numerically. The ℓTPQ formulation gives a useful theoretical basis to describe the emergent hydrodynamic behavior of quantum many-body systems furnished with a numerical efficiency applicable to both the nonrelativistic and relativistic regimes.

A new concept of electrode shape and arrangement is proposed to develop a multi-stage plasma synthetic jet actuator for the low-voltage operation. Exposed and covered electrodes, which have complicated shapes due to electrical wiring to the inner side of annular electrodes, are fabricated by an inkjet printing process using a silver nanoparticle-based ink. The plasma synthetic jet actuator developed in this study can be operated at 1000 V or lower. The discharge spreads uniformly from only the inner side of each annular electrode, inducing a unidirectional ionic wind toward the center of the coaxial electrode circle. Particle image velocimetry measurements reveal that the wall-normal jet induced by the multi-stage plasma synthetic jet actuator can be characterized as an axisymmetric free shear flow. The electrical and mechanical characteristics are similar to the linear-type dielectric-barrier-discharge plasma actuators. We also demonstrate that the printed electronics technique is suitable for the generation of arbitrary electrode shapes and arrangements and hence is a powerful tool for the realization of industrial applications of active airflow control devices using atmospheric pressure discharge.

Human norovirus is the leading cause of acute nonbacterial gastroenteritis in people of all ages worldwide. Currently, no licensed norovirus vaccine, pharmaceutical drug, or therapy is available for the control of norovirus infection. Here, we used a rice transgenic system, MucoRice, to produce a variable domain of a llama heavy-chain antibody fragment (VHH) specific for human norovirus (MucoRice-VHH). VHH is a small heat- and acid-stable protein that resembles a monoclonal antibody. Consequently, VHHs have become attractive and useful antibodies (Abs) for oral immunotherapy against intestinal infectious diseases. MucoRice-VHH constructs were generated at high yields in rice seeds by using an overexpression system with RNA interference to suppress the production of the major rice endogenous storage proteins. The average production levels of monomeric VHH (7C6) to GII.4 norovirus and heterodimeric VHH (7C6-1E4) to GII.4 and GII.17 noroviruses in rice seed were 0.54 and 0.28% (w/w), respectively, as phosphate buffered saline (PBS)-soluble VHHs. By using a human norovirus propagation system in human induced pluripotent stem-cell-derived intestinal epithelial cells (IECs), we demonstrated the high neutralizing activity of MucoRice expressing monomeric VHH (7C6) against GII.4 norovirus and of heterodimeric VHH (7C6-1E4) against both GII.4 and GII.17 noroviruses. In addition, MucoRice-VHH (7C6-1E4) retained neutralizing activity even after heat treatment at 90°C for 20 min. These results build a fundamental platform for the continued development of MucoRice-VHH heterodimer as a candidate for oral immunotherapy and for prophylaxis against GII.4 and GII.17 noroviruses in not only healthy adults and children but also immunocompromised patients and the elderly.

Tracheobronchial lesions are rare extramuscular complications for idiopathic inflammatory myopathies including dermatomyositis. We herein report a 65-year-old woman with tracheal ulcer during the progression of dermatomyositis-associated interstitial lung disease. Treatment with corticosteroids combined with immunosuppressive agents resulted in improvement of the tracheal ulcer and pulmonary involvement. We believe that the tracheal ulceration might reflect the disease behaviour of dermatomyositis and dermatomyositis-associated interstitial pneumonia.

Background Radial endobronchial ultrasonography (R-EBUS) has been used in conjunction with transbronchial lung cryobiopsy (TBLC) to diagnose diffuse parenchymal lung disease (DPLD) and to decrease the risk of bleeding complications. The diagnostic utility of different R-EBUS signs, however, remains unknown.Objectives This study aimed to determine whether different R-EBUS signs could be used to more accurately diagnose DPLD and whether bronchial bleeding could be prevented with use of R-EBUS during TBLC.Method Eighty-seven patients with DPLD were included in this multicentre prospective study, with 49 patients undergoing R-EBUS. R-EBUS signals were characterised as displaying either dense or blizzard signs. Pathological confidence of specimens obtained from TBLC was compared between patients with dense versus blizzard signs, and severity of bronchial bleeding was determined based on whether R-EBUS was performed or not.Results All patients with dense signs on R-EBUS showed consolidation on high-resolution CT (HRCT) imaging. Pathological confidence of lung specimens was significantly higher in patients with dense signs versus those with blizzard signs (p

A 72-year-old Japanese man was admitted to our hospital for treatment of severe COVID-19 pneumonia and was started on favipiravir, heparin calcium, and methylprednisolone pulse therapy. He recovered from respiratory failure about one month later. However, he soon developed purpura in his lower limbs and thrombocytopenia, and immune thrombocytopenia was subsequently diagnosed. Although immune thrombocytopenia is one of the early complications of COVID-19, the use of corticosteroids for COVID-19 is thought to be a factor in the late onset of immune thrombocytopenia. In cases of severe COVID-19 for which corticosteroids were used for treatment, autoimmune diseases such as immune thrombocytopenia may manifest themselves late in the disease course.

Transbronchial lung cryobiopsy (TBLC) has been increasingly utilised to diagnose diffuse parenchymal lung diseases (DPLDs) and lung cancers; however, TBLC protocols have not yet been standardised and the rate of complications associated with this procedure vary widely. Therefore, this prospective multicentre observational study investigated the safety and utility of the TBLC technique in patients with diffuse and localised respiratory diseases. This study was conducted at multiple medical centres in Japan between July 2018 and April 2019. The study's primary end-point was the rate of severe or serious adverse events associated with TBLC. Adverse events included bronchial bleeding, pneumothorax, pneumonia, respiratory failure, and an acute exacerbation of interstitial pneumonia. Adverse events were graded according to severity. During the TBLC procedure, an endobronchial balloon catheter for bronchial blockade was used in all patients. Pathological confidence and quality of specimens were categorised into three groups. A total of 112 patients were included. Neither severe nor serious adverse events were identified; therefore, the primary end-point was met. Nineteen patients (17%) experienced no bronchial bleeding. Mild or moderate bronchial bleeding was identified in 67% and 16% of patients, respectively. Mild pneumothoraces were identified in four patients (3.6%). The safety profile in patients aged ≥75 years was not significantly different from younger patients. Definite or probable pathological diagnoses were made in 84.9% of patients. This TBLC protocol with routine use of an endobronchial balloon had an acceptable safety profile and diagnostic yield in patients, including elderly ones, with diffuse and localised respiratory diseases.

An 85-year-old woman with antibiotics-resistant pneumonia after surgery for metastatic brain tumor from lung cancer was consulted to our department. Chest CT showed diffuse GGO bilaterally. BALF showed elevated ratios of lymphocytes and CD4/CD8. Tests for bacteria, mycobacteria, and fungi were negative. She improved following levetiracetam discontinuance and systemic corticosteroid administration, and we diagnosed levetiracetam-induced lung injury. Although levetiracetam is widely used, few reports of levetiracetam-induced pneumonia exist. Changes in chest images may occur after levetiracetam administration if patients have multiple risk factors for development of drug-induced interstitial lung disease. Bronchoscopy is useful for differential diagnosis if new lung lesions appear after starting levetiracetam.

An 85-year-old man was being treated for advanced squamous cell lung carcinoma with nivolumab as a second-line treatment. From the beginning of the third course, erythema appeared on his trunk and gradually progressed. Around the start of the fifth course, erythema spread to the proximal part of all limbs in addition to the trunk and was accompanied by a strong itching sensation. He was diagnosed as having contact dermatitis by a dermatologist because his rash was observed only where the moisture-absorbing fiber material of his underwear made contact with the skin surface. After suspending treatment of nivolumab, changing his underwear to a cotton material, and using moisturizers and steroid ointments, his rash disappeared in about a month and the size of his lung tumors remained reduced. The patient developed contact dermatitis despite the use of similar underwear without any skin problems for several years. We speculated that nivolumab-induced T-cell activation may have occurred in his skin, making him more likely to develop contact dermatitis, whose onset is thought to involve T-cell activation. No cases of contact dermatitis have been reported previously although the frequency of eruption as an immune-related adverse event is relatively high. When using immune checkpoint inhibitors including nivolumab, clinicians need to pay attention to the occurrence of skin disorders related to T-cell activation.

Summary: Gut epithelial organoids are routinely used to investigate intestinal biology; however, current culture methods are not amenable to genetic manipulation, and it is difficult to generate sufficient numbers for high-throughput studies. Here, we present an improved culture system of human induced pluripotent stem cell (iPSC)-derived intestinal organoids involving four methodological advances. (1) We adopted a lentiviral vector to readily establish and optimize conditioned medium for human intestinal organoid culture. (2) We obtained intestinal organoids from human iPSCs more efficiently by supplementing WNT3A and fibroblast growth factor 2 to induce differentiation into definitive endoderm. (3) Using 2D culture, followed by re-establishment of organoids, we achieved an efficient transduction of exogenous genes in organoids. (4) We investigated suspension organoid culture without scaffolds for easier harvesting and assays. These techniques enable us to develop, maintain, and expand intestinal organoids readily and quickly at low cost, facilitating high-throughput screening of pathogenic factors and candidate treatments for gastrointestinal diseases.

Visceral fat accumulation as observed in Crohn's disease and obesity is linked to chronic gut inflammation, suggesting that accumulation of gut adipocytes can trigger local inflammatory signaling. However, direct interactions between intestinal epithelial cells (IECs) and adipocytes have not been investigated, in part because IEC physiology is difficult to replicate in culture. In this study, we originally prepared intact, polarized, and cytokine responsive IEC monolayers from primary or induced pluripotent stem cell-derived intestinal organoids by simple and repeatable methods. When these physiological IECs were co-cultured with differentiated adipocytes in Transwell, pro-inflammatory genes were induced in both cell types, suggesting reciprocal inflammatory activation in the absence of immunocompetent cells. These inflammatory responses were blocked by nuclear factor-κB or signal transducer and activator of transcription 3 inhibition and by anti-tumor necrosis factor- or anti-interleukin-6-neutralizing antibodies. Our results highlight the utility of these monolayers for investigating IEC biology. Furthermore, this system recapitulates the intestinal epithelium–mesenteric fat signals that potentially trigger or worsen inflammatory disorders such as Crohn's disease and obesity-related enterocolitis.

M cells are intestinal epithelial cells that are specialized to transcytose antigens and bacteria from the intestinal lumen to antigen presenting cells on the other side. Here the authors show that the actin-binding protein Aif1 is highly expressed by intestinal M cells and regulates this transcytosis.

We herein report the first case, to our knowledge, of tracheobronchial ulcer with anti-melanoma differentiation-associated gene 5 (anti-MDA 5) antibody-positive interstitial lung disease (ILD). A 53-year-old man complained of shoulder and wrist pain and was suspected of having polymyalgia rheumatica at another hospital. Thereafter, treatment with prednisolone was started. Although his arthralgia improved, he suffered from progressive dyspnea on exertion and an abnormal shadow was noted on chest X-ray, so he was transferred to our hospital. Chest computed tomography scan revealed ground-glass opacities and intralobular septal thickening. We diagnosed him as having clinically amyopathic dermatomyositis associated with ILD based on the specific skin findings and elevated anti-MDA 5 antibody titer. Fiberoptic bronchoscopy showed ulcerations of the trachea and bronchus. Treatment with dose increments of prednisolone combined with other immunosuppressive drugs resulted in improvement of his respiratory condition and tracheobronchial lesions. Clinicians should be aware that tracheobronchial ulcers can be associated with anti-MDA 5 antibody-positive interstitial lung disease. Keywords: Tracheo-bronchial ulcer, Anti-melanoma differentiation-associated gene 5, Interstitial lung disease

Many factors are associated with a person’s attitude formation and intention towards a behavior. In this study, we examined organizational factors that helped form young athletes attitudes regarding their future plans in high performance sport. Through a mixed method survey design, data was collected from 207 young pre-elite athletes who competed during the 2017 Commonwealth Youth Games in Bahamas. Several organizationally controlled aspects of the games environment were found to contribute to young athlete’s satisfaction with the event including their accommodations, available information regarding their sport and finally, the social and cultural activities during games-time. However, satisfaction with the games environment was not predictive of young athletes future intentions to remain in sport. Qualitative thematic coding denoted two key themes related to athlete plans to continue in high performance sport: level of satisfaction and learning. Further, qualitative results revealed five main impediments to continuing in high performance sport specifically, physiological, psychological, performance, environment and life concerns. The paper contributes to our understanding of the controllable and uncontrollable social and environmental factors in a multi-sport international event. Nationally controlled factors that influence young athletes attitude formation, specifically their satisfaction and intentions to remain in sport.

Pulmonary tumor thrombotic microangiopathy (PTTM) is rare but should be considered as a possible diagnosis in patients with cancer. In this case, PTTM induced by lung cancer was more accurately diagnosed using cell block immunohistochemistry of pulmonary microvascular cytology (PMC) because we could confirm that lung adenocarcinoma was the origin of PTTM by the positive result of TTF-1 for atypical cells in PMC. The PMC procedure was minimally invasive and safer than lung biopsy. We believe that the cell block technique of PMC should be considered as one diagnostic option in PTTM. Keywords: Pulmonary tumor thrombotic microangiopathy, Pulmonary microvascular cytology, Cell block technique

An amendment to this paper has been published and can be accessed via a link at the top of the paper.