Body weight loss is a simple and useful indicator of prognosis and predictive tolerability in the first year of nintedanib therapy in patients with interstitial lung disease.

BACKGROUND: Nintedanib is generally safe and well tolerated and can improve prognosis in patients with various interstitial lung diseases (ILDs). Appropriate management of adverse events of nintedanib is important to ensure its long-term persistent use. Weight loss is a routinely assessed adverse event in clinical practice. This study aimed to elucidate whether body weight change in the first year of nintedanib therapy can indicate prognosis and predict tolerability in patients with ILD. METHODS: We analysed 245 consecutive ILD patients treated with nintedanib. We calculated the slope of body weight change using baseline weight and that recorded closest after the first year and then categorized percent change in body weight at this time. Significant weight loss was defined as that ≥5%. RESULTS: Subjects included 67 patients with idiopathic pulmonary fibrosis (IPF) and 76 with non-IPF progressive fibrosing-ILD including fibrotic hypersensitivity pneumonitis (n = 16), unclassifiable (n = 35), connective tissue disease-ILD (n = 21), and nonspecific interstitial pneumonia (n = 4). Older age, low body weight at initial examination, significant weight loss, and lower %FVC were significant predictors of discontinuation of nintedanib. Patients with weight loss ≥5% over the first year showed worse survival than those with weight loss <5% regardless of whether IPF existed or BMI indicated obesity. CONCLUSIONS: Careful monitoring of body weight change might suggest useful information for predicting long-term use of nintedanib and mortality risk in ILD patients treated with nintedanib. Appropriate body weight management is needed to prevent adverse events of nintedanib itself.

Clinical significance of para-carinal air cysts in patients with pleuroparenchymal fibroelastosis: The relationship with pneumomediastinum and pneumothorax.

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.

Emergent centrality in rank-based supplanting process.

We propose a stochastic process of interacting many agents, which is inspired by rank-based supplanting dynamics commonly observed in a group of Japanese macaques. In order to characterize the breaking of permutation symmetry with respect to agents' rank in the stochastic process, we introduce a rank-dependent quantity, overlap centrality, which quantifies how often a given agent overlaps with the other agents. We give a sufficient condition in a wide class of the models such that overlap centrality shows perfect correlation in terms of the agents' rank in the zero-supplanting limit. We also discuss a singularity of the correlation in the case of interaction induced by a Potts energy.

The Japan Monkey Centre Primates Brain Imaging Repository of high-resolution postmortem magnetic resonance imaging: The second phase of the archive of digital records.

A comparison of neuroanatomical features of the brain between humans and our evolutionary relatives, nonhuman primates, is key to understanding the human brain system and the neural basis of mental and neurological disorders. Although most comparative MRI studies of human and nonhuman primate brains have been based on brains of primates that had been used as subjects in experiments, it is essential to investigate various species of nonhuman primates in order to elucidate and interpret the diversity of neuroanatomy features among humans and nonhuman primates. To develop a research platform for this purpose, it is necessary to harmonize the scientific contributions of studies with the standards of animal ethics, animal welfare, and the conservation of brain information for long-term continuation of the field. In previous research, we first developed a gated data-repository of anatomical images obtained using 9.4-T ex vivo MRI of postmortem brain samples from 12 nonhuman primate species, and which are stored at the Japan Monkey Centre. In the present study, as a second phase, we released a collection of T2-weighted images and diffusion tensor images obtained in nine species: white-throated capuchin, Bolivian squirrel monkey, stump-tailed macaque, Tibet monkey, Sykes' monkey, Assamese macaque, pig-tailed macaque, crested macaque, and chimpanzee. Our image repository should facilitate scientific discoveries in the field of comparative neuroscience. This repository can also promote animal ethics and animal welfare in experiments with nonhuman primate models by optimizing methods for in vivo and ex vivo MRI scanning of brains and supporting veterinary neuroradiological education. In addition, the repository is expected to contribute to conservation, preserving information about the brains of various primates, including endangered species, in a permanent digital form.

Can transbronchial lung cryobiopsy benefit adaptive treatment strategies in connective tissue disease-associated interstitial lung disease?

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.

A Novel Rat Model of Embolic Cerebral Ischemia Using a Cell-Implantable Radiopaque Hydrogel Microfiber.

The failure of neuroprotective treatment-related clinical trials, including stem cell therapies, may be partially due to a lack of suitable animal models. We have developed a stem cell-implantable radiopaque hydrogel microfiber that can survive for a long time in vivo. The microfiber is made of barium alginate hydrogel containing zirconium dioxide, fabricated in a dual coaxial laminar flow microfluidic device. We aimed to develop a novel focal stroke model using this microfiber. Using male Sprague-Dawley rats (n=14), a catheter (inner diameter, 0.42 mm; outer diameter, 0.55 mm) was navigated from the caudal ventral artery to the left internal carotid artery using digital subtraction angiography. A radiopaque hydrogel microfiber (diameter, 0.4 mm; length, 1 mm) was advanced through the catheter by slow injection of heparinized physiological saline to establish local occlusion. Both 9.4-T magnetic resonance imaging at 3 and 6 h and 2% 2,3,5-triphenyl tetrazolium chloride staining at 24 h after stroke model creation were performed. Neurological deficit score and body temperature were measured. The anterior cerebral artery-middle cerebral artery bifurcation was selectively embolized in all rats. Median operating time was 4 min (interquartile range [IQR], 3-8 min). Mean infarct volume was 388 mm3 (IQR, 354-420 mm3) at 24 h after occlusion. No infarction of the thalamus or hypothalamus was seen. Body temperature did not change significantly over time (P = 0.204). However, neurological deficit scores before and at 3, 6, and 24 h after model creation differed significantly (P < 0.001). We present a novel rat model of focal infarct restricted to the middle cerebral artery territory using a radiopaque hydrogel microfiber positioned under fluoroscopic guidance. By comparing the use of stem cell-containing versus non-containing fibers in this stroke model, it would be possible to determine the efficacy of "pure" cell transplantation in treating stroke.

Patient background and prognosis of chronic pulmonary aspergillosis in fibrosing interstitial lung disease.

Several previous reports have shown interstitial lung disease (ILD) to be a predictor of poor prognosis in patients with chronic pulmonary aspergillosis (CPA). However, there is a lack of clarity regarding patient background and the prognostic factors in CPA associated with ILD (CPA-ILD). Therefore, we assessed these points to obtain valuable information for clinical practice. We retrospectively surveyed and collected data from 459 patients who had serum examination for anti-Aspergillus antibody. Of these patients, we extracted and investigated CPA-ILD patients. We ultimately analyzed 32 CPA-ILD patients. Patient background factors more frequently showed the patients to be older (mean: 74.9 years), male (75.0%), and to have a smoking history (71.9%). Median survival time from the diagnosis of ILD was 76.0 months, whereas that from the diagnosis of CPA-ILD was 25.5 months. No significant differences in survival were found in regard to each ILD pattern and the presence of idiopathic pulmonary fibrosis. A higher level of C-reactive protein was a significant predictor of mortality by Cox regression analysis. CPA complicating ILD is associated with poor prognosis. ILD patients with older age, male sex, and smoking history should be aware of the potential for the development of CPA in ILD. If such patients have elevated markers of inflammation, prompt induction of antifungal treatment may improve their prognosis. Clinicians should be aware of which complications of CPA may lead to a poor prognosis for any ILD not just those limited to idiopathic pulmonary fibrosis or usual interstitial pneumonia pattern.

Impact of progressive fibrosing interstitial lung disease (ILD) in ILD patients complicated with secondary spontaneous pneumothorax.

BACKGROUND: Secondary spontaneous pneumothorax (SSP) in interstitial lung disease (ILD) may influence prognosis of any ILD, and SSP onset predicts poor outcome in idiopathic pulmonary fibrosis (IPF). Recently, progressive fibrosing ILD (PF-ILD) has rapidly acquired importance. OBJECTIVE: We hypothesized that PF-ILD would strongly influence the prognosis of patients with any ILD complicated with SSP. METHODS: We retrospectively surveyed and collected data from patients hospitalized for SSP from January 2016 to June 2020. PF-ILD was defined as the following occurring within 24 months before SSP develops: relative decline in %forced vital capacity (FVC) ≥10% or two of the following: relative decline in %FVC between 5% and 10%, worsening respiratory symptoms, or increased extent of fibrosis on high-resolution computed tomography. RESULTS: We analyzed 32 patients hospitalized for SSP in ILD. This study comprised 18 patients with PF-ILD and 14 patients with non-PF-ILD. PF-ILD patients had lower body mass index (BMI) and %FVC. No significant differences in survival regarding follow-up period from the time of ILD diagnosis and hospitalization for SSP were observed between the PF-ILD and non-PF-ILD patients. Older age and lower BMI were significant predictors of mortality by multivariate Cox regression analysis. ROC analysis showed BMI ≤17.8 kg/m2 to reliably predict poor prognosis. CONCLUSIONS: Regardless of whether patients have PF-ILD, older age and lower BMI in patients with ILD places them at higher risk of developing SSP, and prognosis is poor if SSP develops. Therefore, clinical management of physique is important to improve the prognosis of ILD patients.

Delayed onset of severe immune thrombocytopenia associated with COVID-19 pneumonia.

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.

A novel model of ischemia in rats with middle cerebral artery occlusion using a microcatheter and zirconia ball under fluoroscopy.

The failure of neuroprotective treatment-related clinical trials may be partially caused by unestablished animal models. Existing animal models are less likely to provide occlusion confined to the middle cerebral artery (MCA), making transarterial intervention difficult. We aimed to develop a novel focal stroke model using a microcatheter and zirconium dioxide that is non-magnetic under fluoroscopic guidance, which can monitor MCA occlusion and can improve hemorrhagic complications. Using male Sprague Dawley rats (n = 10), a microcatheter was navigated from the caudal ventral artery to the left internal carotid artery using an X-ray fluoroscopy to establish local occlusion. All rat cerebral angiographies were successful. No rats had hemorrhagic complications. Eight (80%) rats underwent occlusion of the MCA bifurcation by zirconium dioxide. Accidentally, the left posterior cerebral artery was failure embolized in 2 rats (20%). The median operating time was 8 min. All rats of occlusion MCA revealed an incomplete hemiparesis on the right side with neurological deficit score ranging from 1 to 3 (median 1, interquartile range 1-3) at 24 h after the induction of ischemia. Moreover, 2% 2,3,5-triphenyl tetrazolium chloride staining showed that the median infarct volume (mm3) was 280 (interquartile range 267-333) 24 h after the left MCA bifurcation occlusion. We present a novel rat model for focal stroke using a microcatheter and zirconium dioxide which does not affect the MRI. The model is predictable which is well confined within the territory supplied by the MCA, and reproducibility of this model is 80%. Fluoroscopy was able to identify which the MCA occlusion and model success while creating the model. It permitted exclusion of animals with complications from the experiment.

Marmoset angiography just by percutaneous puncture of the caudal ventral artery.

Surgery in humans is continuously evolving and promoted minimally invasive treatment. On the other hand, despite the importance of the 3Rs principles for experimental animals is well documented, no reports describe specific methodologies for implementing "refinement" in practice. Here, we describe a new technique, the "Ohta Method" for caudal arthrocentesis in the pursuit of the 3Rs for animal experiments and the development of innovative methods for investigating systemic organ arteries through minimally invasive procedures. This procedure requires only a percutaneous puncture of the caudal artery without any injury to the limb or body trunk. In addition, it does not cut down the artery, making hemostasis easier and recovering arterial damage easier. We will show multiple organ artery angiographies in marmoset for the first time in the world. The principle described in this paper could also be applied to many other small animals, such as rats. Moreover, using this method, multiple doses of the drug or cells can be administered to the target organ at the time of therapeutic intervention, thereby enabling the establishment of more sophisticated and complex therapeutic intervention studies as translational research.

Utilizing Dynamic Phosphorous-31 Magnetic Resonance Spectroscopy for the Early Detection of Acute Compartment Syndrome: A Pilot Study on Rats.

INTRODUCTION: Disasters, including terrorism and earthquakes, are significant threats to people and may lead to many people requiring rescue. The longer the rescue takes, the higher the chances of an individual contracting acute compartment syndrome (ACS). ACS is fatal if diagnosed too late, and early diagnosis and treatment are essential. OBJECTIVE: To assess the ability of dynamic phosphorus magnetic resonance spectroscopy (31P-MRS) in the early detection of muscular damage in ACS. MATERIALS AND METHODS: Six ACS model rats were used for serial 31P-MRS scanning (9.4 Tesla). Skeletal muscle metabolism, represented by the levels of phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP), was assessed. The PCr/(Pi + PCr) ratio, which decreases with ischemia, was compared with simultaneously sampled plasma creatine phosphokinase (CPK), a muscle damage marker. RESULTS: The PCr/(Pi + PCr) ratio significantly decreased after inducing ischemia (from 0.86 ± 0.10 to 0.18 ± 0.06; p < 0.05), while CPK did not change significantly (from 89 ± 29.46 to 241.50 ± 113.28; p > 0.05). The intracellular and arterial pH index decreased over time, revealing significant differences at 120 min post-ischemia (from 7.09 ± 0.01 to 6.43 ± 0.13, and from 7.47 ± 0.03 to 7.39 ± 0.04, respectively). In the reperfusion state, the spectra and pH did not return to the original values. CONCLUSIONS: The dynamic 31P-MRS technique can rapidly detect changes in muscle bioenergetics. This technique is a promising non-invasive method for determining early muscular damage in ACS.

A reproducible swine model of a surgically created saccular thoracic aortic aneurysm.

A reproducible swine thoracic aortic aneurysm (TAA) model is useful for investigating new therapeutic interventions. We report a surgical method for creating a reproducible swine saccular TAA model. We used eight female swine weighing 20-25 kg (LWD; ternary species). All procedures were performed under general anesthesia and involved left thoracotomy. Following aortic cross-clamping, the thoracic aorta was surgically dissected and the media and intima were resected, and the dissection plane was extended by spreading the outer layer for aneurysmal space. Subsequently, only the adventitial layer of the aorta was sutured. At 2 weeks after these procedures, angiography and computed tomography were performed. After follow-up imaging, the model animals were euthanized. Macroscopic, histological, and immunohistological examinations were performed. All model animals survived, and a saccular TAA was confirmed by follow-up imaging in all cases. The mean length of the shorter and the longer aortic diameter after the procedure were 14.01 ± 1.0 mm and 18.35 ± 1.4 mm, respectively (P<0.001). The rate of increase in the aortic diameter was 131.7 ± 13.8%, and the mean length of aneurysmal change at thoracic aorta was 22.4 ± 1.9 mm. Histological examination revealed intimal tears and defects of elastic fibers in the media. Immunostaining revealed MMP-2 and MMP-9 expressions at the aneurysm site. We report our surgical method for creating a swine saccular TAA model. Our model animal may be useful to investigate new therapeutic interventions for aortic disease.

Hairspray Inhalation-induced Interstitial Pneumonitis Evaluated by a Transbronchial Lung Cryobiopsy.

A 60-year-old Japanese woman was admitted to our hospital with a fever and shortness of breath occurring immediately after using hairspray. Chest high-resolution computed tomography (HRCT) showed ground-glass opacities (GGOs) predominantly distributed around the bronchovascular bundles, and a pathological evaluation by a transbronchial lung cryobiopsy (TBLC) revealed fibrotic non-specific interstitial pneumonia (f-NSIP). Her symptoms disappeared without the use of corticosteroids, and GGOs on HRCT improved markedly over time. This case suggests that a pathological evaluation by a TBLC for lung injury due to inhalation pathogen exposure may provide a more accurate diagnosis and a better understanding of the pathology from bronchial to interstitial lesions than transbronchial lung biopsy.

Autologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study.

OBJECTIVE: Arteriosclerosis is an age-related disease and a leading cause of cardiovascular disease. In animal experiments, mesenchymal stem cells and its culture-conditioned medium have been shown to be promising tools for prevention or treatment of arteriosclerosis. On the basis of these evidences, we aimed to assess whether administration of autologous adipose-derived mesenchymal stem cells (Ad-MSC) is safe and effective for treatment of arteriosclerosis. METHODS: We retrospectively reviewed clinical records of patients with arteriosclerosis who had received autologous Ad-MSC administration at our clinic. Patients' characteristics were recorded and data on lipid profile, intimal-media thickness (IMT), cardio-ankle vascular index (CAVI), and ankle-brachial index (ABI) before and after Ad-MSC administration were collected and compared. RESULTS: Treatment with Ad-MSC significantly improved HDL, LDL, and remnant-like particle (RLP) cholesterol levels. No adverse effect or toxicity was observed in relation to the treatment. Of the patients with abnormal HDL values before treatment, the vast majority showed improvement in the values. Overall, the measurements after treatment were significantly increased compared with those before treatment (p < 0.01). In addition, decreases in LDL cholesterol and RLP levels were observed after treatment in patients who had abnormal LDL cholesterol or RLP levels before treatment. The majority of patients with pre-treatment abnormal CAVI values had improved values after treatment. In patients with available IMT values, a significant decrease in the IMT values was found after therapy (p < 0.01). All patients with borderline arteriosclerosis disease had improved laboratory findings after treatment. In general, post-treatment values were significantly decreased as compared with pre-treatment values. Of the patients with normal ABI values before treatment at the same time as CAVI, the vast majority remained normal after treatment. CONCLUSIONS: These findings suggest that Ad-MSC administration is safe and effective in patients developing arteriosclerosis, thereby providing an attractive tool for anti-aging application.

Systematic clustering algorithm for chromatin accessibility data and its application to hematopoietic cells.

The huge amount of data acquired by high-throughput sequencing requires data reduction for effective analysis. Here we give a clustering algorithm for genome-wide open chromatin data using a new data reduction method. This method regards the genome as a string of 1s and 0s based on a set of peaks and calculates the Hamming distances between the strings. This algorithm with the systematically optimized set of peaks enables us to quantitatively evaluate differences between samples of hematopoietic cells and classify cell types, potentially leading to a better understanding of leukemia pathogenesis.

Levetiracetam-induced interstitial lung disease in a patient with advanced lung cancer.

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.

Nivolumab-induced contact dermatitis in a patient with advanced lung cancer.

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.