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Pathogens including autoantigens all failed to induce systemic lupus erythematosus (SLE). We, instead, studied the integrity of host's immune response that recognized pathogen. By stimulating TCR with an antigen repeatedly to levels that surpass host's steady-state response, self-organized criticality, SLE was induced in mice normally not prone to autoimmunity, wherein T follicular helper (Tfh) cells expressing the guanine nucleotide exchange factor DOCK8 on the cell surface were newly generated. DOCK8 + Tfh cells passed through TCR re-revision and induced varieties of autoantibody and lupus lesions. They existed in splenic red pulp and peripheral blood of active lupus patients, which subsequently declined after therapy. Autoantibodies and disease were healed by anti-DOCK8 antibody in the mice including SLE-model (NZBxNZW) F1 mice. Thus, DOCK8 + Tfh cells generated after repeated TCR stimulation by immunogenic form of pathogen, either exogenous or endogenous, in combination with HLA to levels that surpass system's self-organized criticality, cause SLE., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Backgrounds: Endoscopic tattooing failure by deep mural injection or tattoo leakage-induced massive staining causes localization errors or decreased laparoscopic visualization. To overcome these, we developed a novel tattoo needle with comparatively shorter needle (length, 2.5 mm) and minimal-caliber catheter (volume, 0.3 mL)., Aims: The single-center, prospective observational study aimed to determine the efficacy and safety of a small-doze endoscopic tattooing prior to laparoscopic surgery for colorectal cancer, using the needle., Methods: Patients with colorectal cancer indicated for laparoscopic surgery were recruited. With the novel needle, a single tattoo was created at the anterior wall close to the lesion. During laparoscopic surgery, surgeons assessed the tattoo visibility, tattoo leakage, and the disturbance of laparoscopic view by tattoo leakage. The primary endpoint was an accurate localization by visible tattoo. Secondary endpoints were adverse events related to tattooing, the need for intraoperative endoscopy, and tattoo leakage., Results: A total of 383 tattoos in 358 patients were analyzed. Accurate tumor localization rate was 96.6% (95% confidence interval [CI]: 94.3-98.0%). No adverse events occurred. Intraoperative colonoscopy was performed in 7 (1.8%) patients with invisible tattoo. Tattoo leakage was found in 4.2% (95%CI: 2.6-6.7%), and leakage disturbed the laparoscopic view of the surgical plane in 0.7% (95%CI: 0.3-2.3%)., Conclusions: Prior to laparoscopic surgery for colorectal cancer, our endoscopic tattooing with a standardized protocol using a novel needle is considered a simple, highly reliable localization technique with an extremely safe profile, which would be valuable to reduce physician's efforts and redundant medical resources. Trial registration number UMIN000021012. Date of registration: June 2016., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Bengalese finches (Lonchura striata var. domestica) have more complex song traits than their wild ancestors, white-rumped munias (Lonchura striata). Domesticated finches are likely able to allocate more resources to reproduction (e.g. singing) rather than to mechanisms intended for coping with predation, which are no longer needed under domesticated conditions. Here, we aimed to examine the effects of changes in selection pressure due to domestication on the behaviour of Bengalese finches and to contemplate the possible evolutionary mechanisms underlying these changes. To do so, we compared neophobic responses to novel-object conditions as an assessment of reactions to potential predators. We studied groups of Bengalese finches and white-rumped munias and found that Bengalese finches were more likely to eat the food provided to them under novel-object conditions. Bengalese finches had a shorter latency time to eat, and this latency time was less affected by the novel object in the case of Bengalese finches compared to white-rumped munias. Therefore, Bengalese finches have reduced neophobic responses due to domestication. The behavioural strategies of white-rumped munias appear to be more suitable for natural environments, which include unpredictable risks, whereas Bengalese finches have likely adapted their behaviour to the conditions of artificial selection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Short-chain fatty acids produced by the gut bacterial fermentation of non-digestible carbohydrates, e.g., fructo-oligosaccharide (FOS), contribute to the maintenance of skeletal muscle mass and oxidative metabolic capacity. We evaluated the effect of FOS ingestion on protein expression of soleus (Sol) and extensor digitorum longus muscles in mice exposed to microgravity (μ-g). Twelve 9-week-old male C57BL/6J mice were raised individually on the International Space Station under μ-g or artificial 1-g and fed a diet with or without FOS (n = 3/group). Regardless of FOS ingestion, the absolute wet weights of both muscles tended to decrease, and the fiber phenotype in Sol muscles shifted toward fast-twitch type following μ-g exposure. However, FOS ingestion tended to mitigate the μ-g-exposure-related decrease in oxidative metabolism and enhance glutathione redox detoxification in Sol muscles. These results indicate that FOS ingestion mildly suppresses metabolic changes and oxidative stress in antigravity Sol muscles during spaceflight., (© 2021. The Author(s).)

Aim: Accurate preoperative diagnosis of lateral lymph node metastasis (LLNM) from lower rectal cancer is important to identify patients who require lateral lymph node dissection (LLND). We aimed to create an effective prediction model for LLNM using machine learning by combining preoperative information., Methods: We retrospectively examined patients who underwent primary rectal cancer surgery with unilateral or bilateral LLND between April 2010 and March 2020 at a single institution. Using the machine learning software "Prediction One" (Sony Network Communications), we developed a prediction model in the training cohort that included 267 consecutive patients (500 sides) from April 2010. Clinicopathological data obtained from the preoperative examinations were used as the learning items. In the validation cohort that included subsequent patients until March 2020, we compared the discriminating powers of the prediction model and the conventional method using the short-axis diameter of the largest lateral lymph node, as detected on magnetic resonance imaging., Results: The area under the receiver operating characteristic curve (AUC) of the prediction model was 0.903 in the validation cohort comprising 56 patients (107 sides). This indicated significantly higher predictive power than that of the conventional method (AUC = 0.754; P  = .022). Using the cutoff values defined in the training cohort, the accuracy, sensitivity, and specificity of the prediction model were 80.4%, 90.0%, and 79.4%, respectively. The model was able to correctly predict four of five sides comprising LLNM with the short-axis diameters ≤4 mm., Conclusion: Machine learning contributed to the creation of an effective prediction model for LLNM., Competing Interests: Conflict of interest: The authors declare no conflicts of interest for this article. Ethical approval: All study protocols were approved by the Institutional Review Board of the Shizuoka Cancer Center (Institutional code: J2020‐57‐2020‐1–3)., (© 2021 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

BRG1, one of core subunits of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancers. Previously, we reported significant downregulation of the phosphorylation level of BRG1 on Ser 1452 (<10%) in cell lines derived from ovarian clear cell carcinoma with frequent recurrence and acquired drug resistance. In this study, we tried to elucidate the roles of BRG1 phosphorylation, using cell lines expressing wild-type, phosphorylation-mimic (brg1-S 1452 D), or non-phosphorylatable (brg1-S 1452 A) BRG1. Quantitative proteomic analyses revealed upregulation of proteins and phosphoproteins related to linker histone H1s, histone methylation, and protein ubiquitylation in brg1-S 1452 D cells, which may coordinately promote the chromatin inactivation and ubiquitin-dependent degradation of target proteins. Consistent with these results, brg1-S 1452 D cells exhibited an increase in condensed chromatin and polyubiquitylated proteins. In brg1-S 1452 D cells, we also detected downregulation of various cancer-related proteins (e.g., EGFR and MET) as well as decreased migration, proliferation, and sensitivity to taxanes and oxaliplatin. Together, our results reveal that BRG1 phosphorylation drives tumor malignancy by inhibiting the functions of SWI/SNF complex in chromatin activation, thereby promoting expression of various cancer-related proteins. SIGNIFICANCE: For the first time we demonstrated that the mutation on Ser 1452 phosphorylation site of BRG1, a component of SWI/SNF chromatin remodeling complex, changed protein and phosphoprotein levels of linker histone H1s, binding competitor of histone H1s, and histone methylase/demethylase involved in the heterochromatic histone modifications to promote the chromatin inactivation. In phosphorylation-mimic mutant, significant decrease of various cancer-related proteins as well as migration, proliferation, and sensitivity to specific antitumor agents were detected. Our results reveal that BRG1 phosphorylation drives tumor malignancy by inhibiting the functions of SWI/SNF complex in chromatin activation, thereby promoting expression of various cancer-related proteins., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite the frequent detection of KRAS driver mutations in patients with colorectal cancer (CRC), no effective treatments that target mutant KRAS proteins have been introduced into clinical practice. In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type KRAS (n = 390) and those carrying KRAS mutations in codon 12 (n = 240). CRC patients with wild-type KRAS harboring mutations in HRAS, NRAS, PIK3CA, PIK3CD, PIK3CG, RALGDS, BRAF, or ARAF were excluded from the analysis. At least 11 promising candidate molecules showed greater than two-fold change between the KRAS G12 mutant and wild-type and had a Benjamini-Hochberg-adjusted P value of less than 1E-08, evidence of significantly differential expression between these two groups. Among these 11 genes examined in cell lines transfected with KRAS G12 mutants, BMP4, PHLDA1, and GJB5 showed significantly higher expression level in KRAS G12A, G12D, and G12V transfected cells than in the wild-type transfected cells. We expect that this study will lead to the development of novel treatments that target signaling molecules functioning with KRAS G12-driven CRC., (© 2021. The Author(s).)

Aims: In contrast to cardiovascular disease, low rather than high ventilatory inefficiency, evaluated by the minute ventilation-carbon dioxide output ( V' E - V' CO2 )-slope, has been recognized as being related to greater disease severity in chronic obstructive pulmonary disease (COPD). To better care for patients with cardiopulmonary disease, understanding the physiological correlation between ventilatory inefficiency and exercise limitation is necessary, but remains inadequate. Given that oxygen uptake ( V' O2 ) evaluated by cardiopulmonary exercise testing (CPET) depends on both the ventilatory capability and oxygen extraction, i.e., the difference between inspiratory and expiratory oxygen concentration (ΔFO 2 ), the aim of this study was to investigate the correlations between V' E - V' CO2 -slope and the ΔFO 2 during exercise and their physiological implications in patients with COPD. Methods: A total of 156 COPD patients (mean age, 70.9 ± 7.2 years) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV and 16 controls underwent CPET with blood gas analysis. Results: With the progression of COPD, mechanical ventilatory constraints together with a slower respiratory frequency led to exertional respiratory acidosis. In GOLD IV cases, (1) decrease in the dependence of reduced peak V' O2 on V' E led to an increase in its dependence on peak ΔFO 2 during exercise; and (2) the ΔFO 2 - V' CO2 -slope became steeper, correlating with the severity of exertional respiratory acidosis (r = 0.6359, p < 0.0001). No significant differences in peak exercise ΔFO 2 or V' E - V' CO2 -slope were observed among the various GOLD stages. In all subjects, including controls, peak exercise ΔFO 2 had the strongest correlation with the V' E - V' CO2 -slope (r = -0.8835, p < 0.0001) and correlated well with body mass index (r = 0.3871, p < 0.0001), although it did not correlate with the heart rate- V' CO2 -relationship and V' E . Conclusions: Ventilatory efficiency related to CO 2 clearance might depend on exertional oxygen extraction in the body. Measuring ΔFO 2 might be a key component for identifying ventilatory inefficiency and oxygen availability. Increasing ΔFO 2 would help to improve ventilatory inefficiency and exercise tolerance separately from cardiac and ventilatory capability in COPD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Miki, Tsujino, Maekuara, Matsuki, Miki, Hashimoto, Kagawa, Kawasaki, Kuge and Kida.)

Background: Persistent descending mesocolon (PDM) is typically asymptomatic. However, features such as adhesion and variations in vessel anatomy could affect the surgical techniques for colorectal cancer (CRC). This study aimed to investigate the frequency and radiological features of PDM. Short-term outcomes after conventional laparoscopic surgery (CLS) for CRC with PDM were also investigated to assess the feasibility of CLS and identify strategies for minimally invasive surgery (MIS) in CRC with PDM., Methods: Patients who underwent MIS, including CLS and robot-assisted laparoscopic surgery (RALS), for left-sided CRC between April 2016 and June 2019, were investigated. PDM was defined as the existence of the right border of the descending colon inside the right border of the left kidney based on preoperative computed tomography findings., Results: Radiological findings of 837 patients were examined, and PDM was found in 19 (2.3%) patients. Radiality of the inferior mesenteric artery (IMA) was found in 5 of 19 (26.3%) PDM cases, which was significantly higher than that in non-PDM cases. The median lengths between the IMA and inferior mesenteric vein (IMV) and between the IMV and descending colon in PDM cases were 14.8 mm and 17.2 mm, respectively, which were significantly shorter than those in non-PDM cases. Short-term outcomes were evaluated only in CLS cases since the rate of hybrid surgery among RALS cases differed between non-PDM and PDM cases (0% vs. 44.4%), which would affect the surgical outcomes. The short-term outcomes in 447 CLS cases were similar between PDM and non-PDM cases. The frequency of extracorporeal division of the left colic artery (LCA) and IMV was significantly higher in PDM than in non-PDM cases (70.0% vs. 5.7%)., Conclusions: This radiological definition of PDM was feasible. CLS for left-sided CRC with PDM was feasible, and dividing the LCA and IMV extracorporeally would be vital for safe surgery.

The worldwide microplastic pollution in our environment is a matter of great concern. Harmful effects of plastics have been reported in various types of organisms including murine animals. We examined the presence of microplastics in four types of shellfish purchased from fish markets in Okayama, Japan and served to the public: short-neck clam (Ruditapes philippinarum, asari in Japanese), hard-shell clam (Meretrix lusoria, hamaguri), brackishwater clam (Cyrenidae, shijimi), and oyster (Crassostrea gigas, kaki). Our analyses demonstrated that approx. 3 pieces of microplastics were present per single shellfish, based on the division of the total number of pieces of microplastic obtained from all 4 types of shellfish by the total number of shellfish examined. Since health problems in humans due to microplastics have not yet been confirmed, further examinations of the effects of ingested microplastics are needed., Competing Interests: No potential conflict of interest relevant to this article was reported.

This study aimed to evaluate improvement of tongue-palatal contact patterns during swallowing after orthognathic surgery in mandibular prognathism patients. Thirty patients with mandibular prognathism treated by orthognathic surgery (average age of 27 years, 3 months) and 10 controls (average age 29 years, 6 months) participated in this study. Tongue-palatal contact patterns of patients before and three months after surgery were evaluated by electropalatography (EPG) as well as controls. Whole total of tongue-palatal contact at 0.3, 0.2, and 0.1 sec before complete tongue-palatal contact during swallowing were evaluated. The duration of swallowing phases was also examined. Complete contact of tongue-tip in the alveolar part of individual artificial EPG plate were shown at 0.3, 0.2, and 0.1 sec before complete tongue-palatal contact in the controls, although incomplete contact in the alveolar part were shown at 0.3 sec in mandibular prognathism patients. Whole total of tongue-palatal contact at 0.3 and 0.2 sec before complete tongue-palatal contact was significantly lower in the patients before surgery than in the controls (p<0.05). However, these values increased after surgery. The duration of oral and pharyngeal phase was significantly longer in the patients before surgery than in the controls and the patients after surgery (p<0.01). This study demonstrated that the tongue-palatal contact pattern improved and the duration of oral and pharyngeal phase was shortened in mandibular prognathism patients during swallowing after orthognathic surgery. It is suggested that changes in maxillofacial morphology by orthognathic surgery can induce normal tongue movement during swallowing. (The data underlying this study have been uploaded to figshare and are accessible using the following DOI: https://doi.org/10.6084/m9.figshare.14101616.v1)., Competing Interests: The authors have clearly stated that there are no conflicts of interest in connection with this article.

Background: Urinary dysfunction (UD) remains a significant complication of rectal cancer surgery. In modern surgical treatment for rectal cancer, multiple operative approaches are used. Such approaches include open, laparoscopic, and robotic-assisted surgery; and multiple procedures, including anterior, intersphincteric, and abdominoperineal resection. Thus, modern surgical treatments for rectal cancer have diversified. This study aimed to identify risk factors for early UD (EUD) after total mesorectal excision (TME) and to explore the methods for decreasing postoperative EUD in diverse surgical treatments for rectal cancer., Methods: In our retrospective cohort study, we enrolled patients with lower rectal cancer who underwent TME alone at a single high-volume cancer center between 2010 and 2017. EUD was defined as the presence of ≥ 50 mL residual urine volume. Multivariate analysis was performed to determine clinicopathological factors significantly associated with postoperative EUD., Results: Of a total of 337 eligible patients, 32 patients (10%) had postoperative EUD. Multivariate analysis revealed that only the operative approach (laparoscopic surgery: odds ratio [OR], 8.93; 95% confidence interval [CI], 2.94-27.14, open surgery: OR, 11.55; 95% CI 2.10-63.83) was significantly associated with an increase in postoperative EUD. Robotic-assisted surgery was associated with significant reduction in postoperative EUD., Conclusion: Only robotic-assisted surgery was inversely correlated with postoperative EUD. Robotic-assisted surgery may be a useful approach to protect urinary function in lower rectal cancer surgery.

The association between Mycobacterium avium complex pulmonary disease (MAC-PD) and pleuroparenchymal fibroelastosis (PPFE) has been reported previously, and interstitial pneumonia as a comorbidity is associated with a worse prognosis. However, no study has thoroughly reported on PPFE associated with MAC-PD. The present study investigated the prevalence, clinical characteristics, and prognostic impact of PPFE in patients with MAC-PD. A total of 224 patients, newly diagnosed with MAC-PD, were retrospectively reviewed. At the time of diagnosis, chest high-resolution computed tomography (HRCT), sputum examination, and clinical characteristics were collected. The extent of PPFE and MAC-PD was evaluated semi-quantitatively using HRCT scores. Risk factor analysis for clinical or radiological deterioration necessitating multidrug antimicrobial treatment within 3 years, and all-cause mortality within 5 years, from the initial diagnosis was performed based on the PPFE score. PPFE was observed in 59 out of 224 patients (26.3%). A higher PPFE score was a risk factor for dyspnoea, fatigue, and lower body mass index (BMI) (p<0.05). Although PPFE score did not correlate with clinical or radiological deterioration within 3 years (p=0.576), a higher PPFE score (adjusted OR 1.66, 95% CI 1.06-2.60, p=0.028) and lower BMI (adjusted OR 0.61, 95% CI 0.39-0.94, p=0.028) increased the risk of 5-year mortality. PPFE is a relatively common complication and an independent poor prognostic factor of MAC-PD. This study highlights the need for further studies investigating whether the presence of PPFE can be a clinical indicator for initiating treatment of MAC-PD., Competing Interests: Conflict of interest: Y. Yamamoto has nothing to disclose. Conflict of interest: K. Tsujino has nothing to disclose. Conflict of interest: T. Kuge has nothing to disclose. Conflict of interest: F. Okabe has nothing to disclose. Conflict of interest: T. Kawasaki has nothing to disclose. Conflict of interest: T. Matsuki has nothing to disclose. Conflict of interest: H. Kagawa has nothing to disclose. Conflict of interest: M. Miki has nothing to disclose. Conflict of interest: K. Miki has nothing to disclose. Conflict of interest: M. Mori has nothing to disclose. Conflict of interest: H. Kida has nothing to disclose., (Copyright ©ERS 2021.)

The combination of rifamycin (RFP), ethambutol (EB), and macrolides is currently the standard regimen for treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). However, poor adherence to the standardized regimens recommended by current guidelines have been reported. We undertook a single-centred retrospective cohort study to evaluate the long-term outcomes in 295 patients with MAC-PD following first line treatment with standard (RFP, EB, clarithromycin [CAM]) or alternative (EB and CAM with or without fluoroquinolones (FQs) or RFP, CAM, and FQs) regimens. In this cohort, 80.7% were treated with standard regimens and 19.3% were treated with alternative regimens. After heterogeneity was statistically corrected using propensity scores, outcomes were superior in patients treated with standard regimens. Furthermore, alternative regimens were significantly and independently associated with sputum non-conversion, treatment failure and emergence of CAM resistance. Multivariate cox regression analysis revealed that older age, male, old tuberculosis, diabetes mellitus, higher C-reactive protein, and cavity were positively associated with mortality, while higher body mass index and M. avium infection were negatively associated with mortality. These data suggest that, although different combination regimens are not associated with mortality, first line administration of a standard RFP + EB + macrolide regimen offers the best chance of preventing disease progression in MAC-PD patients.

Abstract: This study aimed to investigate the changes in tongue-palatal contact patterns in patients with mandibular lateral deviation by electropalatography (EPG) before and after sagittal split ramus osteotomy (SSRO). Ten mandibular asymmetry patients who underwent SSRO participated in the study. Tongue-palatal contact patterns for the production of /t/ and /s/ sounds were observed using EPG before surgery and 3 months after surgery, and the changes in EPG pattern were examined. The number of electrode contacts in the 2 vertical columns of the EPG plate was calculated both in the mandibular deviation side and the nondeviation side. The EPG patterns for /t/ and /s/ showed asymmetry before surgery but became normal after surgery. Before surgery, the number of electrode contacts in the 2 vertical columns in the mandibular deviation side was significantly lower than that in the nondeviation side and the normal participants during /t/ and /s/ articulation. However, the number of electrode contacts in the deviation side significantly increased after surgery. This study demonstrated that the tongue-palatal contact patterns for /t/ and /s/ articulation shifted to the direction of mandibular deviation and improved after SSRO., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Although the utility of oscillometry for predicting disease severity in idiopathic pulmonary fibrosis (IPF) had been researched, little has been reported on the mechanism of why respiratory impedance reflects disease severity. In addition, traction bronchiectasis has been considered to reduce respiratory resistance and correlate negatively with airflow obstruction, but this hypothesis has not been validated. The present study aimed to investigate the correlations between oscillometric parameters and fibrosis-related lung abnormalities in IPF and to assess the utility of oscillometry as a surrogate marker for traction bronchiectasis and airflow obstruction. Eighty Japanese patients with IPF underwent high-resolution computed tomography (HRCT), spirometry, and oscillometry and were retrospectively investigated. Fibrosis-related HRCT findings were scored regarding airspace consolidation, honeycombing, architectural distortion, traction bronchiectasis, and fibrosis. Correlations between the HRCT scores, spirometric parameters, and oscillometric parameters were analysed. Respiratory reactance correlated positively with all fibrosis-related HRCT scores. Vital capacity and forced vital capacity (FVC) correlated negatively with oscillometric parameters and HRCT scores, reflecting the severity of restrictive ventilatory deficiency. Respiratory resistance was not related to any of the HRCT scores or forced expiratory volume in 1 s/FVC. However, forced expiratory volume in 1 s/FVC correlated positively with HRCT scores, which showed that airflow obstruction became milder as the disease progressed. In conclusion, respiratory reactance reflects fibrosis and restrictive ventilatory deficiency in IPF. Moreover, respiratory resistance is independent of traction bronchiectasis and airflow obstruction in patients with IPF, which implies that respiratory resistance might reflect different properties of the airways., Competing Interests: Conflict of interest: Y. Yamamoto has nothing to disclose. Conflict of interest: K. Miki has nothing to disclose. Conflict of interest: K. Tsujino has nothing to disclose. Conflict of interest: T. Kuge has nothing to disclose. Conflict of interest: F. Okabe has nothing to disclose. Conflict of interest: T. Kawasaki has nothing to disclose. Conflict of interest: T. Matsuki has nothing to disclose. Conflict of interest: H. Kagawa has nothing to disclose. Conflict of interest: M. Miki has nothing to disclose. Conflict of interest: H. Kida has nothing to disclose., (Copyright ©ERS 2020.)

Rationale: Although gastric aspirate culture is used for diagnosing pulmonary tuberculosis, its usefulness in diagnosing pulmonary infections of nontuberculous mycobacteria (NTM) is unknown. Objectives: To investigate the diagnostic validity of gastric aspirate culture for acid-fast bacilli in NTM pulmonary disease (NTM-PD). Methods: Gastric aspirates were collected from patients with suspected NTM-PD at the Osaka Toneyama Medical Center between December 2006 and February 2018. Patients with a final diagnosis of pulmonary tuberculosis, an observation period of less than 6 months, or fewer than three conducted sputum cultures were excluded from the study. NTM-PD was diagnosed as per American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria. We retrospectively examined the diagnostic validity of gastric aspirate culture in Mycobacterium avium complex (MAC)-PD and M. kansasii- PD by comparing culture results with final diagnoses. This was done first for all patients, and subsequently for patients with negative results for early sputum cultures. In addition, we compared the time required for an NTM-PD diagnosis based on gastric aspiration with that based on ATS/IDSA criteria. Results: Among 475 total patients, 119 (25.1%) had positive NTM gastric aspirate cultures and 154 (32.4%) fulfilled the ATS/IDSA criteria for NTM-PD. The sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPVs) of gastric aspiration were 63.9%, 95.8%, 83.5%, and 88.8% in MAC-PD and 82.4%, 99.6%, 87.5%, and 99.3% in M. kansasii -PD, respectively. Sensitivity, specificity, PPV, and NPV of gastric aspirate cultures of the 378 patients who were undiagnosed based on sputum culture within 120 days were 34.0%, 95.5%, 51.6%, and 91.1% for MAC-PD and 75.0%, 99.5%, 60.0%, and 99.7% for M. kansasii -PD, respectively. Furthermore, gastric aspirate cultures tested in addition to bronchoscopy yielded incremental sensitivity of 8.7% (95.7% vs. 87.0%) and an NPV of 1.3% (99.3% vs. 98.0%) in MAC-PD. In patients with NTM-PD with NTM-positive gastric aspirate cultures, the period between gastric aspirate collection and the positive culture result was shorter than the time between gastric aspirate collection and NTM-PD diagnosis (6 [9-36] d vs. 25 [12-69] d, median [interquartile range], P  < 0.0001]. Conclusions: In settings where acid-fast bacilli pulmonary diseases are suspected, gastric aspirate culture may be helpful for diagnosing MAC-PD and M. kansasii- PD.

Background: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient., Case Presentation: A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly., Conclusion: We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.

Human trophoblast stem cells (hTSCs) derived from blastocysts and first-trimester cytotrophoblasts offer an unprecedented opportunity to study the placenta. However, access to human embryos and first-trimester placentas is limited, thus preventing the establishment of hTSCs from diverse genetic backgrounds associated with placental disorders. Here, we show that hTSCs can be generated from numerous genetic backgrounds using post-natal cells via two alternative methods: (1) somatic cell reprogramming of adult fibroblasts with OCT4, SOX2, KLF4, MYC (OSKM) and (2) cell fate conversion of naive and extended pluripotent stem cells. The resulting induced/converted hTSCs recapitulated hallmarks of hTSCs including long-term self-renewal, expression of specific transcription factors, transcriptomic signature, and the potential to differentiate into syncytiotrophoblast and extravillous trophoblast cells. We also clarified the developmental stage of hTSCs and show that these cells resemble day 8 cytotrophoblasts. Altogether, hTSC lines of diverse genetic origins open the possibility to model both placental development and diseases in a dish., Competing Interests: Declaration of Interests D.M. is supported by FINOX forward grant initiative. G.C. and L.D. have a provisional patent filled on the generation of hiTSCs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The present study aimed to evaluate osmotic pump-mediated controlled release of estrogen in males and androgen in females to analyze the impact on gonadotropin-releasing hormone (GnRH1), catecholamines (CAs) and other associated genes in the catfish, Clarias gariepinus. During pre-spawning phase, catfish were separately implanted osmotic pumps loaded with 17β-estradiol (E 2 ) in males and 17α-methyltestosterone (MT) in females at a dose of 10 μg/100 μl or saline (100 μl) controls into both sexes to release for 21 days and all fishes were maintained as per the duration. Further, GnRH1 expression levels were analysed in the discrete regions of brain after E 2 and MT treatments in male and female catfish, respectively using qPCR which revealed that GnRH1 expression was significantly higher in E 2 treated male as compared to the control. On the other hand, GnRH1 expression was lower in MT treated female when compared to the control in the discrete regions of brain. In addition, certain brain and monoaminergic system related genes showed a differential response. Catfish GnRH1 could be localized in preoptic area-hypothalamus (POA-HYP) that correlated with the expression profile in the discrete regions of catfish brain. Serum levels of sex steroids in the treated male fish indicated that the treatment of E 2 could maintain and impart feminization effect even in the presence of endogenous androgen during gonadal recrudescence while such an effect was not seen in females with androgen treatment. Measurement of CAs, L-3,4-dihydroxyphenylalanine, dopamine and norepinephrine levels in the male and female brain after the controlled release of E 2 and MT, respectively confirmed the modulation of neurotransmitters in the E 2 treated male than MT treated female fish. These results collectively suggest the severity of estrogenic over androgenic compounds to alter reproductive status even at a minimal dose by targeting CAs and GnRH1 at the level of brain of catfish. This study provides insights into the reproductive toxicity of sex steroid analogues at the level of brain GnRH1 and CA-ergic system in addition to serum T, 11-KT and E 2 levels during gonadal recrudescence, which is a crucial period of gametogenesis preceding spawning., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exosomes contain many proteins associated with neurodegenerative diseases. To identify new candidate biomarkers and proteins associated with amyotrophic lateral sclerosis (ALS), we performed liquid chromatography-tandem mass spectrometry proteomic analysis of exosome-enriched fractions isolated from cerebrospinal fluid (CSF) of sporadic ALS patients using gel filtration chromatography. Proteomic data revealed that three proteins were increased and 11 proteins were decreased in ALS patients. The protein with the greatest increase in exosome-enriched fractions of CSF derived from ALS was novel INHAT repressor (NIR), which is closely associated with nucleolar function. By immunohistochemical analysis, we found that NIR was reduced in the nucleus of motor neurons in ALS patients. Our results demonstrate the potential utility of our methodology for proteomic analysis of CSF exosomes and suggest that nucleolar stress might play a role in sporadic ALS pathogenesis through the dysfunction of NIR., (Copyright © 2019 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Background: Although a "no-touch isolation" technique is used in colorectal cancer surgery to reduce the risk of metastatic induction, endoscopic resection (ER) prior to surgery may work against this aim. This study evaluated the effects of initial ER on short- and long-term outcomes in T1 colorectal cancer., Methods: This retrospective cohort study enrolled patients with pathological T1 colorectal cancer who underwent colorectal surgical resection at a Japanese tertiary cancer center between 2002 and 2012. A total of 548 eligible patients were divided into two groups: patients initially treated using surgical resection with lymph node dissection (LND) (primary group, n = 304) and patients treated using initial ER and additional surgical resection with LND (secondary group, n = 244). The inverse probability of treatment weighting (IPTW) method based on propensity score was used to compare postoperative complications and long-term recurrence., Results: The incidence of postoperative complications with Clavien-Dindo classification grade ≥ II was 10.9% and 7.4% in the primary and secondary groups, respectively (p = 0.16). Multivariate analysis with a logistic proportional hazard regression model using IPTW revealed no significant differences in postoperative complications between the two groups (p = 0.79). During a median follow-up after surgery of 61.4 months, recurrence was observed in 3 (1.0%) and 8 (3.3%) patients, respectively (p = 0.06). Multivariate analysis with a Cox proportional hazard regression model using IPTW revealed no significant differences in recurrence between the two groups (p = 0.07)., Conclusion: Our results suggest no significant adverse effects of initial ER prior to surgery on surgical complications and long-term recurrence in T1 colorectal cancer.

Although the diagnostic value of impulse oscillometry (IOS) in bronchiectasis for the differential diagnosis of healthy subjects has been researched, the usefulness of each IOS parameter for predicting disease severity in bronchiectasis has not been thoroughly investigated. In addition, the usefulness of IOS in patients with nontuberculous mycobacteria (NTM) infection has not been reported. This study aimed to determine the predictive significance of respiratory impedance and detect the other most significant IOS parameters for predicting disease severity in bronchiectasis patients and to validate the usefulness of IOS in patients with NTM infection. A total of 206 patients with bronchiectasis who attended clinics at the National Hospital Organization Osaka Toneyama Medical Center were included. Chest high-resolution computed tomography, spirometry and IOS were performed. Hospital admissions, mortality and disease severity indices for bronchiectasis (Bronchiectasis Severity Index (BSI), FACED, and E-FACED scores) were calculated to assess disease severity. The patients were divided into subgroups with and without NTM infection, and subgroup analyses were performed. Respiratory reactance, especially resonant frequency ( f res ), correlated with both BSI and FACED score better than respiratory resistance. Inspiratory but not expiratory impedance was strongly correlated with BSI, FACED and E-FACED scores. Inspiratory f res was the most useful predictor, increasing as the disease became more severe. The usefulness of IOS was almost equivalent in patients both with and without NTM infection. Inspiratory reactance measured by IOS is useful for estimating disease severity in bronchiectasis. Inspiratory f res best predicts disease severity in bronchiectasis patients both with and without NTM infection., Competing Interests: Conflict of interest: Y. Yamamoto has nothing to disclose. Conflict of interest: K. Miki has nothing to disclose. Conflict of interest: K. Tsujino has nothing to disclose. Conflict of interest: T. Kuge has nothing to disclose. Conflict of interest: T. Matsuki has nothing to disclose. Conflict of interest: K. Fukushima has nothing to disclose. Conflict of interest: Y. Oshitani has nothing to disclose. Conflict of interest: H. Kagawa has nothing to disclose. Conflict of interest: K. Yoshimura has nothing to disclose. Conflict of interest: M. Miki has nothing to disclose. Conflict of interest: H. Kida has nothing to disclose., (Copyright ©ERS 2020.)

Female songbirds identify and prefer conspecific male songs. Songs are an important cue for species discrimination. Bengalese finches are domesticated species and their male songs seem to have evolved as they comprise more complex sequences and tonal sounds than the songs of their wild ancestors, white-rumped munias. Previous research suggested that the degeneration of song functionality for species identification may have been one of the factors that promoted the evolution of song complexity in domestic strains. We hypothesized that female responses to conspecific songs have changed between the two strains: white-rumped munias could distinguish songs of their own species more readily than Bengalese finches. Because the song discrimination is affected by developmental experiences, we used adult female Bengalese finches and white-rumped munias reared with or without exposure to songs of their own strains (i.e., socially-reared or untutored). To evaluate their song discrimination, we quantified zenk-labeled cells in the auditory areas after exposure to song stimuli, either with songs of own strains or those of other strains. Socially-reared white-rumped munias exposed to songs of Bengalese finches showed lesser zenk expression than munias exposed to songs of their own strain. However, there were no significant differences among the groups in Bengalese finches. The result suggests that white-rumped munias could distinguish songs of their own species more strictly than Bengalese finches., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of the study was to investigate the effect of chemo-radiation on the genetic and immunological status of rectal cancer patients who were treated with preoperative chemoradiotherapy (CRT). The expression of immune response-associated genes was compared between rectal cancer patients treated (n = 9) and not-treated (n = 10) with preoperative CRT using volcano plot analysis. Apoptosis and epithelial-to-mesenchymal transition (EMT) marker genes were analysed by quantitative PCR (qPCR). Other markers associated with the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TIL) and immune checkpoint molecules, were investigated using immunohistochemistry (IHC). The clinical responses of preoperative CRT for 9 rectal cancer patients were all rated as stable disease, while the pathological tumor regression score (TRG) revealed 6 cases of grade2 and 3 cases of grade1. According to the genetic signature of colon cancers, treated tumors belonged to consensus molecular subtype (CMS)4, while not-treated tumors had signatures of CMS2 or 3. CRT-treated tumors showed significant upregulation of EMT-associated genes, such as CDH2, TGF-beta and FGF, and cancer stem cell-associated genes. Additionally, qPCR and IHC demonstrated a suppressive immunological status derived from the upregulation of inflammatory cytokines (IL-6, IL-10 and TGF-beta) and immune checkpoint genes (B7-H3 and B7-H5) and from M2-type macrophage accumulation in the tumor. The induction of EMT and immune-suppressive status in the tumor after strong CRT treatment urges the development of a novel combined therapy that restores immune-suppression and inhibits EMT, ultimately leading to distant metastasis control., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: The aim of this study was to evaluate the incidence, risk factors, and clinical impact of progression of aortic insufficiency (AI) after left ventricular assist device (LVAD) implantation., Methods: Patients undergoing primary durable LVAD implantation between 2004 and 2018 were included. Significant AI was defined as more than mild AI. Clinical and echocardiographic data were collected. Patients were stratified by degree of pre-LVAD AI into 3 groups: no AI, group I; trace AI, group II; and mild AI, group III., Results: Three hundred sixteen eligible patients underwent LVAD implant, 229 patients (72.5%) in group I, 54 (17.1%) in group II, and 33 (10.4%) in group III. Median follow-up was 469 days. Forty-two patients (13.3%) progressed to significant AI during follow-up. Group III patients had the highest rate of developing significant AI (I, 10.0%; II, 13.0%; III, 36.4%; P = .002). Freedom from significant AI at 1 year after LVAD implant was 94.5% in group I, 86.1% in group II, and 62.4% in group III (P < .001). Predictors of developing significant AI included mild preoperative AI, ischemic cardiomyopathy, and shorter duration of LVAD support. Patients with significant AI after LVAD implantation had higher mortality compared with those without (59.5% vs 37.2%; P = .006)., Conclusions: Although some patients supported with an LVAD develop significant AI, this risk is increased in those with mild AI preoperatively. This finding, in conjunction with the increased mortality risk once significant AI develops, suggests that closer follow-up and management of LVAD patients with mild preoperative AI may be prudent., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: The present study aimed to investigate the effects of hyperbaric oxygen (HBO) treatment on calvarial bone regeneration in young and adult mice., Methods: Calvarial defects of 6.0 mm diameter were created in sixteen 3-week (young) and sixteen 32-week old (adult) mice. The mice were divided into two groups of eight animals each (HBO-treated and control). The 90-min HBO treatment at 2.5 absolute atmospheric pressure and 100 % oxygen was performed for five days a week for 12 weeks. After 2-weeks from the operation, micro-computerized tomography and video microscopy were used to evaluate the regenerated bone volume and microcirculation every two weeks. The protein concentrations of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in exudates of the calvarial tissue field were measured at 1, 2, 3, and 4 weeks after surgery. After 12 weeks, histochemical examination of regenerated calvarial bone was conducted., Results: Regenerated bone was formed earlier in young mice than in adult mice treated with HBO. HBO stimulates angiogenesis in the periosteum around regenerated bone area in both young and adult mice at 2 weeks. VEGF concentrations in the calvarial tissue field were lower in the HBO group than in the control 1 week after operation, although bFGF were higher till the 2nd week in the HBO group than in the control., Conclusions: HBO accelerates bone regeneration earlier in young mice than in adult mice. In the HBO-treated group, bFGF expression was promoted at an early stage, although the expression of VEGF was inhibited., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Exertional prolonged expiration should be identified as a therapeutic target in COPD. The efficacy of expiratory or inspiratory pressure load training (EPT/IPT) based on the degree of prolonged expiration was investigated., Methods: A total of 21 patients with COPD were divided into two groups according to the exertional change in the inspiratory duty cycle ( T I / T tot). For 12 weeks, patients whose exertional T I / T tot decreased received EPT (EPT group, n=11, mean percentage forced expiratory volume in 1 s (%FEV 1 ), 32.8%) and those whose exertional T I / T tot increased received IPT (IPT group, n=10, mean %FEV 1 , 45.1%)., Results: The therapeutic responses were as follows. In both groups, endurance time (EPT, +5.7 min, p<0.0001; IPT, +6.1 min, p=0.0004) on the constant work rate exercise test (WRET) and peak oxygen uptake increased (EPT, p=0.0028; IPT, p=0.0072). In the EPT group the following occurred: 1) soon after commencement of exercise with the constant WRET, the expiratory tidal volume ( V T ex) increased, reducing dyspnoea; 2) V T ex and mean expiratory flow increased and then prolonged expiration (p=0.0001) improved at peak exercise with the incremental exercise test (ET); and 3) St. George's Respiratory Questionnaire total, activity and impact scores were improved. In the IPT group, on both the constant WRET and incremental ET, breathing frequency increased, which led to greater exercise performance with effort dyspnoea., Conclusions: This study showed the benefits of EPT/IPT on exercise performance. If the choice of managing COPD with EPT/IPT is appropriate, inexpensive EPT/IPT may become widespread as home-based training., Competing Interests: Conflict of interest: M. Miki has nothing to disclose. Conflict of interest: K. Tsujino has nothing to disclose. Conflict of interest: M. Miki has nothing to disclose. Conflict of interest: K. Yoshimura has nothing to disclose. Conflict of interest: H. Kagawa has nothing to disclose. Conflict of interest: Y. Oshitani has nothing to disclose. Conflict of interest: K. Fukushima has nothing to disclose. Conflict of interest: T. Matsuki has nothing to disclose. Conflict of interest: Y. Yamamoto has nothing to disclose. Conflict of interest: H. Kida has nothing to disclose., (Copyright ©ERS 2020.)

Background and Aim: If patients with surgically resectable colorectal cancershave synchronous colorectal neoplasms that are difficult to remove by endoscopic mucosal resection, preemptive endoscopic submucosal dissection (ESD) can avoid excessive colorectal resection. The aim of this study was to evaluate the efficacy of the strategy of preemptive ESD and surgery for synchronous colorectal neoplasms., Methods: Patients who underwent preemptive ESD and surgery for synchronous colorectal neoplasms between September 2002 and December 2017 were enrolled in this retrospective cohort study. The proportion of cases in which extended surgery could be avoided following curative ESD was calculated. Clinicopathological characteristics were evaluated for all patients and long-term outcomes were analyzed for patients who underwent curative ESD and surgery., Results: A total of 45 consecutive patients with 47 endoscopically-resected lesions and 46 surgically-resected lesions were retrospectively evaluated. Curative ESD was achieved in 44 lesions (93.6%) and an extended surgical procedure could be avoided in 42 patients (93.3%). Intraoperative perforation occurred in two lesions (4.3%), delayed perforation in one lesion (2.1%), and delayed bleeding in two lesions (4.3%). Final stages were as follows: stage 0, 3 patients (7.1%); stage I, 23 patients (54.8%); stage II, 3 patients (7.1%); stage III, 12 patients (28.6%); and stage IV, 1 patient (2.4%). The 5-year overall survival rates of patients with all pathological stages, stage 0-II, and stage III-IV were 93.7%, 100%, and 79.1%, respectively., Conclusion: The strategy of preemptive ESD and surgery for synchronous colorectal neoplasms is minimally invasive and has a favorable prognosis.

An increasing accumulation of microplastics and further degraded nanoplastics in our environment is suspected to have harmful effects on humans and animals. To clarify this problem, we tested the cytotoxicity of two types of plastic wrap on human cultured liver cells and mouse primary cultured liver cells. Alcohol extracts from plastic wrap, i.e., polyvinylidene chloride (PVDC), showed cytotoxic effects on the cells. Alcohol extracts of polyethylene (PE) wrap were not toxic. The commercially available PVDC wrap consists of vinylidene chloride, epoxidized soybean oil, epoxidized linseed oil as a stiffener and stabilizer; we sought to identify which component(s) are toxic. The epoxidized soybean oil and epoxidized linseed oil exerted strong cytotoxicity, but the plastic raw material itself, vinylidene chloride, did not. Our findings indicate that plastic wraps should be used with caution in order to prevent health risks., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: What qualifies as optimal lymph node (LN) dissection in the surgical management of splenic flexure colon cancer (SFCC) still remains controversial because few studies have evaluated the distribution of LN metastasis of SFCC. The aim of this study was to clarify detailed distribution of LN metastasis and long-term outcomes of SFCC., Methods: This retrospective study enrolled patients who had curative colectomy for primary transverse or descending colon cancer of pathological stage I, II, or III at a single high-volume cancer center between April 2002 and December 2018. The 538 eligible patients were divided into three groups: patients with SFCC (SFCC group, n = 168), patients with proximal transverse colon cancer (PTCC group, n = 290), and patients with distal descending colon cancer (DDCC group, n = 80). LNs were classified into horizontal (pericolic) and vertical (intermediate and main) nodes. Intermediate and main LN station numbers were defined according to the Japanese Society for Cancer of the Colon and Rectum classification. Distributions of LN metastasis and long-term outcomes were compared., Results: In the SFCC group, the mean age was 67.3 ± 10.5 years and 110 patients (65.5%) were male. The proportion of patients with LN metastasis in the intermediate or main region was significantly lower in the SFCC group (8%) than in the PTCC (37%) (p < 0.01) or DDCC group (29%) (p < 0.01) in pathological stage III patients. In the SFCC group, the incidence of pericolic LN metastasis on the oral side of tumor (43%) was significantly higher than in the PTCC group (21%) (p < 0.01) and was similar to that in the DDCC group (42%) (p = 0.51), while in the SFCC group, the incidence of pericolic LN metastasis on the anal side of tumor (17%) was lower than in the PTCC group (31%) and was also similar to that in the DDCC group (21%). There were no significant differences in disease-specific survival rates among all groups., Conclusions: LN metastasis occurred mainly in the pericolic region, especially on the oral side of the tumor in SFCC. It may, therefore, be important to have an adequate bowel resection margin, especially on the oral side, for SFCC.

Background: Oscillometry is a tool to measure respiratory impedance that requires minimal patients' effort. In patients with chronic obstructive pulmonary disease (COPD), the correlation of respiratory impedance at rest with exertional ventilatory parameters, including exercise tolerance, has scarcely been reported. In addition, the utility of oscillometric parameters might differ between the inspiratory and expiratory phases due to airflow obstruction during expiration, but the hypothesis had not been validated. The aim of the present study was to investigate whether oscillometric parameters are associated with exertional ventilatory parameters in patients with COPD., Methods: Fifty-five subjects with COPD who attended clinics at the National Hospital Organization Osaka Toneyama Medical Center performed spirometry, oscillometry, and cardiopulmonary exercise testing (CPET) within 2 weeks. The correlations between parameters of spirometry, oscillometry, and CPET were analyzed using Spearman's rank correlation coefficient, univariate, and multivariate analyses., Results: Respiratory reactance had better correlations with the CPET parameters than respiratory resistance. Moreover, inspiratory reactance at rest correlated with the CPET parameters stronger than expiratory reactance. In particular, inspiratory resonant frequency (Fres-ins) correlated with peak oxygen uptake (r S =-0.549, p<0.01) and dead space to tidal volume ratio at peak exercise (r S =0.677, p<0.01) and the best predicted expiratory tidal volume (V T ex) at peak exercise of all the oscillometric parameters (r S =-0.679, p<0.01). However, the correlation between Fres-ins and V T ex at peak exercise became weak in subjects with severe and very severe COPD during exercise., Conclusion: Measurement of respiratory reactance is useful for the effortless evaluation of not only exertional ventilatory parameters but exercise tolerance in patients with COPD. The correlation of respiratory impedance with exertional ventilatory parameters can become weak in patients with advanced COPD; thus, the measurement of oscillometry might not be appropriate for evaluating exertional ventilatory parameters of patients with advanced COPD., Competing Interests: The authors declare no conflicts of interest in association with the present study., (© 2020 Yamamoto et al.)

Influenza vaccination can trigger various adverse reactions, and thrombocytopenia is also rarely reported. Although patients with mild thrombocytopenia are sometimes asymptomatic, severe thrombocytopenia can cause severe bleeding. We herein report a rare case of severe thrombocytopenia that occurred within one day of influenza vaccination and diffuse alveolar hemorrhage (DAH) leading to acute respiratory failure. The patient was treated with glucocorticoid pulse therapy, intravenous immunoglobulin, and temporary mechanical ventilation, and eventually he made a full recovery. Vaccine-related thrombocytopenia and DAH should be considered adverse reactions, even if they develop very soon after vaccination.

Background: Lung resection in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) has been reported to be associated with favorable outcomes. However, little is known regarding the risk and prognostic factors for refractory and recurrent cases. We aimed to evaluate the overall impact and benefit of adjuvant lung surgery by comparing NTM-PD patients who underwent adjuvant lung resection with those treated exclusively with antibiotics. We also investigated the efficacy of serum IgA antibody against glycopeptidolipid (GPL) core antigen (GPL core antibody) to monitor disease activity and predict the recurrence of disease after adjuvant lung resection., Methods: We retrospectively evaluated the clinical characteristics and surgical outcomes of 35 patients surgically treated for NTM-PD. Furthermore, we compared surgically treated patients and control patients treated exclusively with antibiotics who were matched statistically 1:1 using a propensity score calculated from age, sex, body mass index, and radiologic features of disease., Results: In the surgically treated patients, the median age was 58 (interquartile range, 47-65) years and 65.7% were female. Twenty-eight patients had Mycobacterium avium complex. Operations comprised four pneumonectomies, two bilobectomies, one bilobectomy plus segmentectomy, 17 lobectomies, two segmentectomies, and nine lobectomies plus segmentectomies. Postoperative complications occurred in seven patients (20%), there were no operative deaths, and 33 (94.3%) patients achieved negative sputum culture conversion. Refractory and recurrent cases were associated with remnant bronchiectasis, contralateral shadows, and positive acid-fast bacilli staining or culture. Of 28 statistically matched pairs, long-term sustained negative culture conversion was observed in 23 (82.2%) surgical group patients and in 14 (50.0%) non-surgical group patients (0.0438). The mortality rate was lower in the surgical group, but did not reach statistical significance (one in the surgical group and four in the non-surgical group, p = 0.3516). GPL core antibody was correlated with disease activity and recurrence., Conclusions: NTM-PD patients who underwent adjuvant lung resection experienced overall favorable outcomes and achieved sputum culture conversion more frequently. Long-term mortality may have been reduced by this procedure, and the level of GPL core antibody was shown to be a good clinical indicator of disease activity after surgery.

Background/objective: Paraaortic lymph node (PALN) metastasis influences treatment strategy for colorectal cancer. The aims of this study were to elucidate the diagnostic value of computed tomography (CT) and positron emission tomography (PET) for PALN metastasis from left-sided colorectal cancer., Methods: A total of 108 patients who underwent radical surgery including PALN dissection were included. Size and morphology of PALN were evaluated using CT, and presence of higher FDG uptake was evaluated using PET. Findings of CT and PET were compared with pathological status., Results: The largest major axis ≥11 mm and heterogeneous internal density were predictive factors on multivariate analysis. Eighty five percent of the PALNs ≥11 mm with heterogeneous internal density were pathologically metastatic, whereas 94.1% without them were not metastatic. PET had an accuracy, sensitivity, and specificity of 85.7%, 66.7%, and 94.1%, respectively. In patients with PALNs <11 mm without heterogeneous internal density, the accuracy and specificity of PET improved to 93.8% and 96.6%, respectively. Conversely, in patients with some predictive CT findings, although the positive predictive value of PET increased from 83.3% to 88.9%, the accuracy and sensitivity remained at 70.6% and 66.7%, respectively, and 50.0% were false-negatives., Conclusion: CT had high NPV and relatively high PPV. PET had high specificity but low sensitivity. The addition of PET could be useful to confirm no PALN metastasis in patients with no predictive CT findings. Conversely, the improvement of diagnostic ability was limited in patients with some predictive CT findings., (Copyright © 2019. Published by Elsevier Taiwan LLC.)

An 85-year-old woman was admitted to a hospital with abdominal pain. Five years prior to admission, she had a history of hilar cholangiocarcinoma of pStage IIIC. Contrast-enhanced computed tomography showed a mass between the rectum and uterus as well as bowel obstruction due to the lesion. Colonoscopy showed severe stenosis at the lower rectum and elevation of the submucosal layer with linear erosion. Rectal cancer was suspected, and pelvic recurrence of hilar cholangiocarcinoma or endometrial carcinoma infiltrating the rectum was considered as differential diagnosis. She underwent robot-assisted low anterior resection combined with partial resection of the uterus. The immunohistopathological findings of the resected specimen favored a diagnosis of metastasis of cholangiocarcinoma, rather than primary rectal cancer or endometrial carcinoma. There were no signs of recurrence after 10 months of follow-up. Hilar cholangiocarcinoma is a disease with poor prognosis. Recurrence is frequently experienced even after curative resection. Patients with recurrence are rarely candidates for re-resection. However, better prognosis is reported for those with complete resection., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Multidrug therapy is essential for preventing respiratory failure in patients with highly progressive Mycobacterium avium complex pulmonary disease (MAC-PD). However, the prognosis and long-term outcome following combination therapy is poorly understood., Methods: We retrospectively evaluated the clinical characteristics and long-term outcomes in patients with chemo-naïve progressive MAC-PD, hospitalized for first-line multidrug therapy., Results: Among 125 patients, 86 (68.8%) received standardized treatment (rifampicin, ethambutol, clarithromycin), 25 (20.0%) received a fluoroquinolone (FQ)-containing regimen, and 53 (42.4%) received aminoglycoside injection. The sputum conversion rate was 80.0%, and was independently associated with standardized treatment. The incidence of refractory disease (45.6%) was independently and negatively associated with standardized regimen and aminoglycoside use. Choice of an FQ-containing regimen was not associated with positive outcome. Clarithromycin resistance occurred in 16.8% and was independently associated with refractory disease. MAC-PD-associated death occurred in 3.3% of patients with non-cavitary nodular bronchiectasis (NB) and 21.3% with cavitary MAC-PD over a median follow-up period of 56.4 months. The rates of MAC-PD-associated death were comparable between cavitary-NB and fibrocavitary disease. Concurrent chronic pulmonary aspergillosis (CPA) occurred in 13 (17.3%) patients with cavitary MAC-PD, and age, diabetes mellitus, and CPA were independent risk factors for mortality., Conclusions: Standardized intensive multidrug treatment reduces disease progression and persistence in progressive MAC-PD. Cavitary NB may differ from, rather than being just an advanced stage of, non-cavitary NB. The high incidence and significant mortality of CPA in cavitary MAC-PD highlight the need for early diagnosis and treatment., Competing Interests: The authors declare competing financial interests. Details are available in the online version of the paper. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Investigating protein abundance profiles is important to understand the differences in the slow and fast skeletal muscle characteristics. The profiles in soleus (Sol) and extensor digitorum longus (EDL) muscles in mice exposed to 1 g or 3 g for 28 d were compared. The biological implications of the profiles revealed that hypergravity exposure activated a larger number of pathways involved in protein synthesis in Sol. In contrast, the inactivation of signalling pathways involved in oxidative phosphorylation were conspicuous in EDL. These results suggested that the reactivity of molecular pathways in Sol and EDL differed. Additionally, the levels of spermidine synthase and spermidine, an important polyamine for cell growth, increased in both muscles following hypergravity exposure, whereas the level of spermine oxidase (SMOX) increased in EDL alone. The SMOX level was negatively correlated with spermine content, which is involved in muscle atrophy, and was higher in EDL than Sol, even in the 1 g group. These results indicated that the contribution of SMOX to the regulation of spermidine and spermine contents in Sol and EDL differed. However, contrary to expectations, the difference in the SMOX level did not have a significant impact on the growth of these muscles following hypergravity exposure. SIGNIFICANCE: The skeletal muscle-specific protein abundance profiles result in differences in the characteristics of slow and fast skeletal muscles. We investigated differences in the profiles in mouse slow-twitch Sol and fast-twitch EDL muscles following 28-d of 1 g and 3 g exposure by LC-MS/MS analysis and label-free quantitation. A two-step solubilisation of the skeletal muscle proteins increased the coverage of proteins identified by LC-MS/MS analysis. Additionally, this method reduced the complexity of samples more easily than protein or peptide fractionation by SDS-PAGE and offline HPLC while maintaining the high operability of samples and was reproducible. A larger number of hypergravity-responsive proteins as well as a prominent increase in the wet weights was observed in Sol than EDL muscles. The biological implications of the difference in the protein abundance profiles in 1 g and 3 g groups revealed that the reactivity of each molecular pathway in Sol and EDL muscles to hypergravity exposure differed significantly. In addition, we found that the biosynthetic and interconversion pathway of polyamines, essential factors for cell growth and survival in mammals, was responsive to hypergravity exposure; spermidine and spermine contents in Sol and EDL muscles were regulated by different mechanisms even in the 1 g group. However, our results indicated that the difference in the mechanism regulating polyamine contents is unlikely to have a significant effect on the differences in Sol and EDL muscle growth following hypergravity exposure., Competing Interests: Declaration of Competing Interest We declare that none of the authors have competing financial or non-financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A common strategy for multi-protein expression is to link genes by self-cleaving 2A peptide sequences. Yet, little is known how the 2A peptide-derived N-terminal proline or adjacent non-native residues introduced during cDNA cloning affects protein stoichiometry. Polycistronic reprogramming constructs with altered KLF4 protein stoichiometry can influence induced pluripotent stem cell (iPSC) generation. We studied the impact of N-terminal 2A peptide-adjacent residues on the protein stability of two KLF4 isoforms, and assayed their capacity to generate iPSCs. Here, we show that the N-terminal proline remnant of the 2A peptide, alone or in combination with leucine, introduced during polycistronic cloning, destabilizes KLF4 resulting in increased protein degradation, which hinders reprogramming. Interestingly, the addition of charged and hydrophilic amino acids, such as glutamate or lysine stabilizes KLF4, enhancing reprogramming phenotypes. These findings raise awareness that N-terminal modification with 2A peptide-derived proline or additional cloning conventions may affect protein stability within polycistronic constructs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To compare the surgical outcomes of laparoscopic colectomy (LAC) with Japanese D3 dissection for descending colon cancer (DCC) with those of open colectomy (OC)., Patients and Methods: Seventy-two patients who underwent OC or LAC with D3 dissection for clinical stage II/III DCC between September 2002 and June 2019 were evaluated in terms of short-term outcomes. The long-term outcomes of the 59 patients who underwent surgery between September 2002 and June 2016 were evaluated., Results: Twenty-six patients underwent OC and 46 patients underwent LAC. The blood loss was significantly less in the LAC group. The complication rate was similar in both groups. The rates of 5-year overall survival (95.8% in the OC group vs. 89.9% in the LAC group) and relapse-free survival (79.2% in the OC group vs. 82.1% in the LAC group) were similar in both groups., Conclusion: LAC is an acceptable treatment option for stage II/III DCC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This study was carried out to identify and estimate physiological function of a new type of opsin subfamily present in the retina and whole brain tissues of Japanese eel using RNA-Seq transcriptome method. A total of 18 opsin subfamilies were identified through RNA-seq. The visual opsin family included Rh2, SWS2, FWO, DSO, and Exo-Rhod. The non-visual opsin family included four types of melanopsin subfamily (Opn4x1, Opn4x2, Opn4m1, and Opn4m2), peropsin, two types of neuropsin subfamily (Opn5-like, Opn5), Opn3, three types of TMT opsin subfamily (TMT1, 2, 3), VA-opsin, and parapinopsin. In terms of changes in photoreceptor gene expression in the retina of sexually mature and immature male eels, DSO mRNA increased in the maturation group. Analysis of expression of opsin family gene in male eel brain before and after maturation revealed that DSO and SWS2 expression in terms of visual opsin mRNA increased in the sexually mature group. In terms of non-visual opsin mRNA, parapinopsin mRNA increased whereas that of TMT2 decreased in the fore-brain of the sexually mature group. The mRNA for parapinopsin increased in the mid-brain of the sexually mature group, whereas those of TMT1 and TMT3 increased in the hind-brain of the sexually mature group. DSO mRNA also increased in the retina after sexual maturation, and DSO and SWS2 mRNA increased in whole brain part, suggesting that DSO and SWS2 are closely related to sexual maturation., Competing Interests: The authors declare there are no competing interests, (©2020 Byun et al.)

The criteria for being placed on the list of the International Society for Heart and Lung Transplantation for an orthotopic heart transplant mention nothing about patients with aortic dissection. Nor are there any guidelines pertaining to the patient with type B aortic dissection. Herein, we report the case of a patient with chronic type B aortic dissection for whom we successfully performed a left ventricular assist device implant followed by an orthotopic heart transplant., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Although cavities are an important finding in Mycobacterium avium complex pulmonary disease (MAC-PD), there is little information regarding the types of cavities that indicate disease progression. This study was performed to identify cavity characteristics that were associated with disease progression in patients with MAC-PD., Methods: This retrospective cohort study included 97 patients presenting with MAC-PD with cavities between December 2006 and June 2016. We compared initial and final computed tomography (CT) findings, classified 52 and 45 patients in the progressive and non-progressive cavity groups, respectively, and examined the progression-related imaging features in initial CT images. A progressive cavity was defined by more than two-fold increase in internal diameter or emergence of a new cavity around the initial cavity., Results: Patients in the progressive group were older (p < 0.001), had a lower body mass index (p = 0.043), and showed higher diabetes complication rates (p = 0.005). The initial CT in the progressive group showed a longer maximum internal diameter of the cavity (p < 0.001) and higher rates of cavities close to the chest wall (p < 0.001), multiple cavities (p = 0.023), consolidation around the cavity (p < 0.001), atelectasis (p = 0.011), and pleural thickening (p < 0.001). Multivariable logistic regression analysis revealed that the maximum internal diameter of the cavity (odds ratio [OR]: 1.11, 95% confidence interval [CI]: 1.02-1.21; p=0.012) and consolidation around the cavity (OR: 16.15, 95% CI: 4.05-64.46; p < 0.001) were significantly associated with progressive cavities. In cavities with a maximum internal diameter of ≥10 mm and simultaneous consolidation, the probability of progression was as high as 96.2%. The 10-year mortality rates in the progressive and non-progressive cavity groups were 46.7 and 9.8% (p < 0.001), respectively, while the 10-year respiratory failure rates were 28.1 and 0%, respectively (p < 0.001)., Conclusions: Large cavity size and consolidation on CT showed strong relationships with disease progression, which led to respiratory failure and high mortality rate.