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Human metapneumovirus (hMPV) is a respiratory pathogen that can cause lower respiratory tract infections and pneumonia in immunocompetent adults. Pneumonia caused by hMPV is reportedly more likely to cause bronchial wall thickening and ground-glass opacity (GGO). A 44-year-old woman with no significant medical history developed fever, cough, and nausea. Computed tomography of the chest showed scattered GGOs in the right upper lobe and infiltrating shadows with air bronchograms in the left lingual and bilateral lower lobes. The patient was admitted to our hospital for further evaluation. Atypical pneumonia was suspected and lascufloxacin (LSFX) was started. Multiplex polymerase chain reaction (PCR) detected hMPV on hospital day 2 using the FilmArray Respiratory Panel 2.1. Pneumonia due to hMPV was suspected and LSFX was discontinued. The patient subsequently showed spontaneous improvement and was discharged on hospital day 6 after admission. After discharge, pneumonia continued to improve. Early detection of respiratory pathogens using multiplex PCR can help determine the appropriate treatment strategy. As hMPV can also cause lobar pneumonia, we should consider pneumonia due to hMPV in the differential diagnosis of lobar pneumonia.

Key message It is an absolute necessity to achieve complete control of comorbidities to obtain optimal asthma control. Importantly, type 2 asthma and ECRS share the same inflammatory pathophysiology and are common co‐morbidities. If the initial biologic is insufficiently effective, it is worth considering an alternative biologic.

Key Clinical Message When the chest radiograph of a young patient shows lung hyperlucency, it is important to obtain a detailed clinical history of any previous episodes of childhood infection. Previous chest radiographs should be reviewed to determine whether the condition is congenital or acquired, and thus assist in a diagnosis of SJMS.

Abstract Schizophyllum commune is the third most common causative fungus of allergic bronchopulmonary mycosis(ABPM). Two‐thirds of ABPM caused by S. commune can be positive for Aspergillus fumigatus‐specific IgE, which can be difficult to diagnose. Our patient presented to our hospital with wet cough for 3 months and chest pain for 3 days. Blood tests showed IgE 1522 IU/mL, eosinophils 688/mm3, A. fumigatus ‐specific IgE 2.24 UA/mL, and chest computed tomography showed high‐attenuation mucus. Bronchoscopy showed mucus plugs and speculum examination showed filamentous fungi, but various culture tests did not detect A. fumigatus, Asp f 1‐specific IgE was negative, and S. commune was detected in the culture of bronchial washing. Since he was positive for S. commune‐specific IgE and IgG, he diagnosed ABPM caused by S. commune. These findings demonstrate the importance of identifying the causative fungus in ABPM by detailed examination.

Key Clinical Message Rare but severe, immune‐related adverse events such as myositis and sclerosing cholangitis can occur with immune checkpoint inhibitors in lung cancer treatment. This case report highlights their co‐occurrence after pembrolizumab treatment, indicating the need for vigilance and management strategies in immune checkpoint inhibitors therapy. Abstract Immune checkpoint inhibitors (ICI) are used in advanced treatment of lung cancer but can lead to immune‐related adverse events. ICI‐related myositis and cholangitis are rare, and their combination has not been previously reported. Here, we report the first case of ICI‐related myositis and sclerosing cholangitis. A patient with stage IV lung adenocarcinoma who received one cycle of pembrolizumab with cisplatin and pemetrexed developed myositis. Treatment with prednisolone improved the myositis, but the patient subsequently developed cholangitis. The patient did not respond to a regimen of prednisolone, mycophenolate mofetil, and azathioprine, and eventually died due to worsening lung cancer. An autopsy confirmed the presence of ICI‐related myositis and sclerosing cholangitis.

Abstract Several reports have described dupilumab‐induced eosinophilic pneumonia (EP) after treatment with dupilumab in patients with type 2 inflammatory disease. Other reports have suggested the efficacy of dupilumab for chronic EP (CEP). Whether dupilumab can be continued in patients with type 2 inflammatory disease who develop EP during dupilumab treatment remains unclear. We present herein three cases with different clinical presentations involving dupilumab and EP. In Case 1, dupilumab was discontinued because of dupilumab‐induced EP during the treatment of asthma. In Case 2, although pre‐existing idiopathic EP worsened during the treatment of eosinophilic chronic rhinosinusitis (ECRS), dupilumab was continued. In Case 3, CEP and ECRS were successfully treated with dupilumab and corticosteroids were discontinued. In conclusion, treatment with dupilumab in patients with type 2 inflammatory disease and idiopathic EP is worth considering if the benefits are deemed to outweigh the risks and careful attention is given to the clinical course.

Key message Tepotinib may cause hand‐foot skin reactions with keratotic changes. When such changes are observed in the hands or toes after starting tepotinib treatment, its side effects should be considered, and corticosteroid ointment or withdrawal of tepotinib should be considered if necessary.

Key message The pathogenesis of allergic bronchopulmonary aspergillosis involves not only eosinophils but also plasma cells that produce immunoglobulin E. Dupilumab may be an effective alternative to corticosteroids because it inhibits T cell to plasma cell differentiation by blocking IL4.

Key message Cryoprobes represent an option for bronchial foreign body removal in cases of bronchial obstruction due to viscous substances such as mochi at body temperature.

Key message The key feature of Poland syndrome is asymmetry in the chest wall. Clinicians should be alert to abnormalities of the chest wall as well as the lungs if there is abnormal chest radiograph lucency.

Abstract The present case involved a 78‐year‐old woman with repeated recurrences of allergic bronchopulmonary mycosis (ABPM) who presented to our outpatient clinic with a chief complaint of dyspnoea with respiratory failure. Computed tomography (CT) of the chest showed atelectasis of the lower lobes due to mucus plugs. Blood and biochemical tests showed a high peripheral blood eosinophil count (1330/μL) and elevated immunoglobulin E (15,041 IU/mL; normal,

Key message Chest drainage is a basic and important procedure in the treatment of pneumothorax. When properly implemented, even the most severely ill patients may be able to be treated without surgical intervention.

Key message Asthma is one of the most common diseases. However, in patients with refractory asthma, chest imaging assessment should be performed, bearing in mind the possibility of other diseases.

Key message Pleural amyloidosis does not present with specific imaging findings and is difficult to diagnose unless pleural biopsy is performed. However, distinguishing pleural amyloidosis from malignant disease is important and biopsy should be performed wherever possible to establish a treatment plan as early as possible.

Abstract Cryptococcosis is an invasive fungal infection that can occur in cancer patients. A case of pulmonary cryptococcosis in a patient treated with erlotinib + ramucirumab for epidermal growth factor receptor (EGFR) L858R point mutation‐positive non‐small cell lung cancer is presented. During chemotherapy, a new pulmonary nodule was found and considered progressive disease. Examination of the biopsy specimen taken to identify EGFR T790M mutation incidentally led to the diagnosis of pulmonary cryptococcosis. Three months after taking fluconazole, chest computed tomography showed that the pulmonary nodule had shrunk. New pulmonary nodules during lung cancer treatment require careful attention, not only because of disease progression, but also because of the possibility of infection in an immunocompromised host.

Long-term experiments using organoids and tissues are crucial for drug development. Microfluidic devices have been regularly used in long-term experiments. However, microbubbles often form in these devices, and they may damage and starve cells. A method involving the application of negative pressure has been reported to remove microbubbles from microfluidic devices composed of polydimethylsiloxane; however, negative pressure affects the cells and tissues in microfluidic devices. In this study, a local microbubble removal method was developed using a microfluidic device with 0.5 mm thin polydimethylsiloxane sidewalls. The thin sidewalls counterbalanced the negative and atmospheric pressures, thereby localizing the negative pressure near the negatively pressurized chamber. Microbubbles were removed within 5 mm of the negatively pressurized chamber; however, those in an area 7 mm and more from the chamber were not removed. Using the local removal method, a long-term perfusion test was performed, and no contact was confirmed between the bubbles and the simulated tissue for 72 h.

Abstract To prevent accidents in minimally invasive surgeries, force limiters have been developed for forceps grippers. When a force limiter is in use, if the absolute value of its spring constant is reduced, the risk of damage to the organs decreases. This paper proposes the use of a leaf spring buckling mechanism as a force limiter for forceps. The results obtained indicate that the spring constant of a buckled leaf spring is lower than that of a normal coil spring. Furthermore, the use of a leaf spring allows the independent adjustment of its thickness and width, based on the stress and force values. This enables an easy calibration of the threshold value. In the experiments, the spring constant of the buckled leaf spring was $$1.5 \times 10^{-1}$$ 1.5 × 10 - 1 N/mm, which is half of that of a normal coil spring. After calibrating the gripping force, it was confirmed that the force limiter reduced the extent of damage to the dummy organs in the ex vivo experiments.

Abstract The discriminative power of CURB-65 for mortality in community-acquired pneumonia (CAP) is suspected to decrease with age. However, a useful prognostic prediction model for older patients with CAP has not been established. This study aimed to develop and validate a new scoring system for predicting mortality in older patients with CAP. We recruited two prospective cohorts including patients aged ≥ 65 years and hospitalized with CAP. In the derivation (n = 872) and validation cohorts (n = 1,158), the average age was 82.0 and 80.6 years and the 30-day mortality rate was 7.6% (n = 66) and 7.4% (n = 86), respectively. A new scoring system was developed based on factors associated with 30-day mortality, identified by multivariate analysis in the derivation cohort. This scoring system named CHUBA comprised five variables: confusion, hypoxemia (SpO2 ≤ 90% or PaO2 ≤ 60 mmHg), blood urea nitrogen ≥ 30 mg/dL, bedridden state, and serum albumin level ≤ 3.0 g/dL. With regard to 30-day mortality, the area under the receiver operating characteristic curve for CURB-65 and CHUBA was 0.672 (95% confidence interval, 0.607–0.732) and 0.809 (95% confidence interval, 0.751–0.856; P

Abstract A 76‐year‐old woman underwent transbronchial lung cryobiopsy (TBLC) and transbronchial lung biopsy (TBLB) for examination of interstitial infiltrates. After the examination, the patient's consciousness became clouded, and head computed tomography showed an air embolus. She was started on 100% oxygen, and her consciousness improved, but she remained hemiplegic on the left side and dysphagic. Vascular air embolism (VAE) is a rare but serious complication. Although cases of VAE have been reported with conventional transbronchial forceps biopsy, cases of VAE after TBLC are quite rare, and thus this case is reported.

Abstract Background Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. Methods We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. Results Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. Conclusions Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

Abstract Background Idiopathic non-specific interstitial pneumonia (iNSIP), idiopathic pleuroparenchymal fibroelastosis (iPPFE), and unclassifiable idiopathic interstitial pneumonia (IIP) are IIPs with chronic fibrotic phenotypes, and unlike idiopathic pulmonary fibrosis, they have often been treated with anti-inflammatory drugs, including corticosteroids and immunosuppressants. However, the impact of bronchoalveolar lavage (BAL) lymphocytosis on the effects of anti-inflammatory therapy has never been evaluated. This study aimed to elucidate whether BAL lymphocytosis can be used to predict the efficacy of anti-inflammatory drugs for iNSIP, iPPFE, and unclassifiable IIP. Methods Japanese patients diagnosed with iNSIP, iPPFE, and unclassifiable IIP by multidisciplinary discussion were identified using the nationwide registry. Eligible patients were stratified into four groups with and without BAL lymphocytosis and anti-inflammatory therapy to compare overall survival (OS) and changes in lung function. BAL lymphocytosis was defined as a lymphocyte differential count > 15%, and the cut-off was corroborated by survival classification and regression tree analysis. Results Overall, 186 patients (37 iNSIP, 16 iPPFE, and 133 unclassifiable IIP) were analyzed. Limited to patients treated with anti-inflammatory drugs (n = 123), patients with BAL lymphocytosis had a better prognosis [hazard ratio (HR), 0.26; 95% confidence interval (CI), 0.11–0.63; P = 0.003], higher slope of forced vital capacity (FVC) % predicted for 2 years, and longer OS (log-rank test, P = 0.012) than those without BAL lymphocytosis. On multivariate analysis, BAL lymphocytosis (HR 0.31; 95% CI 0.13–0.75; P = 0.009) was a prognostic factor for OS, along with age and FVC % predicted. Conversely, for patients managed without anti-inflammatory therapy (n = 63), the presence or absence of BAL lymphocytosis had no prognostic value. Conclusions BAL lymphocytosis is associated with good outcomes in patients treated with anti-inflammatory drugs, but has no prognostic value when anti-inflammatory drugs are not used. BAL lymphocytosis may provide a predictive biomarker for identifying patients with iNSIP, iPPFE and unclassifiable IIP who are likely to benefit from anti-inflammatory drugs.

Objectives: The aim of this study was to evaluate the diagnostic utility of a novel test kit that could theoretically detect all serogroups of Legionella pneumophila for diagnosing Legionella pneumonia, in comparison with existing kits. Methods: This study was conducted in 16 hospitals in Japan from April 2016 to December 2018. Three urinary antigen test kits were used: the novel kit (LAC-116), BinaxNOW Legionella (Binax), and Q-line Kyokutou Legionella (Q-line). In addition, sputum culture and nucleic acid detection tests and serum antibody tests were performed where possible. The diagnostic accuracy and correlations of the novel kit with the two existing kits were analyzed. Results: In total, 56 patients were diagnosed with Legionella pneumonia. The sensitivities of LAC-116, Binax, and Q-line were 79%, 84%, and 71%, respectively. The overall match rate between LAC-116 and Binax was 96.8% and between LAC-116 and Q-line was 96.4%. One patient had L. pneumophila serogroup 2, and only LAC-116 showed a positive result, whereas Binax and Q-line did not. Conclusions: The novel Legionella urinary antigen test kit was useful for diagnosing Legionella pneumonia. In addition, it could detect Legionella pneumonia caused by non-L. pneumophila serogroup 1.

Objectives: Nursing and healthcare-associated pneumonia (NHCAP) was proposed by the Japanese Respiratory Society to refer to healthcare-associated pneumonia. This study aimed to investigate whether antipseudomonal antibiotic therapy improved the prognosis of NHCAP patients at high risk for antimicrobial-resistant pathogens. Methods: Consecutive hospitalised NHCAP patients in Kurashiki Central Hospital between October 2010 and December 2016 were prospectively enrolled. NHCAP patients who were at high risk for antimicrobial resistance were defined as those who received antimicrobials in the preceding 90 days and/or were on tube feeding. The patients who received antipseudomonal antibiotics were defined as the guideline-concordant (GC) therapy group, and the others were defined as the guideline-discordant (GD) therapy group. The primary outcome was 30-day mortality. Inverse probability of treatment weighting (IPTW) analysis was used to reduce biases. Results: There were 277 patients with NHCAP; a majority (78.0%) were discharged from a hospital in the preceding 90 days. There were 52 patients in the GC group and 225 patients in the GD group. The 30-day mortality rate was significantly higher in the GC group than in the GD group (17.3%, 9/52 vs. 7.1%, 16/225; P = 0.03). After IPTW analysis, the GC therapy, compared with GD therapy, did not improve the 30-day mortality (OR 1.71, 95% CI 0.65–4.47; P = 0.28). Conclusions: Not all NHCAP patients, even those at high risk for antimicrobial resistance, need antipseudomonal antimicrobial treatment. The treatment strategy for NHCAP patients should be individualised, according to the pneumonia severity, risk for antimicrobial-resistant pathogens, and antibiogram in each hospital.

Objectives: The usefulness of serial procalcitonin (PCT) measurements for predicting the prognosis and treatment efficacy for hospitalised community-acquired pneumonia (CAP) patients was investigated. Methods: This prospective, multicentre, cohort study enrolled consecutive CAP patients who were hospitalised at 10 hospitals in western Japan from September 2013 to September 2016. PCT and C-reactive protein (CRP) were measured on admission (PCT D1 and CRP D1), within 48–72 h after admission (PCT D3 and CRP D3), and within 144–192 h after admission. CURB-65 and the Pneumonia Severity Index (PSI) were assessed on admission. The primary outcome was 30-day mortality; secondary outcomes were early and late treatment failure rates. Results: A total of 710 patients were included. The 30-day mortality rate was 3.1%. On multivariate analysis, only PCT D3/D1 ratio >1 [odds ratio (95% confidence interval): 4.33 (1.46–12.82),P = 0.008] and PSI [odds ratio (95% confidence interval): 2.32 (1.07–5.03), P = 0.03] were significant prognostic factors. Regarding treatment efficacy, PCT D3/D1 >1 was a significant predictor of early treatment failure on multivariate analysis. PCT D3/D1 with the PSI significantly improved the prognostic accuracy over that of the PSI alone. Conclusions: PCT should be measured consecutively, not only on admission, to predict the prognosis and treatment efficacy in CAP. Keywords: Biomarker, C-reactive protein, Pneumonia, Procalcitonin, Prognosis

Abstract A 79‐year‐old woman presented to the emergency department with a 1‐week history of progressively worsening dyspnoea on exertion. Chest computed tomography (CT) showed bilateral consolidation. On laboratory findings, the line blot assay for human T‐cell leukaemia virus type 1 was positive, the white blood cell count was 33,000/μl (atypical lymphocytes 8500/μl, 26% of the total white blood cell count) and β‐d‐glucan was increased to 391.1 pg/ml. In bronchoalveolar lavage fluid, there was a small number of atypical lymphocytes, and the polymerase chain reaction for Pneumocystis jirovecii was positive. Sulfamethoxazole‐trimethoprim and corticosteroid were administered, but the lung shadows remained. Adult T‐cell lymphoma/leukaemia (ATLL) cell infiltration was suspected, and transbronchial lung cryobiopsy was performed, which showed no infiltration of lymphoma cells into the lung. The lung shadow showed an improving trend on chest CT. She was diagnosed with chronic type ATLL and discharged without chemotherapy.

Key message A case of coronavirus disease 2019 (COVID‐19)‐induced adult multisystem inflammatory syndrome (MIS) and fatal acute limb ischaemia is presented. Arterial thrombosis and MIS are reported as complications of COVID‐19. This case further highlights that arterial thrombosis and MIS can occur in COVID‐19.

A 60-year-old man with a history of 4 cycles of atezolizumab treatment for non-small cell lung cancer presented to our hospital with a chief complaint of proximal muscle-dominant spasms. Blood tests showed elevated creatine phosphokinase (CPK) of 8450 U/L and hypothyroidism. There was little improvement even after stopping levetiracetam and pregabalin, and no suspicious physical findings of myositis. After levothyroxine was started for hypothyroidism, his muscle cramps and serum CPK level improved. Hypothyroidism as an immune-related adverse event can cause muscle spasms and is important in the differential diagnosis of muscle spasms in patients treated with immune checkpoint inhibitors.

Microfluidic liquid cells have been developed to visualize nanoscaled biological samples in liquid using a scanning electron microscope (SEM) through an electron-transparent membrane (ETM). However, despite the combination of the high-resolution visualization of SEM and the high experimental capability of microfluidics, the image is unclear because of the scattering of the electron beam in the ETM. Thus, this study developed a microfluidic liquid cell with a super-thin ETM of thickness 10 nm. Because the super-thin ETM is excessively fragile, the bonding of a silicon–nitride-deposited substrate and a polydimethylsiloxane microchannel before silicon anisotropic etching was proposed prevented the super-thin ETM from damage and breakage due to etching. With this protection against etchant using the microchannel, the yield of the fabricated super-thin ETM increased from 0 to 87%. Further, the scattering of the electron beam was suppressed using a microfluidic liquid cell with a super-thin ETM, resulting in high-resolution visualization. In addition, T4 bacteriophages were visualized using a super-thin ETM in vacuum. Furthermore, the cyanobacterium Synechocystis sp. PCC6803 in liquid was visualized using a super-thin ETM, and sub-microscopic structures on the surface were observed.

Abstract Background In patients with non-HIV Pneumocystis jirovecii pneumonia (PjP), computed tomography imaging reveals ground grass opacities (GGO). Previous reports show that some patients with non-HIV PjP exhibit GGO with crazy paving. However, there have been no studies on the association between crazy paving GGO and non-HIV PjP clinical outcomes. Here, at the diagnosis of non-HIV PjP, we reviewed high-resolution computed tomography (HRCT) findings that included GGO types and evaluated the prognostic impact of crazy paving GGO on the clinical outcomes of non-HIV PjP immunocompromised patients. Methods We retrospectively reviewed the clinical information including the HRCT findings of patients diagnosed with non-HIV PjP from five institutions between 2006 and 2015. The GGO types included those with or without crazy paving. The associations between clinical factors such as HRCT findings and in-hospital mortality were assessed using the Cox regression model. Results Sixty-one patients were included in our study. Nineteen patients died at a hospital. All patients exhibited GGO on HRCT imaging at diagnosis of non-HIV PjP. The HRCT findings included crazy paving GGO (29 patients, 47.5%), consolidations (23 patients, 37.7%), bronchiectasis (14 patients, 23.0%), and centrilobular small nodules (30 patients, 49.2%). Cysts were not observed in any patient. Multivariate analysis revealed that crazy paving GGO and low serum albumin levels were independent risk factors for mortality. Conclusions At the diagnosis of non-HIV PjP, patients with crazy paving GGO on HRCT imaging and low serum albumin levels may have a poor prognosis.

A 40-year-old Japanese man was diagnosed with systemic lupus erythematosus. Chest computed tomography showed patchy consolidation in both lungs. A cryobiopsy and bronchoalveolar lavage showed organizing pneumonia, not acute lupus pneumonia or diffuse alveolar hemorrhage. This case demonstrates the usefulness of cryobiopsy for the management of systemic lupus erythematosus interstitial lung disease.

Small cell lung cancer (SCLC) transformation is a rare resistance mechanism to anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), for which cytotoxic chemotherapy is often initiated. However, no case has been reported so far in which the SCLC component disappeared after chemotherapy and the tumor responded to ALK-TKI treatment again. A 41-year-old, never-smoker man was diagnosed with multiple metastatic lung adenocarcinoma harboring ALK gene rearrangements. After tumor re-growth was treated with alectinib, histological analysis of re-biopsy of the primary lesion showed combined small cell carcinoma, and cytotoxic chemotherapy was administered. After resistance to chemotherapy developed, the third biopsy of the primary lesion showed the original ALK gene rearrangements without the SCLC component. Alectinib was re-administered, and partial response was obtained. Biopsy for ALK-positive lung cancer that progressed after chemotherapy for SCLC transformation might be useful for decision-making regarding the therapeutic strategy.

Abstract Background Quick Sepsis-related Organ Failure Assessment (qSOFA) is a new screening system for sepsis. The prognostic performance of qSOFA for patients with suspected infections outside the intensive care unit (ICU) is similar to that of full SOFA; however, its performance for community-acquired pneumonia (CAP) has not yet been evaluated in detail. The objectives of the present study were to compare the prognostic performance of qSOFA with existing pneumonia severity scores, such as CURB-65 (confusion, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30/min, systolic blood pressure

Abstract Background Pneumococcal pneumonia causes high morbidity and mortality among adults. This study aimed to identify risk factors for bacteremic pneumococcal pneumonia, and to construct a prediction model for the development of bacteremia in patients with community-acquired pneumococcal pneumonia. Methods We retrospectively analyzed data from patients hospitalized with community-acquired pneumococcal pneumonia between April 2007 and August 2015. Logistic regression models were applied to detect risk factors for pneumococcal bacteremia, and a receiver operating characteristic curve was used to devise a prediction model. Results Based on the results of sputum cultures, urine antigen tests, and/or blood cultures, 389 patients were diagnosed with pneumococcal pneumonia, 46 of whom had bacteremia. In the multivariate analysis, age 20 mg/dL were identified as independent risk factors for the development of pneumococcal bacteremia. The bacteremia prediction score based on receiver operating characteristic curve analysis had a sensitivity of 0.74 and a specificity of 0.78 in patients with two risk factors. The area under the receiver operating characteristic curve was 0.77 (95% confidence interval (CI), 0.70–0.85). Conclusions Age

Abstract Background LUX-Lung 3 showed afatinib improved progression-free survival (PFS) compared with cisplatin plus pemetrexed in patients with epidermal growth factor receptor (EGFR) mutations. In this study, chemotherapy efficacy tended to differ between patients with Leu858Arg (L858R) point mutation and Exon 19 deletion (Del-19); PFS in L858R patients (8.1 months) was greater than in Del-19 patients (5.6 months). We investigated whether there is any difference in efficacy of cisplatin plus pemetrexed between Del-19 and L858R. Methods This study is a multicenter retrospective study. We reviewed medical records of patients who had received cisplatin plus pemetrexed as first line chemotherapy. Efficacies were evaluated between EGFR mutation status: Del-19 and L858R. Wild type cases were reference arm only, and not included in any statistical analysis. Results Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78 patients, 46.2%); and L858R (42/78, 53.8%). Median PFS of L858R group (9.4 months, 95% confidence interval [CI]: 7.0–12.6) was significantly longer than Del-19 group (5.5 months, 95% CI, 3.6–8.6) (p = 0.049). Response rate (RR) and OS presented no significant difference between L858R and Del-19. In multivariate analysis, EGFR mutation status (L858R versus Del-19) was the only significant factor for longer PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62–0.98) (p = 0.033). Conclusion Our study indicated better efficacy of cisplatin plus pemetrexed in L858R than in Del-19 patients. In EGFR-mutant NSCLC, EGFR-TKIs are undoubtedly the premier therapy. However, in second line or later settings, cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients.

Abstract Background Because of a limited number of reports, we aimed to investigate the clinical characteristics of patients with Legionella pneumonia due to non-Legionella pneumophila serogroup 1 and the diagnostic usefulness of the six-point scoring system for such patients compared with patients with pneumonia caused by L. pneumophila serogroup 1. Methods We retrospectively analysed patients diagnosed with Legionella pneumonia due to non-L. pneumophila serogroup 1 between March 2001 and June 2016. We examined the clinical characteristics, including symptoms, laboratory findings, radiologic findings, pneumonia severity, initial treatment and prognosis. We also calculated scores using the six-point scoring system in these patients. Furthermore, we compared the clinical characteristics and six-point scores between non-L. pneumophila serogroup 1 patients and L. pneumophila serogroup 1 patients among hospitalized community-acquired pneumonia patients enrolled prospectively between October 2010 and July 2016. Results Eleven patients had pneumonia due to non-L. pneumophila serogroup 1; their median age was 66 years and 8 patients (72.7%) were male. The most common pathogen was L. pneumophila serogroup 3 (6/11), followed by L. pneumophila serogroup 9 (3/11), L. pneumophila serogroup 6 (1/11) and L. longbeachae (1/11). Non-specific symptoms, such as fever and cough, were common. Six patients (54.5%) had liver enzyme elevation, but no patient developed hyponatraemia at

Simple microfluidic systems for handling large particles such as three-dimensional (3D) cultured cells, microcapsules, and animalcules have contributed to the advancement of biology. However, obtaining a highly integrated microfluidic device for handling large particles is difficult because there are no suitable microvalves for deep microchannels. Therefore, this study proposes a microvalve with a trapezoid-shaped cross-section to close a deep microchannel. The proposed microvalve can close a 350 μm deep microchannel, which is suitable for handling hundreds of micrometer-scale particles. A double-inclined lithography process was used to fabricate the trapezoid-shaped cross-section. The microvalve was fabricated by bonding three polydimethylsiloxane layers: a trapezoid-shaped liquid channel layer, a membrane, and a pneumatic channel layer. The pneumatic balloon, consisting of the membrane and the pneumatic channel, was located beneath a trapezoid-shaped cross-section microchannel. The valve was operated by the application of pneumatic pressure to the pneumatic channel. We experimentally confirmed that the expansion of the pneumatic balloon could close the 350 μm deep microchannel.

Tissue assays have improved our understanding of cancers in terms of the three-dimensional structures and cellular diversity of the tissue, although they are not yet well-developed. Perfusion culture and active chemical gradient formation in centimeter order are difficult in tissue assays, but they are important for simulating the metabolic functions of tissues. Using microfluidic technology, we developed an H-shaped channel device that could form a long concentration gradient of molecules in a tissue that we could then analyze based on its appearance and content. For demonstration, a cylindrical pork tissue specimen was punched and equipped in the H-shaped channel device, and both ends of the tissue were exposed to flowing distilled and blue-dyed water for 100 h. After perfusion, the tissue was removed from the H-shaped channel device and sectioned. The gradient of the blue intensity along the longitudinal direction of the tissue was measured based on its appearance and content. We confirmed that the measured gradients from the appearance and content were comparable.

The small intestine has the majority of a host’s immune cells, and it controls immune responses. Immune responses are induced by a gut bacteria sampling process in the small intestine. The mechanism of immune responses in the small intestine is studied by genomic or histological techniques after in vivo experiments. While the distribution of gut bacteria, which can be decided by the fluid flow field in the small intestinal tract, is important for immune responses, the fluid flow field has not been studied due to limits in experimental methods. Here, we propose a microfluidic device with chemically fixed small intestinal tissue as a channel. A fluid flow field in the small intestinal tract with villi was observed and analyzed by particle image velocimetry. After the experiment, the distribution of microparticles on the small intestinal tissue was histologically analyzed. The result suggests that the fluid flow field supports the settlement of microparticles on the villi.

Abstract Background There have been few data on the chemotherapy in elderly advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS), and usefulness of chemotherapy for such patients remains unclear. The objective of this study was to identify factors that predicted the survival benefit of chemotherapy. Methods All consecutive elderly patients (≥75 years) with advanced NSCLC, Eastern Cooperative Oncology Group PS ≥2, EGFR mutation wild type/unknown, and newly diagnosed from January 2009 to December 2012 at a tertiary hospital were retrospectively reviewed. Results We enrolled 59 patients, and 31 patients received at least one chemotherapy regimen (chemotherapy group). However, 28 patients received best supportive care (BSC) alone (BSC group). The proportion of PS 2 and serum albumin levels was significantly higher in the chemotherapy group than in the BSC group. In the chemotherapy group, log-rank testing did not show statistically significant differences in overall survival (OS) between the single-agent therapy group and carboplatin-based doublet therapy group; however, the OS of patients receiving chemotherapy for only 1 cycle (early termination) was significantly shorter than patients receiving chemotherapy for ≥2 cycles. Hypoalbuminemia was not only a risk factor for the early termination of chemotherapy but also an independent prognostic factor in the chemotherapy group. A receiver operating characteristic curve analysis showed that the best cut-off value was 3.40 g/dL. In patients with serum albumin levels ≥3.40 g/dL, OS was significantly better in the chemotherapy group than in the BSC group (p = 0.0156), however, patients with serum albumin levels

Abstract Background To identify the prognostic factors for survival in patients with interstitial pneumonia with autoimmune features (IPAF) who meet the serological domain of the IPAF criteria. Methods We retrospectively analysed 99 IPAF patients who met the serological domain and were hospitalised at the Respiratory Medicine Unit of Kurashiki Central Hospital from 1999 to 2015. The high-resolution computed tomography findings were usual interstitial pneumonia (UIP; n = 1), non-specific interstitial pneumonia (NSIP; n = 63), NSIP with organizing pneumonia (OP) overlap (n = 15), and OP (n = 20). One patient who had radiological UIP pattern, and met the serological and clinical domains was excluded. The clinical characteristics, radiological findings, administered therapy, and prognosis of the remaining 98 IPAF patients who met the serological and morphological domains were analysed. Results The median age of the 98 IPAF patients was 68 years, and 41 (41.8%) of them were men. Twelve (12.2%) of the 98 IPAF patients developed other characteristics and were diagnosed with connective tissue disease (CTD) later during the median follow-up of 4.5 years. Univariate Cox analysis revealed systemic sclerosis (SSc)-specific and SSc-associated antibodies (ANA nucleolar pattern, ANA centromere pattern, anti-ribonucleoprotein and anti-Scl-70) positive IPAF, radiological NSIP pattern, bronchoalveolar lavage fluid lymphocytes >15%, and age as significant prognostic factors for survival. Multivariate Cox analysis revealed radiological NSIP pattern (hazard ratio [HR], 4.48; 95% confidence interval [CI], 1.28–15.77, p = 0.02) and age (HR, 1.07; 95% CI, 1.02–1.11, p = 0.01) were significantly associated with worse survival. Conclusions We confirmed that radiological NSIP pattern and age are poor prognostic factors for the survival of IPAF patients. This study suggested that the autoantibodies that are highly specific for certain connective tissue diseases might be less important for the prognosis of IPAF compared with the radiological-pathological patterns. The relatively high proportion of IPAF patients who developed CTD later suggests the importance of careful observation for evolution to CTD in IPAF.

Abstract Background Patients with Mycobacterium avium complex (MAC) lung disease (LD) have a heterogeneous prognosis. This study aimed to develop and validate a prognostic scoring model for these patients using independent risk factors for survival. Methods We retrospectively analyzed the data of patients with MAC-LD from two hospitals (cohort 1, n = 368; cohort 2, n = 118). Cohort 1 was evaluated using a multivariate Cox proportional hazards model to identify independent risk factors for overall survival (OS). A prognostic scoring model composed of these factors was developed, and cohort 1 was stratified into three groups according to risk using the log-rank test. Finally, the prognostic scoring model was validated using the data of cohort 2. Results Seven independent risk factors for OS were selected from cohort 1, including the male sex, age ≥ 70 years, the presence of a malignancy, body mass index

Abstract Background To date, only few studies have examined the prognostic factors of community-acquired pneumonia (CAP) defined according to the latest criteria, which excludes healthcare-associated pneumonia (HCAP). Therefore, we aimed to investigate the factors that affect prognosis, and evaluate the usefulness of existing pneumonia severity scores for predicting the prognosis of CAP. Methods We retrospectively analyzed patients with CAP, excluding HCAP, who were enrolled prospectively between April 2007 and February 2016. Four patients who used macrolides other than azithromycin (AZM) were excluded. We used age, sex, comorbidities, laboratory findings and antimicrobial therapy as prognostic variables. The primary outcome was 30-day mortality and secondary outcome was ICU admission. We also performed receiver operating characteristic curve analysis of Pneumonia Severity Index (PSI), Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) severe criteria, CURB-65 and A-DROP pneumonia severity scores. Results Among 1834 CAP patients, mean age was 73.5 ± 14.3 years; 1281 (69.8%) were men; and 30-day mortality was 6.7% (122/1834). In total, 1830 patients were analyzed. Multivariate analysis identified age [Odds Ratio (OR): 1.04, 95% Confidence Interval (CI): 1.02–1.07], chronic obstructive pulmonary disease (COPD) [OR: 1.77, 95% CI: 1.13–2.76], malignancy (OR: 2.25, 95% CI: 1.25–4.06), body temperature (OR: 0.81, 95% CI: 0.67–0.99), respiratory rate (OR: 1.04, 95% CI: 1.01–1.07), PaO2/FiO2 ≤ 250 (OR: 3.15, 95% CI: 1.93–5.14), Alb (OR: 0.27, 95% CI: 0.19–0.39), BUN (OR: 1.01, 95% CI: 1.00–1.02), and mechanical ventilation (OR: 2.99, 95% CI: 1.75–5.12) as prognostic factors. AZM and β-lactam combination therapy significantly reduced 30-day mortality (OR: 0.50, 95% CI: 0.26–0.97). Areas under the curve of PSI, IDSA/ATS severe criteria, CURB-65 and A-DROP were 0.759, 0.746, 0.754 and 0.764, respectively. Conclusions Increasing age, presence of COPD and malignancy as comorbidities, hypothermia, tachypnea, PaO2/FiO2 ratio ≤250 mmHg, low Alb level, high BUN level and mechanical ventilatory support predict a worse prognosis; AZM combination therapy should be considered for CAP, excluding HCAP. All four pneumonia severity scores are useful for assessing the severity of CAP defined by the latest criteria. Trial registration UMIN-CTR UMIN000004353 . Registered 7 October 2010. Retrospectively registered.

Abstract Background Chronic fibrosing idiopathic interstitial pneumonia (CFIIP) has a potential risk of acute exacerbation (AE). However, the usefulness of cellular analysis of bronchoalveolar lavage fluid (BALF) has never been evaluated. This study aimed to evaluate the impact of the lymphocyte differential count > 15% in BALF on the mortality of patients with AE of CFIIP. Methods We retrospectively analysed 37 patients with AE of CFIIP who underwent BAL on admission. Patients were divided into two groups: one group consisting of those with a lymphocyte differential count > 15% and the other consisting of those with a lymphocyte differential count ≤ 15%. We compared the 90-day mortality between the two groups as the primary outcome, using the two-tailed log-rank test. Results The median follow-up duration was 6.9 months. Twenty-four patients had a lymphocyte differential count > 15%. The 90-day mortality was significantly higher in the group with a lymphocyte differential count ≤ 15% than in the group with a lymphocyte differential count > 15% (long rank test, p = 0.003). In the multivariate analysis a lymphocyte differential count > 15% was shown to be an independent favourable prognostic factor for 90-day mortality (HR: 0.125; 95% CI: 0.0247–0.589; p = 0.009). Conclusions A lymphocyte differential count > 15% in BALF may be associated with favourable outcomes in patients with AE of CFIIP.

Microfluidic devices utilizing spheroids play important roles in in vitro experimental systems to closely simulate morphological and biochemical characteristics of the in vivo tumor microenvironment. For the observation and analysis of the inner structure of spheroids, sectioning is an efficient approach. However, conventional microfluidic devices are difficult for sectioning, and therefore, spheroids inside the microfluidic channels have not been sliced well. We proposed a microfluidic device created from embedding resin for sectioning. Spheroids were cultured, embedded by resin, and sectioned in the microfluidic device. Slices of the sectioned spheroids yielded clear images at the cellular level. According to morphological and immunohistochemical analyses of the slices of the spheroid, specific protein distribution was observed.

The uniform dispersion of cells in a microchamber is important to reproduce results in cellular research. However, achieving this is difficult owing to the laminar flow caused by the small dimensions of such a chamber. In this study, we propose a technique to achieve a uniform distribution of cells using a micropillar array inside a microchamber. The cells deform when they pass through a gap between the micropillars. The deformation causes a repetitive clog-and-release process of cells at the gaps between the micropillars. The micropillar array generates random flow inside the microchamber, resulting in the uniform distribution of the cells via cell accumulation. In the experiment, the distribution of cells in the microchamber with the micropillar array is uniform from end to end, whereas that in the microchamber without the micropillar array is centered. The deviation of the cell distribution from the ideally uniform distribution in the microchamber with the micropillar array is suppressed by 63% compared with that in the microchamber without the micropillar array. The doubling time of the cells passed through the micropillar array did not change relative to that of normal N87 cells. This technique will be helpful for reproducing results in cellular research at the micro scale or for those using microfluidic devices.

The small number of high-migratory cancer cells in a cell population make studies on high-migratory cancer cells difficult. For the development of migration assays for such cancer cells, several microfluidic devices have been developed. However, they measure migration that is influenced by microstructures and they collect not only high-migratory cells, but also surrounding cells. In order to find high-migratory cells in cell populations while suppressing artifacts and to collect these cells while minimizing damages, we developed a microfluidic high-migratory cell collector with the ability to sort cancer cells according to cellular migration and mechanical detachment. High-migratory cancer cells travel further from the starting line when all of the cells are seeded on the same starting line. The high-migratory cells are detached using a stretch of cell adhesive surface using a water-driven balloon actuator. Using this cell collector, we selected high-migratory HeLa cells that migrated about 100 μm in 12 h and collected the cells.

This paper proposes a microfluidic device for screening molecules such as aptamers, antibodies, proteins, etc. for target cell-specific binding molecules. The discovery of cancer cell-specific binding molecules was the goal of this study. Its functions include filtering non-target cell-binding molecules, trapping molecules on the surface of target cells, washing away unbound molecules, and collecting target cell-specific binding molecules from target cells. These functions were effectively implemented by using our previously developed micro pillar arrays for cell homogeneous dispersion and pneumatic microvalves for tall microchannels. The device was also equipped with serially connected filter chambers in which non-target cells were cultured to reduce the molecules binding to non-target cells as much as possible. We evaluated the performance of the device using cancer cell lines (N87 cells as target cells and HeLa cells as non-target cells) and two fluorescent dye-labeled antibodies: Anti-human epidermal growth factor receptor 2 (anti-HER2) antibody that binds to target cells and anti-integrin antibody that binds to non-target cells. The results showed that the device could reduce anti-integrin antibodies to the detection limit of fluorescent measurement and collect anti-HER2 antibodies from the target cells.

We in-situ observed the deformation of a gold single real contact point at the nanoscale during friction experiment in order to reveal the mechanism of friction. In this experiment, a special experimental setup combining between micro-electro-mechanical system (MEMS) and transmission electron microscope (TEM), called MEMS-in-TEM, was utilized for the stable visualization of the real contact point. Gold tips with electrostatic actuators were gently brought into contact and were rubbed each other at a quasi-static speed under TEM observation. Between tips, the gold single real contact point was formed and deformed in shear. During this deformation, the ends of the real contact point travelled 2.8 nm along the surface of the gold tips, although those of silicon and silver did not move. The maximum friction was 60 nN, repeating the stick-slip behavior from 35 to 60 nN. This result will be helpful to understand the mechanism of friction at the nanoscale and the lubrication mechanism of solid lubricants.

Observing the atomic-level deformation of a frictional interface in real-time is important step to elucidate the mechanism of lubrication. We have combined the nano-scale handling capabilities of MEMS technology with the unsurpassed observation ability of TEM and developed a MEMS-in-TEM experimental setup. Our MEMS device had Ag tips with two degree-of-freedom controlled by electrostatic actuators. Opposing tips were brought into contact using the actuator. After forming a contact, one tip was actuated laterally but slowly enough to maintain the contact between the tips. We succeeded in observing the nano-scale deformation of Ag junction in real time.

We used inclined lithography to fabricate a pneumatic microvalve for tall microchannels such as those used to convey large cells. The pneumatic microvalve consists of three layers. The upper layer is the actual liquid microchannel, which has a parallelogram-shaped cross section of width 500 μm, height 100 μm, and an acute angle of 53.6°. The lower layer is a pneumatic microchannel that functions as an actuator, and the middle layer is a thin polydimethylsiloxane membrane between the upper and lower layers. The operation of the pneumatic microchannel actuator causes the thin membrane to bend, resulting in the bending of the liquid microchannel and its closure. It was confirmed that the closure of the liquid microchannel completely stopped the flow of the HeLa cell suspension that was used to demonstrate the operation of the microvalve. The HeLa cells that passed through the microchannel were also observed to retain their proliferation and morphological properties.