Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma.

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 based on the capsaicin concentration that induced at least two (C2) or five 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 of ≤ 2.44 µM) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-interleukin (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 with those in 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.

Efficacy of dupilumab for airway hypersecretion and airway wall thickening in patients with moderate-to-severe asthma: A prospective, observational study.

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.

Minimizing the risk of injury to the popliteal artery during pullout repair of medial meniscus posterior root tears: A cadaveric study.

Background: The purpose of this study was to investigate the positional effect of guide pins used in the transtibial pullout repair of medial meniscus posterior root tears on the popliteal artery. Methods: We used eight cadaveric knees. Two 2.4-mm guide pins were inserted into the posterior root of the medial meniscus at 50° to the articular surface from the medial edge of the tibial tuberosity (anteromedial group) and the anterior edge of the medial collateral ligament (posteromedial group) using an aiming guide placed at the posterior root attachment of the medial meniscus from the anteromedial portal. The posterior capsule was dissected, and the popliteal artery was identified. The positional effect of the guide pins on the popliteal artery was photographed arthroscopically at 0°, 30°, 60°, and 90° knee flexion angles. The popliteal artery diameter and the minimum distance between the popliteal artery center and the guide pin tip were measured. Results: At 90° knee flexion, most of the guide pins in the anteromedial (6 knees; 75 %) and posteromedial groups (7 knees; 87.5 %) collided with the femoral intercondylar wall. The rate of collision was significantly higher at the 90° knee flexion position than that at other angles (p = 0.02). The average shortest distance between the popliteal artery center and the guide pin tip at 0° knee flexion in the posteromedial group (5.4 mm ± 3.4 mm) was significantly greater than that at other knee flexion angles, although the mean distance in the posteromedial group was so negligible that the guide pin could penetrate the popliteal artery. Conclusions: Knee flexion at 90° causes less damage to the popliteal artery during the transtibial pullout repair of medial meniscus posterior root tears.

Low Daily Step Count Associated with Small Erector Spine Muscle Area and Sarcopenia in Idiopathic Pulmonary Fibrosis.

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 (ESMCSA) 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 average daily step count was 4,258 (2,155-6,991) steps. The average 6MWD, ESMCSA, and PMV were 413±97 m, 25.5±6.7 cm2, and 270±75.6 cm3, respectively. A linear regression analysis for daily step count showed that the ESMCSA and 6MWD were independent factors for the daily step count, whereas the PMV and skeletal muscle index were not. The daily step count, ESMCSA, and 6MWD were lower in patients with sarcopenia than in those without sarcopenia. Conclusions 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.

Built Environments and Frailty in Older Adults: The JAGES Longitudinal Study Using Mediation Analysis.

OBJECTIVES: The purpose of this study was to investigate the association between subjective built environment and the onset of frailty in older adults living in the community. In addition, we examined whether daily walking time, depressive symptoms, and social support from neighbors and friends are mediating factors. DESIGN: This was a longitudinal study using prospective cohort data from the 2013 Japan Gerontological Evaluation Study. SETTING AND PARTICIPANTS: Participants included 38,829 older adults who were not frail recruited from 22 cities and towns. METHODS: The dependent variable, frailty, was assessed using the Kihon checklist. The explanatory variables were 5 items for the subjective built environment. The mediating variables were walking time of at least 30 minutes per day, a Geriatric Depression Scale (GDS) score of at least 5 points, and social support from neighbors and friends. We performed a causal mediation analysis of mediating effects between each built environment and frailty onset. Furthermore, the proportion of mediation was estimated. RESULTS: After 3 years of follow-up, frailty emerged in 2232 adults (6.7%) in 2016. Access to parks and sidewalks, access to fresh food stores, houses or facilities where people feel free to drop in, and fascinating views, or buildings reduced the onset of frailty. Mediators significantly associated with the built environment and onset of frailty were access to parks and sidewalks (walking time: 5.9%, GDS: 22.9%, social support: 5.9%), access to fresh food stores (GDS: 31.9%, social support: 4.0%), hills and steps (GDS: 20.6%), houses or facilities where people feel free to drop in (walking time: 4.0%, GDS 28.0%, social support: 10.4%), and fascinating views, or buildings (walking time: 7.8%, GDS: 42.1%, social support: 12.0%). CONCLUSIONS AND IMPLICATIONS: We found that walking time, depression, and social support were mediating factors in the relationship between built environment and the onset of frailty.

Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial.

BACKGROUND: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting ß2 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_view.cgi?recptno=R000024253).

Targeting the interleukin-5 pathway improves cough hypersensitivity in patients with severe uncontrolled asthma.

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.

Interstitial pneumonia with autoimmune features and histologic usual interstitial pneumonia treated with anti-fibrotic versus immunosuppressive therapy.

BACKGROUND: Therapeutic strategies in patients with interstitial pneumonia with autoimmune features (IPAF) and histological usual interstitial pneumonia (UIP) pattern (IPAF-UIP) have not been thoroughly evaluated. We compared the therapeutic efficacy of anti-fibrotic therapy with that of immunosuppressive treatment for patients with IPAF-UIP. METHODS: In this retrospective case series, we identified consecutive IPAF-UIP patients treated with anti-fibrotic therapy or immunosuppressive therapy. Clinical characteristics, one-year treatment response, acute exacerbation, and survival were studied. We performed a stratified analysis by the pathological presence or absence of inflammatory cell infiltration. RESULTS: Twenty-seven patients with anti-fibrotic therapy and 29 with immunosuppressive treatment were included. There was a significant difference in one-year forced vital capacity (FVC) change between patients with anti-fibrotic treatment (4 in 27 improved, 12 stable, and 11 worsened) and those with immunosuppressive treatment (16 in 29 improved, eight stable, and five worsened) (p = 0.006). There was also a significant difference in one-year St George's Respiratory Questionnaire (SGRQ) change between patients with anti-fibrotic therapy (2 in 27 improved, ten stable, and 15 worsened) and those with immunosuppressive treatment (14 in 29 improved, 12 stable, and worsened) (p < 0.001). There was no significant difference in survival between the groups (p = 0.32). However, in the subgroup with histological inflammatory cell infiltration, survival was significantly better with immunosuppressive therapy (p = 0.02). CONCLUSION: In IPAF-UIP, immunosuppressive therapy seemed to be superior to anti-fibrotic treatment in terms of therapeutic response, and provided better outcomes in the histological inflammatory subgroup. Further prospective studies are needed to clarify the therapeutic strategy in IPAF-UIP.

Decreased capsaicin cough reflex sensitivity predicts hospitalisation due to COPD.

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.

Utility of serum immunoglobulin A antibody against glycopeptidolipid core antigen in the diagnosis and management of hypersensitivity pneumonitis associated with Mycobacterium avium complex: A case report.

Measurement of the levels of serum immunoglobulin A antibody against glycopeptidolipid (GPL) core antigen, a cell surface antigen found in Mycobacterium avium complex (MAC), has been reported to be useful in the diagnosis and management of pulmonary MAC infection. However, evidence on its utility in hypersensitivity pneumonitis (HP) associated with MAC (i.e., "hot-tub lung") is limited. We herein report a case of HP associated with MAC in which the GPL core antibody levels were serially measured from diagnosis to treatment and thereafter. A 61-year-old man was suspected to have non-fibrotic HP based on the clinical course, laboratory findings, imaging pattern, bronchoalveolar lavage (BAL) lymphocytosis, and histopathological findings. Based on the history of whirlpool bath use, inhalation of aerosolized MAC was suspected as the cause of HP. The GPL core antibody level, measured using an enzyme-linked immunosorbent assay kit, was elevated, suggesting an immunological sensitization to MAC. A provocation test using the patient's whirlpool bath was positive. An identical MAC strain was isolated from the BAL fluid and bathtub. Accordingly, the patient was diagnosed with HP caused by the inhalation of aerosolized MAC from the whirlpool bath. The patient recovered after steroid treatment and discontinuation of the whirlpool bath. The GPL core antibody levels decreased with disease improvement. In conclusion, GPL core antibody levels could be elevated in HP associated with MAC and decrease with disease improvement. Thus, measurement of the GPL core antibody level may be useful for the diagnosis and management of HP associated with MAC.

SARC-F scores can predict health status and daily activity in patients with idiopathic pulmonary fibrosis.

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 ß=0.33, P=0.011) and SARC-F score (standardized ß=-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.

Frequency and impact on clinical outcomes of sarcopenia in patients with idiopathic pulmonary fibrosis.

OBJECTIVES: Sarcopenia is a syndrome characterized by reduced muscle mass and function. It is well-recognized as a complication in chronic diseases such as chronic obstructive pulmonary disease. However, little is known about sarcopenia in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the clinical characteristics of sarcopenia and the association between quality of life and sarcopenia in patients with IPF. METHODS: In this pilot cross-sectional study, 56 Japanese outpatients with IPF (49 men) were enrolled prospectively. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia 2019. Its associations with clinical parameters including age, pulmonary functions, physical performance, and patient-reported outcomes (PROs) were examined. RESULTS: The frequency of sarcopenia was 39.3% (n = 22) in this cohort. There were significant differences in St George's Respiratory Questionnaire (p = .005), modified Medical Research Council score (p = .004), and Hospital and Anxiety Depression Scale depression score (p = .030) between the sarcopenic and non-sarcopenic groups. On multivariate regression analysis, 6-min walk distance (6MWD) was an independent factor associated with sarcopenia (odds ratio 1.241, 95% confidence interval 1.016-1.515, p = .034). CONCLUSION: Sarcopenia was associated with PROs and physical performance in patients with IPF.

Built environments and frailty in older adults: A three-year longitudinal JAGES study.

BACKGROUND: This study investigated the relationship between built environments and the onset of frailty after 3 years. METHODS: This was a longitudinal study using prospective cohort data from the 2013 Japan Gerontological Evaluation Study on 38,829 older adults nested in 562 comunnities who were not frail. The dependent variable, frailty, was assessed using the Kihon checklist. The explanatory variables were eight items for the built environment at the individual and community levels. To consider each level of built environment simultaneously, multilevel Poisson regression analysis was used to calculate risk ratios and 95% confidence intervals. RESULTS: After 3 years of follow-up, the onset of frailty was 2740 (7.1%) in 2016. At the individual level, there was an increased risk of developing frailty in negative built environments, such as locations with graffiti or garbage (incidence rate ratio (IRR), 1.15; confidence interval (CI), 1.05-1.25). Positive built environments, such as areas with access to parks and sidewalks (IRR, 0.78; CI, 0.70-0.88), lowered the risk of developing frailty. At the community level, the risk of developing frailty was lower only in areas with locations difficult for walking (hills or steps) (IRR, 0.97; CI, 0.94-0.99). CONCLUSIONS: At the individual level, frailty onset was associated with all built environments. However, irrespective of their answers, there was a lower risk of developing frailty among older adults living in areas where walking was difficult. It would be desirable to verify whether the risk of developing frailty can be reduced by changing the built environment.

Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel.

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 (IC50) 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 IC50 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.

Tolerability, adverse events, and efficacy of treatment for Mycobacterium avium complex pulmonary disease in elderly patients.

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.

Pulmonary rehabilitation for idiopathic pleuroparenchymal fibroelastosis: A retrospective study on its efficacy, feasibility, and safety.

BACKGROUND: The beneficial effects of pulmonary rehabilitation (PR) for patients with idiopathic pleuroparenchymal fibroelastosis (IPPFE) remain unknown. This study aimed to examine the efficacy, feasibility, and safety of PR for IPPFE. METHODS: We retrospectively investigated 25 patients with IPPFE referred for PR between April 2007 and March 2017. The PR mainly consisted of a 10-week exercise training program. The primary outcome was a change in 6-min walk distance (6MWD). Secondary outcomes included changes in dyspnea (transition dyspnea index [TDI]), anxiety and depression (hospital anxiety and depression scale [HADS]), and health-related quality of life (HRQoL) (St George's respiratory questionnaire [SGRQ]). RESULTS: Thirteen patients participated in the PR program (PRP). Recurrent pneumothorax was the most common reason for patients not participating in the PRP. Four patients discontinued the PRP due to the recurrence of pneumothorax, new onset of pneumomediastinum, stroke, and another reason, respectively. Nine patients completed the PRP. Significant improvement was observed in 6MWD (median [interquartile range], 90 m [55-116 m]; P = 0.033). Clinically important improvements in the 6MWD, and TDI, HADS-anxiety, HADS-depression, and SGRQ total domain scores were observed in seven (78%), five (56%), four (44%), four (44%), and five (56%) of the nine patients, respectively. CONCLUSIONS: Patients with IPPFE benefited from PR in terms of exercise capacity, dyspnea, anxiety, depression, and HRQoL. Pneumothorax and pneumomediastinum may impede the implementation of a PRP for patients with IPPFE. While careful patient selection is required, PR may be an efficacious non-pharmacological approach for managing disabilities in patients with IPPFE.

Low extracellular pH inhibits nucleotide excision repair.

Nucleotide excision repair (NER) is the main pathway to repair bulky DNA damages including pyrimidine dimers, and the genetic dysregulation of NER associated proteins is well known to cause diseases such as cancer and neurological disorder. Other than the genetic defects, 'external factors' such as oxidative stress and environmental chemicals also affect NER. In this study, we examined the impact of extracellular pH on NER. We prepared the culture media, whose pH values are 8.4 (normal condition), 7.6, 6.6 and 6.2 under atmospheric CO2 conditions. Human keratinocytes, HaCaT, slightly died after 48 h incubation in DMEM at pH 8.4, 7.6 and 6.6, while in pH 6.2 condition, marked cell death was induced. UV-induced pyrimidine dimers, pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs), were effectively repaired at 60 min and 24 h, respectively, which were remarkably inhibited at pH 6.6 and 6.2. The associated repair molecule, TFIIH, was accumulated to the damaged sites 5 min after UVC irradiation in all pH conditions, but the release was delayed as the pH got lower. Furthermore, accumulation of XPG at 5 min was delayed at pH 6.2 and 6.6, and the release at 60 min was completely suppressed. At the low pH, the DNA synthesis at the gaps created by incision of oligonucleotides containing pyrimidine dimers was significantly delayed. In this study, we found that the low extracellular pH inhibited NER pathway. This might partially contribute to carcinogenesis in inflamed tissues, which exhibit acidic pH.

Nano-Arthroscopic Ultrasound-Guided Excision of Unresolved Osgood-Schlatter Disease.

The nano-arthroscopic ultrasound-guided ossicle excision technique is used in the management of an unresolved Osgood-Schlatter disease. The NanoScope is inserted slightly lateral to the proximal patella tendon and moved on between the ossicle and anterior surface of the proximal tibia under ultrasonographic guidance. The 5-mm skin incision is made as a working portal on the medial side of the proximal patella tendon. The proximal border of the ossicle is clearly identified after bursectomy. Then, the ossicles are removed piece by piece using a 2-mm arthroscopic punch. During the resection, the remaining ossicle is continuously confirmed by ultrasound. Finally, the complete excision of the ossicle is shown by the nano-arthroscopic view and ultrasound. The patient is allowed to have a full weight-bearing and an unrestricted range of motion on the day of surgery. Patients are permitted to resume their sports activities without any restriction after 6 weeks. This technique is recommended to athletes who suffer from painful unresolved Osgood-Schlatter disease because of the benefits of it being a minimally invasive surgery with an early postoperative recovery.

What parameters can be used to identify early idiopathic pulmonary fibrosis?

Elucidating the disease process of early idiopathic pulmonary fibrosis (IPF) will help clinicians in addressing the contentious issues of when and in which patients, therapeutic intervention should be initiated. Here, we discuss several possible parameters for diagnosing early IPF and their clinical impacts. Physiologically, early IPF can be considered as IPF with normal or mild impairment in pulmonary function. Radiologically, early IPF can be considered as IPF with a small extent and/or early features of fibrosis. Symptomatically, early IPF can be considered as asymptomatic or less symptomatic IPF. IPF at Gender-Age-Physiology index stage I can be considered early IPF. Interstitial lung abnormalities are defined as parenchymal abnormalities in more than 5% of the lung in patients with no prior history of interstitial lung disease, and in some cases, this seems to be equivalent to early IPF. Previous clinical trials showed the effect of antifibrotic therapies in early IPF, but the effects of therapy are uncertain in early IPF outside of clinical trials, such as in cases of IPF with normal pulmonary function, IPF without honeycombing or traction bronchiectasis, and asymptomatic IPF. Moreover, little has been reported on disease progression in such conditions. Because the conceptual framework of early IPF may vary depending on its definition, not only is a diagnosis of early IPF important but prediction of disease progression is also crucial. Further investigations are needed to identify biomarkers that can detect patients who may experience greater degrees of disease progression and require treatment even with those forms of early IPF.

The diagnostic utility of the frequency scale for the symptoms of gastroesophageal reflux disease questionnaire (FSSG) for patients with subacute/chronic cough.

BACKGROUND: The frequency scale for the symptoms of GERD (FSSG) questionnaire, which originally consists of acid-reflux and dysmotility symptom domains, is a succinct questionnaire to evaluate gastroesophageal reflux disease (GERD) symptoms. OBJECTIVES: To evaluate the utility of subjective questionnaire of GERD for the diagnosis of GERD-related cough by using FSSG questionnaire. METHODS: We recruited 256 patients with subacute/chronic cough between April 2012 and March 2018, who were analyzed using FSSG questionnaire and blood eosinophil counts. GERD-related cough was inferred through the presence of classic reflux symptoms including heartburn and/or typical coughing trigger (e.g. phonation, rising, lying, eating, and intake of certain food). The diagnosis was confirmed by response to specific treatments for GERD. Receiver operating characteristic curve analysis was performed to determine the cutoff score for the diagnosis. RESULTS: One-hundred ten patients (43%) were diagnosed as having GERD-related cough. FSSG questionnaire was relevant for diagnosing GERD-related cough, with the area under the curve (AUC) of 0.70 (p < 0.0001, cutoff score 7 points, sensitivity 75%, specificity 62%). When limited to patients with blood eosinophils of ≤150/µL or those with sputum eosinophils of ≤3%, sensitivity and specificity of the diagnosis was increased, respectively (sensitivity and specificity; 79% and 65% for blood eosinophils and 82% and 68% for sputum eosinophils. p < 0.0001, AUC 0.74 for both). CONCLUSIONS: The subjective questionnaire of GERD (FSSG) would be helpful in diagnosing GERD-related cough, particularly in patients with low blood or sputum eosinophil counts.