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Abstract: Segmental-SCEFs of rabbits after sciatic nerve stimulation were detected by neuromagnetic recordings, and conductive neural activities and synaptic activities in the spinal cord were able to be visualized. The measurement of segmental-SCEFs could be a helpful method to evaluate the function of the spinal cord. [Copyright &y& Elsevier]

The multimodality treatment approach for advanced breast cancer provides survival advantages with decreased locoregional and distant recurrences, but these intensive anti-tumour treatments cause severe myelosuppression. Thus, in this study, the usefulness of pre-operative anti-tumour treatment without myelosuppression was investigated. Nine patients with advanced breast carcinoma underwent pre-operative hyperthermic tumour ablation (HTA) using an 8 MHz radiofrequency (RF) heating device (Thermotron RF-8) combined with a grounded needle electrode. The patients had a mean age of 58.3 ± 13.9 years and included four patients with stage IIIA, two with stage IIIB and three with stage IV cancer. The target temperature was over 50°C. They tolerated pre-operative HTA therapy well with no early or late complications. The initial mean tumour size was 122.1 ± 71.5 cm³ and the post-HTA tumour size was 82.2 ± 63.4 cm³; the reduction rate was significant (p = 0.000 293). After the pre-operative HTA, all patients underwent surgery with Level III nodal extirpation. Postoperatively, no locoregional recurrence was observed. Microscopic examination of the primary focus showed complete coagulation necrosis expanding for a diameter of 3.5-5.0 cm. Taken together, the pre-operative HTA was a safe, well-tolerated and effective treatment, achieving tumour reduction as well as complete coagulation necrosis that resulted in a large volume of destruction in breast cancer tissue. [ABSTRACT FROM AUTHOR]

Explains the characteristics of waste management systems on dairy cattle farms in Japan. Housing, milking and waste handling systems of dairy farms; Storage volumes and slurry treatment for hog farms; Land irrigation of the treated liquid fraction.

Background: Dupilumab exerts clinical effects, including improved sinus opacification, olfactory function, and quality of life, in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNPs). Meanwhile, only a few studies have reported its effects on nasal airway resistance and olfactory function, particularly in the Japanese population. Predictors of response remain unclear., Objective: To assess the comprehensive efficacy and therapeutic response to dupilumab in patients with severe CRSwNP with comorbid asthma., Methods: In 16 adult patients with severe CRSwNP with comorbid asthma, the efficacy of 48-week dupilumab treatment, including olfactory function measured by a T&T olfactometer, nasal airway resistance measured by rhinomanometry, nasal polyp score, Lund-Mackay computed tomography score, and 22-item Sinonasal Outcome Test (SNOT-22), was assessed. Regarding asthma, the annualized rate of exacerbations, 7-item Asthma Control Questionnaire (ACQ-7), and spirometry were assessed. Treatment responsiveness was analyzed., Results: With 48-week dupilumab treatment, olfactory function, nasal airway resistance, nasal polyp score, Lund-Mackay computed tomography score, and SNOT-22 scores improved significantly. Regarding comorbid asthma, the annualized rate of exacerbations decreased, and ACQ-7 scores and lung function improved significantly. According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2020/European Forum for Research and Education in Allergy and Airway Diseases criteria, 15 patients (94%) were moderate-to-excellent responders at 48 weeks of treatment. Patients with higher SNOT-22 scores, ACQ-7 scores, the rate of asthma exacerbations in the previous year, and blood eosinophil counts benefited more from the treatment., Conclusion: Dupilumab improved upper and lower airway outcomes especially in patients with severe CRSwNP with comorbid, poorly controlled asthma., Trial Registration: UMIN Clinical Trials Registry: UMIN000038669., Competing Interests: Disclosures The authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The high frequency of productive cough in idiopathic pulmonary fibrosis (IPF) impacts quality of life. Reduced normal lung volume is linked to cough severity, predicting poorer outcomes. Insights could enhance IPF management and patient wellbeing. https://bit.ly/4bPOCzC., Competing Interests: Conflict of interest: The authors declare that they have no competing interests., (Copyright ©The authors 2024.)

Background: Viral or atypical bacterial respiratory infections are involved in the new development and the pathogenesis of asthma. Though an association between pertussis and asthma has been expected, few studies have reported it consistently. We assessed the prevalence and clinical relevance of pertussis infection in adult patients with asthma., Methods: In this prospective, cross-sectional study, newly referred, adult patients with asthma (n = 107) and with non-asthmatic subacute/chronic cough (n = 31) were enrolled. The prevalence of pertussis in patients with asthma and in those with non-asthmatic subacute/chronic cough was assessed. Next, the prevalence of newly diagnosed asthma was compared between asthmatic patients with and without pertussis. Finally, demographic characteristics of patients, blood test results, pulmonary function test results, and questionnaire scores were compared between the two patient groups., Results: The prevalence of pertussis infection was significantly higher in patients with asthma than in those with non-asthmatic subacute/chronic cough (36% vs 10%; P = 0.004). The prevalence of newly diagnosed asthma was significantly higher in asthmatic patients with pertussis than in those without (74.4% vs 50.0%; P = 0.014). The physical, psychological, and total scores of the Leicester Cough Questionnaire were significantly lower in asthmatic patients with pertussis than in those without (all P < 0.05). The acid-reflux, dyspeptic, and total scores of the Frequency Scale for Symptoms of Gastroesophageal Reflux Disease (GERD) (FSSG) were significantly higher in asthmatic patients with pertussis than in those without (all P ≤ 0.05). The FSSG acid-reflux score was negatively correlated with the cough-specific quality of life (QOL) score only in asthmatic patients with pertussis (rho = -0.68, P = 0.01)., Conclusions: The prevalence of pertussis infection was significantly higher in adult patients with asthma than in those with non-asthmatic subacute/chronic cough. In patients with asthma, comorbid pertussis infection may play a role in newly diagnosed asthma and may contribute to impaired cough-specific QOL partly due to worsening acid-reflux symptoms of GERD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Patients with idiopathic pulmonary fibrosis (IPF) often experience sarcopenia and malnutrition. However, this has not been fully examined through longitudinal surveys. This study investigated whether sarcopenia and malnutrition were associated with 1-year outcomes in IPF., Methods: We evaluated sarcopenia and nutritional status in 64 outpatients with IPF. We assessed the time-to-event for respiratory-related hospitalizations or deaths 12 months after enrollment. Sarcopenia was diagnosed by the criteria of the Asian Working Group for Sarcopenia, 2019. Nutritional status was assessed by serum transthyretin and the Geriatric Nutritional Risk Index (GNRI)., Results: The average age was 73.6 ± 7.9 years, and the percent predicted forced vital capacity (FVC) was 81.9 ± 15.7%. Of the 64 patients, 24 (37.5%) had sarcopenia. The median serum transthyretin level and mean GNRI were 23.8 mg/dL and 102, respectively. Eleven patients (17.2%) experienced respiratory-related hospitalization or death within the first year. Cox regression analysis showed that the % predicted diffusion capacity for carbon monoxide, lowest oxygen saturation in the 6-min walk test, serum transthyretin level, and GNRI were significant predictors of 1-year outcomes. The Kaplan-Meier method, which divided the patients into two groups based on a transthyretin level of 22.6 mg/dL, showed a significant difference (P < 0.001, log-rank test). Sarcopenia and the percent predicted FVC did not predict the 1-year outcomes., Conclusions: This pilot study represents the first longitudinal survey assessing patients with IPF for sarcopenia and malnutrition. Serum transthyretin levels may predict respiratory-related hospitalization or death within 1 year in patients with IPF., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to evaluate the efficacy and safety of linaclotide in patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) who did not respond to treatment with magnesium oxide (MgO)., Methods: This study was designed as a multicenter, open-label, single-arm, exploratory study. Patients with CC or IBS-C who took MgO and those meeting the medication initiation criteria were administered linaclotide at a daily dosage of 500 μg for 12 weeks. The primary endpoint was a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score from baseline, which was evaluated by using a paired t-test., Key Results: The patients' mean age (± standard deviation) was 67.6 ± 13.82 years. The full analysis set included 61 patients. The JPAC-QOL total score was 1.60 at baseline and 0.70 at 12 weeks, with a significant mean change of -0.89 ± 0.721 (p < 0.001). Several secondary endpoints also showed improvement. The frequency of spontaneous bowel movement (SBM) and complete SBM increased by 2.70 ± 7.254 (p < 0.01) and 2.81 ± 5.254 times, respectively (p < 0.001). The Bristol Stool Form Scale, abdominal bloating severity, and straining severity scores improved by 1.33 ± 1.274 (p < 0.001), -0.16 ± 0.563 (p < 0.05), and -0.46 ± 0.795 (p < 0.001) points, respectively. The safety analysis set included 65 patients, 7 of whom had diarrhea, which improved with dose reduction and drug withdrawal., Conclusion & Inferences: The study was conducted in an older adult population, similar to real clinical practice. Linaclotide may be an option for treating CC that shows an inadequate response to conventional therapy., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The Japan Gastroenterological Association published the first version of its clinical guidelines for chronic constipation 2023. Based on the latest evidence, these guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic constipation. They include flowcharts for both diagnosis and treatment of chronic constipation. In the treatment of chronic constipation, the first step involves differentiating between secondary forms, such as organic disease-associated constipation, systemic disease-associated constipation, and drug-induced constipation. The next step is to determine whether the chronic constipation stems from a motility disorder, a form of primary chronic constipation. For functional constipation and constipation-predominant irritable bowel syndrome, treatment should be initiated after evaluating symptoms like reduced bowel movement frequency type or defecation difficulty type. The first line of treatment includes the improvement of lifestyle habits and diet therapy. The first drugs to consider for oral treatment are osmotic laxatives. If these are ineffective, secretagogues and ileal bile acid transporter inhibitors are candidates. However, stimulant laxatives are exclusively designated for as-needed use. Probiotics, bulk-forming laxatives, prokinetics, and Kampo medicines, for which there is insufficient evidence, are considered alternative or complementary therapy. Providing the best clinical strategies for chronic constipation therapy in Japan, these clinical guidelines for chronic constipation 2023 should prove useful for its treatment worldwide., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

We report a case of a 69-year-old woman with pleural mesothelioma presenting in the posterior mediastinum with a maximum diameter of 25 cm. She had a chronic cough and a pleural effusion was noted on chest X-ray. The examination of the effusion showed high hyaluronic acid levels, and mesothelioma was suspected. A chest computed tomography scan showed a huge mediastinal mass, which caused rapid progression of respiratory failure and compression of the heart. Sufficient tissue samples could not be obtained before death. The patient died approximately 1 month after the initial visit, and a pathological autopsy was performed. The diagnosis of malignant pleural mesothelioma was made. Malignant pleural mesothelioma with a huge posterior mediastinal mass such as in this case is considerably rare; however, it is a rapidly progressing form of the disease and is reported here as an important differential diagnosis for mediastinal tumours., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Single-strand breaks (SSBs) are the most frequent type of lesion, and replication across such lesions leads to double-strand breaks (DSBs). DSBs that arise during replication are repaired by homologous recombination (HR) and are suppressed by fork reversal. Poly[ADP-ribose] polymerase I (PARP1) and the proofreading exonuclease activity of replicative polymerase ε (Polε) are required for fork reversal when leading strand replication encounters SSBs. However, the mechanism underlying fork reversal at the SSB during lagging-strand replication remains elusive. We here demonstrate that the Pold4 subunit of replicative polymerase δ (Polδ) plays a role in promoting fork reversal during lagging strand replication on a broken template. POLD4 -/- cells exhibited heightened sensitivity to camptothecin (CPT) but not to other DNA-damaging agents compared to wild-type cells. This selective CPT sensitivity in POLD4 -/- cells suggests that Pold4 suppresses DSBs during replication, as CPT induces significant SSBs during replication, which subsequently lead to DSBs. To explore the functional interactions among Pold4, Polε exonuclease, and PARP1 in DSB suppression, we generated PARP1 -/- , POLD4 -/- , Polε exonuclease-deficient POLE1 exo-/- , PARP1 -/- /POLD4 -/- , and POLD4 -/- /POLE1 exo-/- cells. These epistasis analyses showed that Pold4 is involved in the PARP1-Polε exonuclease-mediated fork reversal following CPT treatment. These results suggest that Pold4 aids in fork reversal when lagging strand replication stalls on a broken template. In conclusion, the Pold4 subunit of Polδ has roles in the PARP1-Polε exonuclease-mediated fork reversal, contributing to the suppression of DSBs., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients., Methods: In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed., Results: With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders., Conclusions: Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear., Objective: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction., Methods: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined on the basis of capsaicin concentration that induced at least 2 coughs (C2) or 5 coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation., Results: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 ≤ 2.44 μmol) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-IL-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared to their counterparts., Conclusion: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD., Competing Interests: Disclosure statement Supported in part by a research grant from MSD Life Science Foundation, Public Interest Incorporated Foundation (RA-020 to Y.K.), a research grant from the Japanese Respiratory Society Research Grants Program (to K.I.), and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT; 24K11373 to Y.K.). Disclosure of potential conflict of interest: K. Ito reports speaker honoraria from AstraZeneca. Y. Kanemitsu reports research grants from Novartis, MSD, and Sanofi; and honoraria for lectures, presentations, and educational events from GSK, AstraZeneca, Kyorin, Sanofi, Novartis, and Zeria. K. Fukumitsu reports research grants from Novartis, GSK, and Daiichi Sankyo. S. Fukuda reports speaker honoraria from AstraZeneca. T. Uemura reports honoraria for lectures and presentations from AstraZeneca, MSD, Novartis, and Chugai. H. Ohkubo reports research grants and honoraria for lectures from Boehringer Ingelheim. A. Niimi reports honoraria for lectures and presentations from AstraZeneca, Kyorin, Novartis, GSK, Sanofi; and personal fees for participating on advisory boards from AstraZeneca, MSD, Kyorin, and Bayer. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective The daily step count is associated with mortality in idiopathic pulmonary fibrosis (IPF). However, the factors associated with this phenomenon are not yet fully understood. We therefore clarified its association with clinical parameters. Methods Fifty-nine patients with IPF with available data for daily step counts; 6-minute walk distance (6MWD); chest, abdominal, and pelvic computed tomography (CT); pulmonary function; psychological evaluations; and sarcopenia assessments were prospectively enrolled. The daily step count was measured continuously for seven consecutive days. The cross-sectional areas of the erector spinae muscles at the level of the 12th vertebra (ESM CSA ) and psoas major muscle volume (PMV) obtained by CT were assessed. Results The average age of the patients was 73.3±8.1 years old, and the percent predicted forced vital capacity was 81.6%±15.8%. The median daily step count was 4,258 (2,155-6,991) steps. The average 6MWD, ESM CSA , and PMV were 413±97 m, 25.5±6.7 cm 2 , and 270±75.6 cm 3 , respectively. A linear regression analysis for daily step count showed that the ESM CSA and 6MWD were independent factors for the daily step count, whereas the PMV and skeletal muscle index were not. The daily step count, ESM CSA , and 6MWD were lower in patients with sarcopenia than in those without sarcopenia. Conclusion A lower daily step count was associated with a smaller erector spinae muscle area and sarcopenia in patients with IPF. Further studies are warranted to confirm the importance of physical therapy for muscle strengthening in patients with IPF.

Objectives: Chronic constipation is a common gastrointestinal disorder, and management is crucial. Computed tomography (CT) is useful for evaluating rectal fecal mass but limited owing to radiation exposure, cost, and inaccessibility at certain facilities. Ultrasonography (US) avoids these pitfalls, but it is unknown whether it accurately assesses rectal feces. In this study, we evaluated the diagnostic performance of US compared with CT as the gold standard for assessing rectal feces., Methods: We prospectively evaluated rectal fecal mass retention using US performed within 1 h of CT to assess the degree of agreement between methodologies. Rectal stool findings were evaluated on three levels: no stool (R1), presence of stool (R2), and hard stool filling (R3)., Results: The sample included 100 patients (55 men, 45 women), of whom 47 were constipated. The kappa coefficients for rectal content detection were excellent between US and CT ( p <0.001). Eighty-two cases (R1: 46 cases; R2: 28 cases; R3: 8 cases) were matched with CT and US findings, and 18 were not. Cases that did not match had low urine or high gas volumes. CT and US findings showed high agreement in constipation (kappa coefficient 0.674, p <0.001) and non-constipation groups (kappa coefficient 0.677, p <0.001). All cases with R3 on CT were found in the constipation group, while more than half of the cases with R1 on CT were in the non-constipation group., Conclusions: CT and US showed high agreement in evaluating rectal fecal mass retention, indicating that US can substitute CT., Competing Interests: Conflicts of Interest Atsushi Nakajima has received honoraria from PDR Adiopharma Inc. Astellas, Mylan EPD, EA Pharma, Kowa Pharma, Taisyo Pharma and Bioferumin Pharma., (Copyright © 2024 The Japan Society of Coloproctology.)

Transgrafting, a grafting technique that uses both genetically modified (GM) and non-GM plants, is a novel plant breeding technology that can be used to improve the efficiency of crop cultivation without introducing foreign genes into the edible parts of non-GM plants. This technique can facilitate the acquisition of disease resistance and/or increased yield. However, the translocation of low-molecular-weight compounds, ribonucleic acid (RNA), and proteins through graft junctions raises a potential safety risk for food crops. Here, we used a transgenic tobacco plant expressing a firefly luciferase gene ( LUC ) to examine the translocation of the LUC protein beyond the graft junction in grafted plants. We observed the bi-directional translocation of LUC proteins in transgrafted tobacco plants, i.e., from the rootstock to scion and vice versa. Transcriptomic analysis revealed that transcripts of the LUC gene were undetectable in non-GM plant bodies, indicating that the LUC protein itself was translocated. Moreover, the movement of the LUC protein is an episodic (i.e., non-continuous) event, since non-GM samples showing high LUC activity were flanked by non-GM samples showing no apparent LUC activity. Translocation from the GM to non-GM part depends on the characteristics of GM plant bodies; here, the enhanced translocation of the LUC protein into the non-GM scion was observed when LUC-expressing rootstocks with hairy roots were used. Moreover, the quantity of translocated LUC protein was far below the level that is generally required to induce an allergenic response. Finally, since the LUC protein levels of plants used for transgrafting are moderate and the LUC protein itself is relatively unstable, further investigation is necessary regarding whether the newly expressed protein in GM plants is highly stable, easily translocated, and/or highly expressed., Competing Interests: Conflicts of Interest: The authors declare that they have no conflicts of interest., (©2024 Food Safety Commission, Cabinet Office, Government of Japan.)

Background: The prevalence of constipation in Japan is estimated to be 2-5%. Constipation is a disease found in older adults. In particular, Japan is an aging society, with 65% of men and 80.5% of women aged 65 years or older accounting for the majority of its population. Chronic constipation may be associated with survival, cardiovascular events, decreased quality of life, and death. This study summarizes the recent findings regarding constipation treatment practice in Japan., Summary: Until recently, the diagnosis of constipation was mainly based on medical interviews; however, with the recent development of handheld ultrasound devices, both physicians and nurses can easily and objectively diagnose fecal retention. Magnesium oxide and stimulant laxatives have been the mainstay treatments; however, since 2012, more than five new drugs for treating constipation have become available in Japan., Key Messages: Magnesium oxide is less effective in patients who use acid-secretion inhibitors and patients who have undergone total gastrectomy and should be cared for hypermagnesemia. In addition, regular use of stimulant laxatives may lead to colonic inertia and decreased bowel movements; therefore, they should be used only occasionally. The following is an overview of the different uses of conventional and newer laxatives for treating constipation., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Chronic intestinal pseudo-obstruction (CIPO) is a rare intractable disease with limited treatment options. Small intestinal bacterial overgrowth (SIBO) often co-occurs with several diseases, including CIPO. While rifaximin (RFX) is effective in treating SIBO, its efficacy for CIPO remains unclear. Here, we aimed to investigate the efficacy and safety of RFX in adult patients with CIPO. Twelve patients were randomly assigned to receive RFX (400 mg three times daily, n=8) or a placebo (PBO, n=4) for 4 weeks. The global symptom score for abdominal bloating (GSS-bloating) and an original whole gastrointestinal symptoms score (O-WGSS) were collected, and a glucose hydrogen breath test (GHBT) and abdominal computed tomography (CT) were performed. No significant differences were observed in the primary endpoint. GSS-bloating improved by 75% and 25% in the PBO and RFX groups, respectively, and O-WGSS improved by 25% in both groups. No significant differences were observed in secondary and other endpoints, including the SIBO eradication rate in the GHBT and small intestinal volume on CT. In a post hoc analysis of SIBO-positive patients with CIPO (4/4 and 4/8 in the PBO and RFX groups), SIBO was eradicated in 25% and 75% of the patients (PBO and RFX groups, respectively) at the end of treatment, indicating a high eradication rate in the RFX group. Furthermore, the small intestinal gas volume decreased in the RFX group, and no severe adverse events occurred. Although no significant improvements were observed in subjective indicators, RFX may be beneficial in alleviating SIBO and reducing the small intestinal gas volume in SIBO-positive patients with CIPO., Competing Interests: AN reports grant and research support from Gilead, Mylan EPD, EA Pharma, Kowa, Taisho, and Biofermine. AN is a consulting advisor for Gilead, Boehringer Ingelheim, BMS, Kowa, Astellas, EA Pharma, and Mylan EPD. The other authors have no conflicts of interest to declare., (©2024 BMFH Press.)

Background: Cough is a troublesome symptom of asthma because it is associated with disease severity and poor asthma control. Bronchial thermoplasty (BT) may be effective in improving cough severity and cough-related quality of life in severe uncontrolled asthma., Objective: To evaluate the efficacy of BT for cough in severe uncontrolled asthma., Methods: Twelve patients with severe uncontrolled asthma were enrolled in this study between 2018 May and March 2021 and arbitrarily divided into cough-predominant [cough severity Visual Analog Scale (VAS) ≥ 40 mm, n = 8] and typical asthma (cough VAS <40 mm, n = 4) groups. Clinical parameters, such as capsaicin cough sensitivity [C-CS: the concentrations to inhaled capsaicin required to induce at least two (C2) and five (C5) coughs], lung function, and type-2-related biomarkers (fractional nitric oxides and absolute eosinophil counts) and cough-related indices [cough severity VAS and the Leicester Cough Questionnaire (LCQ)] were evaluated before and 3 months after performing BT., Results: BT significantly improved both cough-related indices and C-CS in the cough-predominant group. Changes in C-CS were significantly correlated with changes in the LCQ scores (C5: r = 0.65, p = 0.02 for all patients, and r = 0.81, p = 0.01 for the cough-predominant group)., Conclusions: BT may be effective for cough in severe uncontrolled asthma by improving C-CS. However, further larger cohort studies are necessary to confirm the effect of BT for cough in asthma., Clinical Trial Registration: This study was registered in the UMIN Clinical Trials Registry (Registry ID UMIN: 000031982)., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Capsaicin cough sensitivity (C-CS) reflects airway neuronal dysfunction and may be a significant biomarker of asthma. Although mepolizumab reduces cough in patients with severe uncontrolled asthma, it is unclear whether the cough reduction is associated with improved C-CS., Objective: To clarify the effect of biologics on C-CS and cough-specific quality of life (QoL) in patients with severe uncontrolled asthma using our previous study cohort., Methods: Overall, 52 consecutive patients who visited our hospital for severe uncontrolled asthma were included in the original study cohort, and 30 patients were eligible for this study. Changes in C-CS and cough-specific QoL were compared between patients treated with the anti-interleukin-5 (IL-5) pathway (n = 16) and those treated with other biologics (n = 14). The C-CS was measured as the concentration of capsaicin required to induce at least 5 coughs., Results: Biologics significantly improved C-CS (P = .03). Anti-IL-5 pathway therapies significantly improved C-CS, whereas other biologics did not (P < .01 and P = .89, respectively). The C-CS improved significantly more in the anti-IL-5 pathway group than in the group treated with other biologics (P = .02). Changes in C-CS significantly correlated with improvements in cough-specific QoL in the anti-IL-5 pathway group (r = 0.58, P = .01) but not in the group treated with other biologics (r = 0.35, P = .22)., Conclusion: Anti-IL-5 pathway therapies improve C-CS and cough-specific QoL, and targeting the IL-5 pathway may be a therapeutic strategy for cough hypersensitivity in patients with severe uncontrolled asthma., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background/aims: Natural history of chronic intestinal pseudo-obstruction (CIPO), a rare disease characterized by episodes of non-mechanical obstruction, is unclear in adults. This study evaluates the clinical course of CIPO and palliative care needs of patients., Methods: From October 2010 to September 2021, 74 patients who underwent cine MRI and had a definitive diagnosis of CIPO were prospectively included. We investigated disease etiology and outcomes, age at onset, nutritional status at consultation (body mass index and serum albumin), hydrogen breath test results, and total parenteral nutrition (TPN) during the disease course., Results: Forty-seven patients (64%) were women, with a mean age of 44 years at onset and 49 years at diagnosis. Primary CIPO was observed in 48 patients (65%). Secondary CIPO was observed in 26 cases (35%), of whom 18 (69%) had scleroderma. The mean body mass index, serum albumin level, and hydrogen breath test positivity rate were 17 kg/m 2 , 3.8 mg/dL, and 60%, respectively. TPN and invasive decompression therapy were required by 23 (31%) and 18 (24%) patients, respectively. Intestinal sterilization was performed in 51 (69%) patients and was effective in 33 (65%); of these, 28 (85%) were taking metronidazole. Seven (9%) patients used opioids. There were 9 deaths (12%), including 5 (56%) from infection and 2 (22%) from suicide. Of the deaths, 6 (67%) and 4 (44%) underwent TPN management and decompression therapy, respectively. Fifty-one patients (69%) wanted palliative care., Conclusion: CIPO is a rare, severe, and under-recognized disease. Standardization of treatment strategies, including palliative care and psychiatric interventions, is desired.

Background and Aim: Ischemic colitis (IC) is a benign disease associated with acute lower gastrointestinal bleeding and frequent recurrence. While several studies have investigated risk factors for IC onset, few have assessed the risk factors for recurrent IC. This study aimed to identify risk factors for recurrent IC., Methods: Potential risk factors for recurrence were assessed by examining medical records and laboratory findings in this single-center retrospective study. We extracted the following data from the patients' medical records: patient characteristics, clinical signs and symptoms, laboratory findings, method of treatment, length of hospital stay, disease course, and the frequency of IC morbidities. Patients with IC were selected from a total of 439 312 patients over an 11-year period. Patients were divided into recurrent and nonrecurrent IC groups., Results: In total, 225 patients met the diagnostic criteria for IC during the specified study period; of these, 204 patients (90.7%) and 21 patients (9.3%) were included in the nonrecurrent and recurrent IC groups, respectively. Univariate and multivariate analyses showed a significant association between IC recurrence and both cerebral infarction ( P  = 0.008, odds ratio [OR] = 6.3) and history of appendectomy ( P  = 0.0005, OR = 6.2). The median (interquartile range [IQR]) follow-up time for all patients was 1556 (353-2768) days; this was much longer than the median (IQR) time to recurrence of 291 (64-907) days in the recurrent IC group., Conclusion: The results of this study suggest that prior cerebral infarction and appendicectomy may be risk factors for IC recurrence., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

A 34-year-old pregnant woman in the 34th week of gestation with uncontrolled asthma was admitted because of asthma exacerbation. Although she received bronchodilators and systemic corticosteroids, respiratory failure rapidly progressed. Chest computed tomography revealed a mass occluding approximately 80% of the tracheal lumen. After urgent Caesarean section, endobronchial resection was performed. The pathological findings of the resected tumor were compatible with tracheal glomus tumor. Tracheal tumors are often misdiagnosed as asthma, but its complication with asthma is rare. Even if the diagnosis of asthma is definitive, clinicians should consider coexisting diseases, including tracheal tumors, when asthma control is poor.

Background: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS)., Objective: We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial., Methods: A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 μg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS., Results: A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders., Conclusion: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma., Trial Registration: Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000024253)., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs., Methods: Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 μM was defined as heightened C-CS., Results: Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 μM vs. 8.91 ± 5.5 μM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD., Conclusions: Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Objective: Omalizumab has demonstrated clinical efficacy in patients with severe allergic asthma sensitized to perennial allergens and/or severe pollinosis through inhibition of IgE-dependent allergic response. When considering the "one airway, one disease" concept, sensitization to pollen could predict responsiveness to omalizumab. This study aimed to assess whether the pretreatment specific IgE response could be a predictor of responsiveness to omalizumab in severe allergic asthma sensitized to perennial allergens., Methods: In this retrospective study, 41 adult patients with severe allergic asthma sensitized to perennial allergens (27 females; mean age 59 years) who had completed 52-week omalizumab treatment were enrolled. The Global Evaluation of Treatment Effectiveness was performed, and demographic characteristics and the positive ratios of specific IgE responses classified into five subgroups (pollen, dust mite, house dust, mold, and animal dander) were compared between responders and non-responders. Multivariate logistic regression analyses were performed to identify predictors of responsiveness to omalizumab., Results: Thirty-one patients (76%) were identified as responders. The number of sensitized aeroallergen subgroups and sensitization to pollens were significantly higher in responders than in non-responders (both p<0.05). Multivariate logistic regression analysis showed that sensitization to pollen (OR = 8.41, p = 0.02) was independently associated with the effectiveness of omalizumab., Conclusion: Pretreatment serum pollen-specific IgE could be a predictor of responsiveness to omalizumab., Competing Interests: Dr Kensuke Fukumitsu reports grants from Novartis Pharma, GSK; personal fees from AstraZeneca, Boehringer Ingelheim, Novartis Pharma, and Kyorin, outside the submitted work. The authors declared neither financial nor non-financial competing interests with respect to the research, authorship, and/or publication of this article., (© 2023 Tajiri et al.)

Introduction: Patients with chronic obstructive pulmonary disease (COPD) are often hospitalised due to severe acute exacerbation (AE) or community-acquired pneumonia (CAP). Previous studies revealed the association of cough reflex sensitivity with the pathophysiology of COPD and pneumonia. We hypothesised that cough reflex sensitivity may be associated with severe AE or CAP requiring hospitalisation in patients with COPD., Methods: We prospectively recruited 68 patients with COPD between June 2018 and January 2020. Patient characteristics, lung and cardiac functions, and biomarkers, including capsaicin cough reflex sensitivity and blood eosinophil count, were evaluated at enrolment. All participants were monitored for AE or CAP requiring hospitalisation for 12 months. We determined the risk factors and ORs for hospitalisation in patients with COPD using a multivariate analysis., Results: Eight patients experienced AE (n=3) or CAP (n=5) and required hospitalisation during follow-up. Patients in the hospitalisation+ group had higher modified Medical Research Council scores and blood eosinophil counts (≥300 µL) than those in the hospitalisation- group. Capsaicin cough reflex sensitivity tended to decrease in the hospitalisation+ group compared with that in the hospitalisation- group. Multivariate analysis revealed that a decreased capsaicin cough reflex and high eosinophil count (≥300 µL) were predictive risk factors for future hospitalisation due to AE-COPD or CAP., Conclusion: In addition to eosinophils, decreased capsaicin cough reflex sensitivity was associated with hospitalisation due to AE-COPD or CAP. Capsaicin cough reflex sensitivity in patients with COPD may play a role in the prevention of severe AE or pneumonia requiring hospitalisation., Trial Registration Number: UMIN000032497., Competing Interests: Competing interests: YK received research grants from Novartis Pharma, MSD, Sanofi, and Kyowa-Kirin Corporation and personal fees from GSK, Novartis Pharma, AstraZeneca, Sanofi, and Kyorin. KF received research grants from Novartis Pharma and GSK. SF received personal fees from AstraZeneca and Eli Lilly. HO received a research grant from Boehringer Ingelheim. KM received personal fees from Pfizer and Chugai Pharmaceutical. TO reports personal fees from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Pfizer, Chugai Pharmaceutical, MSD, Daiichi Sankyo, and Asahi Kasei Pharma, as well as research grants and personal fees from Kyowa Hakko Kirin, Boehringer Ingelheim, Ono Pharmaceutical, and Novartis. MT has received a research grant from Pfizer. AN reports personal fees from Astellas, AstraZeneca, Kyorin, GSK, MSD, Shionogi, Bayer, Sanofi, Taiho, and Boehringer Ingelheim, and research grants from Astellas, Kyorin, Boehringer Ingelheim, Novartis, MSD, Daiichi Sankyo, Taiho, Teijin, Ono, Takeda, and Sanofi Pharmaceutical. The other authors did not receive any grants or personal fees., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

SARS-CoV-2 infection causes a variety of physiological responses in the lung, and understanding how the expression of SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), and its proteolytic activator, transmembrane serine protease 2 (TMPRSS2), are affected in patients with underlying disease such as interstitial pneumonia will be important in considering COVID-19 progression. We examined the expression of ACE2 and TMPRSS2 in an induced usual interstitial pneumonia (iUIP) mouse model and patients with IPF as well as the changes in whole-lung ACE2 and TMPRSS2 expression under physiological conditions caused by viral infection. Histopathological and biochemical characteristics were analyzed using human specimens from patients with IPF and precision-cut lung slices (PCLS) from iUIP mouse model showing UIP with honeycombing and severe fibrosis after non-specific interstitial pneumonia. ACE2 expression decreased with acute lung inflammation and increased in the abnormal lung epithelium of the iUIP mouse model. ACE2 is also expressed in metaplastic epithelial cells. Poly(I:C), interferons, and cytokines associated with fibrosis decreased ACE2 expression in PCLS in the iUIP model. Hypoxia also decreases ACE2 via HIF1α in PCLS. Antifibrotic agent, nintedanib attenuates ACE2 expression in invasive epithelial cells. Patients with IPF are at a higher risk of SARS-CoV-2 infection due to the high expression of ACE2. However, ACE2 and TMPRSS2 expression is decreased by immune intermediaries, including interferons and cytokines that are associated with viral infection and upon administration of antifibrotic agents, suggesting that most of the viral infection-induced pathophysiological responses aid the development of resistance against SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial of financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miura, Ohkubo, Nakano, Bourke and Kanazawa.)

Purpose: Recently, single-inhaler triple therapy (SITT) has demonstrated efficacy in patients with uncontrolled asthma who were symptomatic despite treatment with inhaled corticosteroids/long-acting β2 agonists. However, the characteristics of patients who benefit from SITT remain unclear in the real-world. The aim of this study was to examine the predictors of responsiveness to SITT in patients with asthma., Patients and Methods: A total of 45 patients with asthma who had regularly visited our respiratory clinic and were started on SITT from March 2019 to March 2021 were retrospectively analyzed. Patients' demographic characteristics, residual respiratory symptoms, type 2 biomarkers, and lung function before SITT were assessed from the patients' medical records. Predictors of responsiveness to four-week SITT were evaluated in these patients. The definition of responders was based on the physician-assessed global evaluation of treatment effectiveness., Results: Thirty-four (75%) of 45 patients were identified as responders to SITT. Non-responders showed significantly lower forced vital capacity (FVC) (%predicted) values, and complained of dyspnea more frequently than responders before SITT (p = 0.01 and p = 0.02, respectively). There were no significant differences in demographic characteristics and type 2 biomarkers between responders and non-responders. Clinical predictors of poor response to SITT were residual dyspnea (OR = 0.14, p = 0.02), low FVC (%predicted) values (OR = 1.05, p = 0.01), and FVC (%predicted) <80% (OR = 0.11, p = 0.02). Multivariate analysis showed that poor response to SITT was associated with residual dyspnea before SITT (OR = 0.14, p = 0.02). On the other hand, patients with residual dyspnea had significantly lower FEF 25-75 (%predicted) values than patients without residual dyspnea before SITT (p = 0.04)., Conclusion: Residual dyspnea, reflecting small airways dysfunction, may predict poor responsiveness to short-term SITT in patients with asthma., Competing Interests: Dr Kensuke Fukumitsu reports grants from Novartis Pharma and GSK; personal fees from AstraZeneca, Boehringer Ingelheim, Novartis Pharma, and Kyorin, outside the submitted work. Dr Yoshihiro Kanemitsu reports grants and/or personal fees from Novartis Pharma, MSD, Sanofi, AstraZeneca, GSK, and Kyorin, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Ito et al.)

Background: The strength, assistance in walking, rising from a chair, climbing stairs, and falls questionnaire (SARC-F) is widely used for screening sarcopenia. We aimed to examine the association of SARC-F scores with the measurements of quality of life and activity in patients with idiopathic pulmonary fibrosis (IPF)., Methods: This cross-sectional pilot study prospectively enrolled 54 patients with IPF who completed pulmonary function tests, the 6-min walk test, the chronic obstructive pulmonary disease assessment test (CAT), St. George's Respiratory Questionnaire (SGRQ), the Hospital Anxiety and Depression Scale, and a daily step count. The daily step count was measured continuously for 7 consecutive days using a tri-axis accelerometer device., Results: The mean age was 73.6±7.9 years and the mean percent predicted forced vital capacity was 80.4%±15.6%. The median [interquartile range] SARC-F score, SGRQ total scores, and CAT scores were 2 [1-3.25], 28.8 [14.4-46.9], and 13 [7-22], respectively. SARC-F scores were correlated with the percent predicted forced vital capacity (r=-0.51, P<0.001), CAT score (r=0.57, P<0.001), SGRQ total score (r=0.77, P<0.001), Hospital Anxiety and Depression Scale anxiety score (r=0.31, P=0.025), and Hospital Anxiety and Depression Scale depression score (r=0.28, P=0.041). Linear regression analyses revealed that the 6-minute walk test (6MWT) (standardized β=0.33, P=0.011) and SARC-F score (standardized β=-0.39, P=0.005), but not the CAT score and SGRQ total score, were significant predictors for daily step count., Conclusions: SARC-F scores were correlated with health status and daily activity in patients with IPF. Further studies are warranted to validate the utility of the SARC-F in patients with IPF., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-813/coif). ANi serves as an unpaid editorial board member of Journal of Thoracic Disease. HO received research grants from Fukuda Life Tech Chubu, and Nippon Boehringer Ingelheim Co., Ltd, regarding the submitted work. The authors have the following competing interests outside the submitted work. HO received honoraria for lectures from Nippon Boehringer Ingelheim Co., Ltd. Kensuke Fukumitsu received research grants from Novartis Pharma and GSK. SF received honoraria for lectures from AstraZeneca and Eli Lilly. YK received research grants from Novartis Pharma, MSD, Sanofi, and Kyowa- Kirin Corporation and honoraria for lectures from GSK, Novartis Pharma, AstraZeneca, Sanofi, and Kyorin. TU received honoraria for lectures from AstraZeneca and Eli Lilly. KM received research support from Nippon Boehringer Ingelheim Co., Ltd., and honoraria for lectures from Pfizer and Chugai Pharmaceutical. TO reports honoraria for lectures from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Pfizer, Chugai Pharmaceutical, MSD, Daiichi Sankyo, and Asahi Kasei Pharma, as well as research grants from Kyowa Hakko Kirin, Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical, and Novartis. ANi reports honoraria for lectures from Astellas, AstraZeneca, Kyorin, GSK, MSD, Shionogi, Bayer, Sanofi, Taiho, and Nippon Boehringer Ingelheim Co., Ltd., and research grants from Astellas, Kyorin, Nippon Boehringer Ingelheim Co., Ltd., Novartis, MSD, Daiichi Sankyo, Taiho, Teijin, Ono, Takeda, and Sanofi Pharmaceutical. The other authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

Background: Chronic constipation leads to poor quality of life, and treatment remains unsatisfactory for patients. In Japan, magnesium oxide has been commonly used as the first choice of treatment for constipation; however, there are some cases of low satisfaction with magnesium oxide treatment. Linaclotide has recently been used to treat chronic constipation. In this study, we will examine whether linaclotide improves symptoms and quality of life in patients showing insufficient response to magnesium oxide., Methods: This is an exploratory multicenter open-label study. The target number of patients is 64: 32 patients with and 32 without abdominal symptoms. Patients with chronic idiopathic constipation or irritate bowel syndrome with constipation diagnosed according to the Rome-IV criteria are eligible. Patients prescribed 0.99-2 g/day of magnesium oxide for at least 4 weeks will be included. Those who consent to the study will continue taking magnesium oxide for 2-4 weeks, and defecation will be documented. Patients who meet the criteria will be prescribed linaclotide (0.5 mg) daily for 12 weeks. The primary endpoint is a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score after 12 weeks of treatment., Conclusion: This is the first study to investigate the usefulness of linaclotide as a second-line treatment for chronic constipation. We will test the efficacy of treatment of constipation in patients with inadequate response to magnesium oxide., Trial Registration: This study is registered with the Japan Registry of Clinical Trials (jRCT, jRCTs031200048)., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study is funded by Astellas Pharma Inc., the distributor of linaclotide. Astellas Pharma Inc. is involved in the drafting of the research protocol, obtaining consent forms, and managing the drugs and their delivery to the institutions., (© 2022 The Authors. Published by Elsevier Inc.)

Leukotriene receptor antagonists (LTRA) are widely used drugs for treating allergic asthma, and they have recently been suggested to have a suppressive effect on carcinogenesis and cancer cell proliferation. Aberrant crypt foci (ACF) are considered a reliable surrogate biomarker of colorectal cancer. This prospective study explored the chemopreventive effect of an LTRA on colonic ACF formation and the safety of the medicine in patients as a pilot trial leading to a colorectal cancer chemoprevention trial., This was a nonrandomized, open-label, controlled trial in patients with colorectal ACFs. The participants were allocated to LTRA or observation groups. Patients in the LTRA group received 10 mg of montelukast orally daily for 8 weeks. After the intervention, colonoscopy was performed to evaluate the changes in the number of ACFs., From November 2017 to March 2020, 40 patients were enrolled. The first 30 were assigned to the LTRA group, and the remaining 10 were assigned to the observation group. In the LTRA group, the mean change in the number of ACFs per patient at 8 weeks from baseline was -2.4 ± 2.2, while the mean change in the observation group was 0.4 ± 2.3 (P = 0.002). There were no severe adverse events., This is the first study to explore the effect of LTRAs against colorectal ACF formation in humans. LTRAs are potential candidates for chemoprevention in colorectal cancer., Prevention Relevance: We conducted the first LTRA chemoprevention trial for human rectal ACFs, which is considered a surrogate marker of colorectal carcinogenesis. 8-week treatment with LTRA suppressed ACF formation and cell proliferation in colonic epithelium. LTRAs are possible candidates for chemoprevention in colorectal cancer. See related Spotlight, p. 637., (©2022 American Association for Cancer Research.)

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC 50 ) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC 50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Although the number of patients with Mycobacterium avium complex (MAC) pulmonary disease has been increasing among the elderly individuals due to population aging in Japan, few studies have reported treatment in elderly patients with MAC pulmonary disease. We conducted a retrospective cohort study to evaluate differences in the tolerability of, adverse events associated with and efficacy of treatment for MAC pulmonary disease in elderly and nonelderly patients., Methods: The medical records of 96 newly diagnosed MAC pulmonary disease patients at Nagoya City University Hospital between April 2014 and March 2019 were reviewed., Results: Elderly patients ≥75 years old started multidrug treatment less frequently than nonelderly patients <75 years old (17 of 41 patients, 41.5% vs. 41 of 55 patients, 74.5%, P = 0.001). The treated elderly patients had more symptoms, more extensive radiological disease and a higher rate of positivity on sputum smear than the treated nonelderly patients. Eleven elderly patients and 19 nonelderly patients continued the initial multidrug regimen (64.7% vs. 46.3%, P = 0.26). Adverse events occurred in 6 elderly patients and 25 nonelderly patients (35.3% vs. 61.0%, P = 0.074). The rates of achievement of sputum conversion and radiological improvement after treatment for over 1 year were similar between the elderly and nonelderly patients (61.5% vs. 75.0%, P = 0.37; 76.9% vs. 78.1%, P = 1)., Conclusions: The tolerability, adverse events, and efficacy of treatment in elderly patients with MAC pulmonary disease were not noticeably different from those in nonelderly patients., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Fibroblasts of different origins are known to possess stromal memory after inflammatory episodes. However, there are no studies exploring human lung fibroblast memory which may predict a subsequent inflammatory response in chronic respiratory diseases and COVID-19. MRC-5 and HF19 human lung fibroblast cell lines were treated using different primary and secondary stimulus combinations: TNFα-WD-TNFα, Poly (I:C)-WD-TNFα, TNFα-WD-Poly (I:C), or LPS-WD-TNFα with a 24-h rest period (withdrawal period; WD) between the two 24-h stimulations. TLR3 and NF-κB inhibitors were used to determine pathways involved. The effect of SARS-Cov-2 spike protein to inflammatory response of lung fibroblasts was also investigated. mRNA expressions of genes and IL6 release were measured using qRT-PCR and ELISA, respectively. Statistical significance was determined by using one- or two-way ANOVA, followed by Bonferroni's post hoc analysis for comparison of multiple groups. Preexposure with Poly (I:C) significantly increased TNFα-induced IL6 gene expression and IL6 release in both cell lines, while it affected neither gene expressions of IL1B , IL2 , IL8 , and MMP8 nor fibrosis-related genes: ACTA2 , COL1A1 , POSTN , and TGFB1 . Inhibition of TLR3 or NF-κB during primary stimulation significantly downregulated IL6 release. Simultaneous treatment of MRC-5 cells with SARS-CoV-2 spike protein further increased TNFα-induced IL6 release; however, preexposure to Poly (I:C) did not affect it. Human lung fibroblasts are capable of retaining inflammatory memory and showed an augmented response upon secondary exposure. These results may contribute to the possibility of training human lung fibroblasts to respond suitably on inflammatory episodes after viral infection., Competing Interests: The following authors received research grants and personal fees outside the submitted work: YK received research grants from Novartis Pharma, MSD, Sanofi, and personal fees from GSK, Novartis Pharma, AstraZeneca, Sanofi, and Kyorin. KF received research grants from Novartis Pharma and GSK. SF received personal fees from AstraZeneca and Eli Lilly. HO received a research grant from Boehringer Ingelheim. KM received personal fees from Pfizer and Chugai Pharmaceutical. TO reports personal fees from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Pfizer, Chugai Pharmaceutical, MSD, Daiichi Sankyo, and Asahi Kasei Pharma, as well as research grants and personal fees from Kyowa Hakko Kirin, Boehringer Ingelheim, Ono Pharmaceutical, and Novartis. AN reports personal fees from Astellas, AstraZeneca, Kyorin, GSK, MSD, Shionogi, Bayer, Sanofi, Taiho, and Boehringer Ingelheim, and research grants from Astellas, Kyorin, Boehringer Ingelheim, Novartis, MSD, Daiichi Sankyo, Taiho, Teijin, Ono, Takeda, and Sanofi Pharmaceutical. The remaining 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 © 2022 Yap, Ueda, Kanemitsu, Takeda, Fukumitsu, Fukuda, Uemura, Tajiri, Ohkubo, Maeno, Ito, Oguri, Ugawa and Niimi.)

Background: Gastroesophageal reflux may be associated with the worsening of asthma by increasing cough reflex sensitivity. Hull Airway Reflux Questionnaire (HARQ) consists of 14 prevalent reflux-related symptoms. It may be useful in predicting the presence of cough reflex hypersensitivity in asthma., Methods: From August 2018 to July 2020, 266 asthmatic patients completed the HARQ. They underwent blood analysis, spirometry, fraction of exhaled nitric oxide (FeNO) measurement, and the capsaicin cough challenge test. Patients were considered to have reflux-related symptoms if their HARQ scores were 13 points or higher. We evaluated the association between reflux-related symptoms and clinical asthma outcomes. Finally, we performed a multivariate analysis to determine the clinical significance of the HARQ for asthma. This study was registered in the University Hospital Medical Information Network (UMIN000040732)., Results: The mean HARQ scores were 13.1 (standard deviation 12.0). Patients in the high HARQ scores group (HARQ ≥13, n = 105) showed a lower prevalence of atopic predisposition, lower levels of FeNO, heightened capsaicin cough reflex sensitivity, poorer asthma control, and more frequent admissions due to asthma than those in the low HARQ groups (all p values < 0.05). The HARQ was useful in selecting patients with poor controlled asthma and those with severe cough when the cut-off value was set at 13. Multivariate analysis revealed that heightened capsaicin cough reflex sensitivity affected reflux-related symptoms, as well as lower levels of FeNO and younger age., Conclusions: Higher HARQ scores (≥13) may be useful in predicting not only poor asthma condition but also the presence of airway neuronal dysfunction in patients with asthma to some extent., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Nintedanib is a multi-tyrosine kinase inhibitor widely used to treat progressive fibrosing interstitial lung diseases because it slows the reduction in forced vital capacity. However, the prognosis for patients treated with nintedanib remains poor. To improve nintedanib treatment, we examined the effects of nintedanib on gene expression in the lungs of induced-rheumatoid arthritis-associated interstitial lung disease model mice, which develop rheumatoid arthritis and subsequent pulmonary fibrosis. Using next-generation sequencing, we identified 27 upregulated and 130 downregulated genes in the lungs of these mice after treatment with nintedanib. The differentially expressed genes included mucin 5B and heat shock protein 70 family genes, which are related to interstitial lung diseases, as well as genes associated with extracellular components, particularly the myocardial architecture, suggesting unanticipated effects of nintedanib. Of the genes upregulated in the nintedanib-treated lung, expression of regulatory factor X2, which is suspected to be involved in cilia movement, and bone morphogenetic protein receptor type 2, which is involved in the pathology of pulmonary hypertension, was detected by immunohistochemistry and RNA in situ hybridization in peripheral airway epithelium and alveolar cells. Thus, the present findings indicate a set of genes whose expression alteration potentially underlies the effects of nintedanib on pulmonary fibrosis. It is expected that these findings will contribute to the development of improved nintedanib strategies for the treatment of progressive fibrosing interstitial lung diseases., Competing Interests: KU and HO received research funding and honoraria from Nippon Boehringer Ingelheim Co., Ltd., and SK received research funding from Boehringer Ingelheim Pharma GmbH & Co. KG. All other authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Asthma is a significant comorbidity of eosinophilic chronic rhinosinusitis (CRS). Type2-driven biomarkers such as sinus tissue eosinophilia and fractional nitric oxide (FeNO) may be utilized to detect high risk patients who develop asthma symptoms after endoscopic sinus surgery (ESS) in CRS patients., Methods: Thirty-six CRS patients without asthma who agreed to undergo ESS between October 2015 and December 2017 were prospectively observed for 12 months following ESS. They were monitored for the development of typical asthma symptoms including dyspnea, wheezes, and cough which responded to anti-asthma medication. Biomarkers were compared between patients who developed asthma symptoms after ESS (asthma symptoms group) and those who did not (non-asthma group). Biomarker changes following ESS intervention were also evaluated., Results: Six patients were lost to follow after ESS. Thus, 30 CRS patients [16 with nasal polyps (NPs) proved by surgery] were followed. Seven (23%) newly complained of asthma symptoms during follow-up. Levels of FeNO and the prevalence of eosinophilic NPs (eosinophils ≥ 70/high power fields) were significantly higher in the asthma symptom group than in non-asthma group [50.7 ppb vs 22.4 ppb for FeNO levels, and 100% ( n  = 3) vs 23% ( n  = 3) for eosinophilic NP prevalence, both p  < 0.05]. Levels of sputum periostin decreased significantly by ESS in the non-asthma group. However, changes of biomarkers after ESS were comparable between the two groups., Conclusions: Eosinophils in NPs (≥70/high power fields) and preoperative FeNO may be significant biomarkers for predicting the development of asthma symptoms after ESS.

Background: The serum creatinine/cystatin C (Cr/CysC) ratio has attracted attention as a marker for sarcopenia, but has not been studied in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to confirm the utility of the serum Cr/CysC ratio in predicting sarcopenia and investigate its clinical relevance., Methods: This cross-sectional pilot study prospectively enrolled patients with stable IPF. IPF was diagnosed through multidisciplinary discussions according to the 2018 international guidelines, and sarcopenia was diagnosed according to the 2019 consensus report of the Asian Working Group for Sarcopenia. Patient-reported outcomes (PROs) were evaluated using the modified Medical Research Council (mMRC) dyspnea scale, chronic obstructive pulmonary disease assessment test (CAT), and King's Brief Interstitial Lung Disease (K-BILD) questionnaire. The associations between serum Cr/CysC ratio and the presence of sarcopenia and other clinical parameters, including PROs scores, were examined., Results: The study enrolled 49 Japanese patients with IPF with a mean age of 73.0 ± 7.7 years and a mean percentage of predicted forced vital capacity of 80.4 ± 15.5%. Sarcopenia was diagnosed in 18 patients (36.7%), and the serum Cr/CysC ratio was 0.86 [0.76-0.94] (median [interquartile range]). The receiver operating characteristic curve analyses for the detection of sarcopenia according to the serum Cr/CysC showed that the area under the curve, optimal cutoff value, specificity, and sensitivity were 0.85, 0.88, 0.65, and 0.94, respectively. Sarcopenia was identified in 13% of patients with a high serum Cr/CysC ratio (≥ 0.88) and 60% of patients with a low serum Cr/CysC ratio (< 0.88) (P < 0.001). Multiple linear regression analysis showed that the serum Cr/CysC ratio was an independent predictive marker of worse PROs evaluated using mMRC (P < 0.05), CAT (P < 0.05), and K-BILD (P < 0.05)., Conclusions: This study showed that the serum Cr/CysC ratio may be a surrogate marker of sarcopenia in patients with IPF. Furthermore, it is important to pay attention to the serum Cr/CysC ratio because a lower serum Cr/CysC ratio is associated with worse PROs. Further studies are required to validate these observations to determine whether the Cr/CysC ratio can be used to detect sarcopenia in patients with IPF., (© 2022. The Author(s).)

Background: S-1, an oral fluoropyrimidine derivative, is widely used for the treatment of several solid tumors. However, there are no predictive markers for its effectiveness., Methods: We retrospectively screened 108 patients with advanced non-small cell lung cancer (NSCLC) treated via S-1 monotherapy and investigated its relationship with cytokeratin 19 fragment (CYFRA 21-1) and CEA pretreatment levels., Results: Sixty-one patients with high CYFRA 21-1 levels had a statistically significant shorter progression-free survival (PFS) and overall survival (OS) than 46 patients with normal levels (median PFS = 42 days vs. 70 days, respectively; p = 0.0014; median OS = 197 days vs. 316 days, respectively, p = 0.0239)., Conclusions: Serum CYFRA 21-1 levels have predictive and prognostic roles in the management of patients with advanced NSCLC on S-1 monotherapy., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: International guidelines define severe uncontrolled asthma. Biologics or bronchial thermoplasty (Bio/BT) are recommended for such patients., Objectives: To determine which definitions of severe uncontrolled asthma are associated with an additional Bio/BT treatment in patients with severe uncontrolled asthma., Methods: Consecutive 107 asthmatics (including 15 patients for whom Bio/BT was introduced within 3 months after examination), classified as treatment step 4 according to the Global Initiative for Asthma 2015 guideline, were eligible for this analysis. Patients were assessed using the European Thoracic Society/American Thoracic Society (ERS/ATS) severe uncontrolled asthma guideline as defined by these 4 characteristics: poor control (ACT < 20), frequent exacerbations (≥2/yr), admissions (≥1/yr), and airflow limitation (forced expiratory volume in 1 second < 80% of predicted), along with comorbidities, and biomarkers, including blood granulocytes, fractional nitric oxide, and capsaicin cough reflex sensitivity (C-CS). These indices were compared between patients with and without Bio/BT introduction, and multivariate logistic regression analysis was performed to determine the association of the 4 definitions with treatment needs for Bio/BT., Results: Patients who were introduced to Bio/BT had heightened C-CS, heavier smoking history, and a greater prevalence of diabetes mellitus than those without ( p < 0.05). Poor asthma control (ACT < 20), frequent exacerbations (≥2/yr), and admissions (≥1/yr) were relevant to the future use of Bio/BT in the multivariate regression analysis. Type 2-related biomarkers including absolute eosinophil counts were higher in patients in the Bio introduction group than in the BT introduction group. Meanwhile, there was no significant difference of the 4 characteristics of severe uncontrolled asthma definition between patients in the Bio and those in the BT groups., Conclusion: Although multiple factors such as treatment cost and asthma phenotypes affect treatment decision-making, the definition of poor asthma control, frequent exacerbations and admission by the ERS/ATS guidelines were important factors for an additional intensive treatment for severe uncontrolled asthma., Trial Registration: UMIN Clinical Trials Registry: UMIN000024734., Competing Interests: Conflict of Interest: Y.K. reports research grants from Novartis Pharma, MSD, Sanofi, and Kyowa-Kirin corporations outside the submitted manuscript. K.F. reports research grants from Novartis Pharma and GSK outside the submitted manuscript. S.F. reports personal fees from AstraZeneca and Eli Lilly Japan outside the submitted work. H.O. reports a research grant from Boehringer Ingelheim outside of the submitted work. K.M. reports personal fees from Pfizer and Chugai Pharmaceutical outside of the submitted work. T. O. reports personal fees from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Pfizer, Chugai Pharmaceutical, MSD, Daiichi Sankyo, and Asahi Kasei Pharma, as well as research grants and personal fees from Kyowa Hakko Kirin, Boehringer Ingelheim, Ono Pharmaceutical, and Novartis outside the submitted work. M. T. reports a research grant from Pfizer outside of the submitted work. A.N. reports personal fees from Astellas, AstraZeneca, Kyorin, GSK, Sanofi, and Boehringer Ingelheim, and research grants from Astellas, Kyorin, Sanofi, Boehringer Ingelheim, Novartis, MSD, Daiichi Sankyo, Taiho, Teijin, Ono, and Takeda Pharmaceutical outside the submitted work. H.N, N.T., R.K., T.T., J.Y., K.I., T.U., and Y.I. did not receive any grants or personal fees., (Copyright © 2022. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Background/aim: The optimal chemotherapy for concurrent chemoradiotherapy (cCRT) of lung cancer is still unclear., Patients and Methods: We investigated the therapeutic effect of different chemotherapy regimens for cCRT of lung cancer in 65 patients at our hospital., Results: Of the 65 patients, 53 were male and 12 female. The median age was 64 years and 58 participants had a smoking history. The histological type was adenocarcinoma in 34 cases, squamous cell carcinoma in 22 cases, and others in 9 cases. Induction therapy consisted of cisplatin plus vinorelbine (CDDP+VNR) in 50 cases, and weekly carboplatin plus paclitaxel (CBDCA+PTX) in 15 cases. In all patients, the overall response rate, disease control rate, median progression survival, and median overall survival were 78.5%, 95.4%, 337 days, and 1,037 days, respectively. The median progression-free survival was 337 days in total; it was significantly longer for CDDP+VNR than CBDCA+PTX. The median overall survival was 1,037 days in total; it tended to be slightly longer for CDDP+VNR than CBDCA+PTX., Conclusion: Different chemotherapy regimens for cCRT possibly have different therapeutic effects., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)