A Case of Miliary Tuberculosis Complicated by Thyroid Involvement: Managing Rifampicin-Induced Thrombocytopenia With Rifabutin.

This case report presents an unusual occurrence of miliary tuberculosis with thyroid tuberculosis in a 75-year-old male patient, who successfully completed the treatment with rifabutin after rifampicin-induced thrombocytopenia. The patient has been suffering from diabetes mellitus and chronic heart failure, and had coronavirus disease of 2019 (COVID-19) just before being diagnosed with miliary tuberculosis. The patient had not been prescribed immunosuppressants and steroids. Chest computed tomography (CT) scans revealed multiple tiny nodules diffusely and equally distributed in bilateral lung fields. Subsequently, polymerase chain reaction (PCR) techniques on the urine samples and culture of sputum demonstrated positivity for Mycobacterium tuberculosis. Thus, we conclusively identified miliary tuberculosis and initiated treatment using anti-tuberculosis drugs. During treatment, the patient developed thyroid tuberculosis, resulting in an enlarged thyroid and hoarseness, but these symptoms improved with continued use of the anti-tuberculosis drugs. Moreover, regarding treatment, the rifabutin dosage was completed after changing drugs due to rifampicin-induced thrombocytopenia. Notably, miliary tuberculosis is rarely complicated by thyroid tuberculosis as a paradoxical reaction, and the substitution of rifabutin for rifampicin-induced thrombocytopenia is not fully studied. We present this case alongside relevant prior data for comprehensive clinical insight.

Neuromedin-U Mediates Rapid Activation of Airway Group 2 Innate Lymphoid Cells in Mild Asthma.

RATIONALE: In asthma, sputum group 2 innate lymphoid cells (ILC2) are activated within 7h after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2 co-localize to sensory neuronal termini expressing the neuropeptide, neuromedin U (NMU) and NMU stimulates type 2 cytokines secretion by ILC2 with additive effects to alarmins, in vitro. OBJECTIVES: Investigate effect of NMU/NMUR1 axis on early activation of ILC2 in asthma. METHODS: M ild asthmatics (n=8) were enrolled in a diluent-controlled, allergen-inhalation challenge study. Sputum ILC2 expression of NMU receptor 1 (NMUR1) and T2 cytokines were enumerated by flow cytometry and airway NMU levels were assessed by ELISA. This was compared to samples from moderate-severe asthmatics (n=9). Flow sort-purified and ex-vivo expanded ILC2 were used for functional assays and transcriptomic analyses. RESULTS: Significant increases in sputum ILC2 expressing NMUR1 were detected 7h post- allergen versus diluent challenge where the majority of NMUR1+ILC2 expressed IL-5/IL-13. Sputum NMUR1+ILC2 were significantly greater in mild versus moderate-severe asthmatics and NMUR1+ILC2 correlated inversely with the dose of inhaled corticosteroid in the latter group. Co-culturing with alarmins upregulated NMUR1 in ILC2, which was attenuated by dexamethasone. NMU stimulated T2 cytokine expression by ILC2, maximal at 6h was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase ½, phospho-inositol 3 kinase but not IL-33 signaling moiety MyD88, in vitro. CONCLUSIONS: The NMU/NMUR1 axis stimulates rapid effects on ILC2, and maybe an important early activator of these cells in eosinophilic inflammatory responses in asthma.

Uncommon Occurrence of Pulmonary Aspergillosis Caused by Aspergillus sydowii: A Case Report.

This case report presents an unusual occurrence of pulmonary aspergillosis caused by Aspergillus sydowii in a 26-year-old male patient. The patient is from Nepal and had no significant medical history and was previously in good health. Chest computed tomography (CT) scans revealed localized bronchiectasis primarily in the left inferior lingular segment and the left lower lobe. Subsequently, bronchial lavage fluid was collected, and a comprehensive culture examination was conducted to confirm the cause of the infection. While Aspergillus fumigatus typically predominates as the cause of pulmonary aspergillosis, our bronchial lavage fluid culture revealed the presence of a filamentous fungus, identified as Aspergillus sydowii through molecular analysis. Thus, we conclusively identified this particular strain of fungus as the etiological factor behind the patient's condition. Notably, pulmonary aspergillosis due to Aspergillus sydowii is exceedingly rare, and we present this case alongside relevant prior data for comprehensive clinical insight. This case underscores the clinical significance of Aspergillus sydowii as a fungal pathogen, emphasizing the importance of early recognition and managing fungal infections.

Carboplatin plus pemetrexed for the elderly incurable chemo-naive nonsquamous non-small cell lung cancer: Meta-analysis.

AIM: In some developed countries, a proportion of nonsquamous non-small cell lung cancer (NSq NSCLC) patients are aged over 70 years when they are diagnosed. However, evidence of lung cancer chemotherapy usually comes from randomized controlled trials that only recruit younger patients with good performance status. In daily practice, less-toxic carboplatin + pemetrexed regimen is often used for elderly patients, although this regimen is not sufficiently supported by rigid evidence for elderly cases. METHODS: The protocol was registered on PROSPERO website (42017058508). Any phase trial that evaluated the efficacy and safety of carboplatin + pemetrexed in the elderly (aged 70 or higher) was included. Binary data were meta-analyzed with the random-model generic inverse variance method. Median survival duration was pooled after logarithmic transformation. RESULTS: Eight studies consisting of 285 patients were included among 882 articles that met the preliminary criteria. The pooled median overall survival and progression-free survivals were 14.9 months (95% confidence interval [95% CI], 12.0-18.4) and 5.4 months (95% CI, 4.5-6.4), respectively. The pooled response rate was 34.0% (95% CI, 27.5-40.5). Hematological adverse events such as neutropenia (≥grade 3; 48.3%; 95% CI, 40.1-56.6), thrombocytopenia (≥grade 3; 27.9%; 95% CI, 15.8-39.9), and anemia (≥grade 3; 17.1%; 95% CI, 8.3-25.8) were frequently observed. However, febrile neutropenia (6.8%; 95% CI, 0.2-13.3), nausea (≥grade 3; 0%; 95% CI, 0.0-4.4%) and treatment-related death (0.6%; 95% CI, 0-5.4%) were rare. CONCLUSION: Carboplatin + pemetrexed can be a good option for the treatment of the elderly with NSq NSCLC.

Modification of oxygen concentrators based on questionnaire survey.

BACKGROUND: In this study, we conducted a questionnaire survey to clarify and improve problems related to oxygen concentrators. METHODS: Using a questionnaire survey of 30 patients receiving long-term oxygen therapy for chronic respiratory failure, we investigated the necessity of using a remote controller, portability, fire prevention system, built-in battery type and so on. Patients were divided into two groups according to age, sex, underlying conditions and amount of oxygen prescribed, then analyzed accordingly. RESULTS: Mean age was 72.3 ± 8.09 years. The mean flow rate for prescribed oxygen was 1.10 L/min at rest and 2.96 L/min under exertion. Median duration of use was 17.5 months. Built-in battery type, environmentally friendly system and voice guidance system received the most attention according to four-grade evaluations of each function. Significant differences were seen in design features in patients less than 72 years old (P = .03), in voice guidance system in patients who only used the equipment during exertion (P = .01), and in brand imaging in those using the equipment under exertion at a flow ≥3 L/min (P = .04). In questionnaire results for the three most desired features, built-in battery type was of primary concern, followed by portability and use of a remote control. CONCLUSIONS: Overall, built-in battery type, portability, use of a remote control and an environmentally friendly system were desired features for oxygen concentrators. Desired features could vary according to age and the amount of oxygen prescribed.

The Platelet Count Can Predict In-hospital Death in HIV-negative Smear-positive Pulmonary Tuberculosis Inpatients.

Objective This retrospective cohort study investigated whether the three components of the blood cell count have prognostic implications in HIV-negative Japanese adult inpatients with smear-positive pulmonary tuberculosis. Methods We reviewed patients who were treated by the isoniazid, rifampicin, pyrazinamide, and ethambutol regimen or by the isoniazid, rifampicin, and ethambutol regimen. The association between the patient data on admission and the survival outcome was evaluated. Results We reviewed 367 consecutive patients (male, 60.5%) with a median age of 72 [interquartile range (IQR), 54-82] years. While the white blood cell count did not differ between the two groups, (discharged alive: 7,000/µL; IQR, 5,500-9,300; died in hospital: 7,200/µL; IQR, 5,600-9,400; p=0.797), hemoglobin level (discharged alive: 11.5 g/dL; IQR, 10.0-13.1; died in hospital: 9.9 g/dL; IQR, 8.6-11.3; p<0.001) and the platelet count (discharged alive: 275,000/µL; IQR, 206,000-345,000; died in hospital: 149,000/µL; IQR, 93,000-236,000; p<0.001) were lower in patients who died in hospital. After dividing patients into hemoglobin- and platelet-based quantiles, the lower quantile class tended to show poorer survival (log-rank test for trend p<0.001 for both). A multi-variable Cox proportional hazards model revealed that hazard ratio for in-hospital death for every 1,000/µL increase of platelet count was 0.997 (95%CI, 0.995-0.999; p=0.010); the hazard ratio for the hemoglobin level was not significant. Conclusion A low platelet count was clearly related to a poor life prognosis in HIV-negative Japanese adult inpatients with smear-positive pulmonary tuberculosis.

The best platinum regimens for chemo-naive incurable non-small cell lung cancer: network meta-analysis.

Platinum regimens still play a key role in chemotherapy for incurable non-small cell lung cancer (NSCLC). Although guidelines list many platina regimens, the best regimens have not yet clarified. Electronic searches were carried out during November 26th-28th, 2016. We included individually randomized trials comparing two or more platinum regimes for incurable chemo-naive NSCLC published in English full papers. The platinum doublets should be either Cisplatin (CDDP), Carboplatin (CBDCA), or Nedaplatin (CDGP) plus one of the third-generation agents. The platinum triplet should be the doublet plus bevacizumab (BEV). The data were independently extracted and cross-checked by two investigators. We did not observed heterogeneity (whole network level Q = 28.9, df = 34, P = 0.717) among 59 pairwise comparisons from 45 studies with 16141 cases for the primary outcome, hazard ratio for overall survival (HRos). Using CBDCA + Paclitaxel (PTX) + BEV as a common comparator, CDGP + Docetaxel (DTX) (HRos = 0.98, 95%CI: 0.75-1.29, P = 0.884), CDDP + Tegafur gimeracil oteracil (S1) (HRos = 1.23, 95%CI: 0.96-1.57, P = 0.099), CBDCA + S1 (HRos = 1.23, 95%CI: 0.99-1.53, P = 0.062), and CDGP + Gemcitabine (GEM) (HRos = 1.24, 95%CI: 0.71-2.17, P = 0.45) did not have significantly poorer HRos. We suggest that these regimens as acceptable first-choice regimens.

Long-Acting ß-Agonists (LABA) Combined With Long-Acting Muscarinic Antagonists or LABA Combined With Inhaled Corticosteroids for Patients With Stable COPD.

CLINICAL QUESTION: Are inhaled long-acting muscarinic antagonists (LAMA) combined with long-acting ß-agonists (LABA) associated with differences in the incidence of chronic obstructive pulmonary disease (COPD) exacerbation and serious adverse events and with differences in quality of life and forced expiratory volume in the first second of expiration (FEV1) vs inhaled LABA plus inhaled corticosteroids therapy for the treatment of stable COPD? BOTTOM LINE: Compared with inhaled LABA combined with corticosteroids, inhaled LAMA combined with LABA may be associated with a lower risk of COPD exacerbation and with greater improvement in FEV1 without differences in the incidence of serious severe adverse events or quality of life.

Factors for Predicting Outcomes among Non-HIV Patients with Pulmonary Tuberculosis.

Objective Onodera's Prognostic Nutritional Index (PNI), determined as "10× albumin (g/dL) + 0.005× lymphocyte count (/µL)," was originally designed to determine the risk of complications following gastrointestinal surgery. This single-center, retrospective observational study was designed to investigate whether or not the PNI can predict the treatment outcome. Methods We consecutively reviewed HIV-negative pulmonary tuberculosis adults in an isolation ward. Most patients were being treated with standard three- or four-drug regimens. Patients were discharged after consecutive negative smears/cultures were confirmed. The risk of all-cause death was assessed using a multivariable Cox proportional hazard model and a log-rank trend test. Results During the observation period, we observed 371 consecutive patients with a median age of 72 (interquartile range [IQR]: 54-82) years. In our cohort, 295 (79.5%) patients were discharged alive, and 76 (20.5%) died in-hospital. Patients who died in-hospital had a lower PNI [median 21.2 (IQR: 18.5-25.9)] than those who were discharged alive [median 35.1 (IQR: 28.0-43.3); p<0.001]. The area under the receiver operating characteristic curve was 0.87. After dividing the patients based on the baseline PNI quartile, those patients with a lower PNI showed a poorer survival than those with a higher PNI (log-rank trend p<0.001). After adjusting for other baseline variables, the baseline PNI was still associated with in-hospital death with a hazard ratio of 0.86 (95% confidence interval: 0.82-0.91, p<0.001). Conclusion Our results showed that a low PNI was clearly related to a poor survival prognosis in smear-positive HIV-negative pulmonary tuberculosis inpatients.

HbA1c level cannot predict the treatment outcome of smear-positive non-multi-drug-resistant HIV-negative pulmonary tuberculosis inpatients.

We conducted a single-center retrospective cohort study to evaluate whether the HbA1c level on admission could predict the in-hospital treatment outcome of smear-positive non-multi-drug-resistant HIV-negative culture-proven pulmonary tuberculosis inpatients. Our standard regimens under the direct observation were HRZE or HRE for the first two months followed by combination therapy with isoniazid and rifampicin. Our cohort consisted of consecutive 239 patients consisted of 147 men and 92 women with a median age of 73 years. The HbA1c level of patients whose HbA1c was above 7.0% on admission showed clear declining trends after admission. HbA1c on admission had no Spearman's rank correlation with time to discharge alive (r = 0.17) and time to becoming non-infective (r = 0.17). By Kaplan-Meier curves and a log-rank trend test, HbA1c quartile subgroups showed no association with times to discharge alive (p = 0.431), becoming non-infective (p = 0.113), and in-hospital death (p = 0.427). Based on multi-variate Cox analysis, HbA1c on admission had no significant impact on time to discharge alive (hazard ratio = 1.03, 95% CI 0.89-1.20, p = 0.659), becoming non-infective (hazard ratio = 0.93, 95% CI 0.80-1.06, p = 0.277), and in-hospital death (hazard ratio = 0.68, 0.43-1.07, p = 0.097). In conclusion, the HbA1c level on admission did not seem to affect in-hospital tuberculosis treatment outcomes in Japanese cohort.

Clarithromycin Suppresses Chloride Channel Accessory 1 and Inhibits Interleukin-13-Induced Goblet Cell Hyperplasia in Human Bronchial Epithelial Cells.

Activation of the interleukin-13 (IL-13) receptor leads to signal transducer and activator of transcription 6 (STAT6) activation and subsequent induction of SAM pointed domain containing ETS transcription factor (SPDEF) and chloride channel accessory 1 (CLCA1), increasing secretion of the gel-forming mucin MUC5AC. Activation of the epidermal growth factor receptor (EGFR) also leads to MUC5AC production via extracellular signal-regulated kinase (ERK1/2). We examined the effect of clarithromycin IL-13 signaling leading to production. Normal human bronchial epithelial (NHBE) cells were grown for 14 days at an air-liquid interface (ALI) with IL-13 and/or clarithromycin. Histochemical analysis was performed using hematoxylin and eosin (HE) staining and MUC5AC immunostaining. MUC5AC, SPDEF, and CLCA1 mRNA expression were evaluated by real-time PCR. Western analysis was used to assess phosphorylation of STAT6 and ERK1/2. Clarithromycin decreased IL-13-induced goblet cell hyperplasia and MUC5AC mRNA expression in a dose-dependent manner. Clarithromycin decreased IL-13-stimulated SPDEF and CLCA1 mRNA expression in a dose-dependent manner, and at 32 µg/ml CLCA1 was profoundly decreased (P < 0.001). Although clarithromycin had no effect on STAT6 phosphorylation induced by IL-13, it decreased constitutive phosphorylation of ERK1/2 (P < 0.05).

HO-1 inhibits IL-13-induced goblet cell hyperplasia associated with CLCA1 suppression in normal human bronchial epithelial cells.

Mucus hypersecretion and goblet cell hyperplasia are common features that characterize asthma. IL-13 increases mucin (MUC) 5AC, the major component of airway mucus, in airway epithelial cells. According to the literature, IL-13 receptor activation leads to STAT6 activation and consequent induction of chloride channel accessory 1 (CLCA1) gene expression, associated with the induction of MUC5AC. Heme oxygenase-1 (HO-1) is an enzyme that catalyzes oxidation of heme to biliverdin, and has anti-inflammatory and anti-oxidant properties. We examined the effects of HO-1 on mucin production and goblet cell hyperplasia induced by IL-13. Moreover, we assessed the cell signaling intermediates that appear to be responsible for mucin production. Normal human bronchial epithelial (NHBE) cells were grown at air liquid interface (ALI) in the presence or absence of IL-13 and hemin, a HO-1 inducer, for 14 days. Protein concentration was analyzed using ELISA, and mRNA expression was examined by real-time PCR. Histochemical analysis was performed using HE staining, andWestern blotting was performed to evaluate signaling transduction pathway. Hemin (4 µM) significantly increased HO-1 protein expression (p b 0.01) and HO-1 mRNA expression (p b 0.001). IL-13 significantly increased goblet cells, MUC5AC protein secretion (p b 0.01) and MUC5AC mRNA (p b 0.001), and these were decreased by hemin by way of HO-1. Tin protoporphyrin (SnPP)-IX, a HO-1 inhibitor, blocked the effect of hemin restoring MUC5AC protein secretion (p b 0.05) and goblet cell hyperplasia. Hemin decreased the expression of CLCA1 mRNA (p b 0.05) and it was reversed by SnPP-IX, but could not suppress IL-13-induced phosphorylation of STAT6 or SAM pointed domain-containing ETS transcription factor (SPDEF) and Forkhead box A2 (FOXA2) mRNA expression. In summary, HO-1 overexpression suppressed IL-13-induced goblet cell hyperplasia and MUC5AC production, and involvement of CLCA1 in the mechanism was suggested.