Quantifying the contribution of smear-negative, culture-positive pulmonary tuberculosis to nosocomial transmission.

BACKGROUND: Despite current guidelines for tuberculosis (TB) control in health care settings, which focused on smear-positive cases, prevention of nosocomial TB transmission continues to be a challenge. Here, we report the results of the first hospital-wide prospective study applying interferon-gamma release assay to investigate the role of smear-negative, culture-positive index cases in nosocomial TB transmission. METHODS: We prospectively identified cases of culture-confirmed smear-negative pulmonary TB receiving aerosol-generating procedures (AGPs) and cases of culture-confirmed smear-positive pulmonary TB admitted at a medical center. Nosocomial transmission was evaluated by screening their close contacts for latent TB infection (LTBI) using an interferon-gamma release assay. RESULTS: A total of 93 smear-negative index receiving AGP and 122 smear-positive index were enrolled. Among them, 13 (14.0%) and 43 (35.2%) index cases, respectively, had secondary cases of LTBI (P < .001). Sputum smear negativity (adjusted odds ratio: 0.20 [0.08-0.48]) and AGP (sputum suction; adjusted odds ratio: 3.48 [1.34-9.05]) are independent factors of transmission. A similar proportion in the close contacts of the 2 index groups had LTBI (17 [15.3%] and 63 [16.0%], respectively), and the former index group contributed to 21.3% of the nosocomial transmission. CONCLUSIONS: Smear-negative, culture-positive index cases receiving AGPs could be as infectious as smear-positive index cases. Hospital TB control policy should also focus on the former group.

Increased Tuberculosis Reactivation Risk in Patients Receiving Immune Checkpoint Inhibitor-Based Therapy.

OBJECTIVE: Reports of tuberculosis (TB) during anticancer treatment with immune checkpoint inhibitors (ICIs) are increasing. However, it is not clear whether the use of ICIs is a significant risk factor for TB, including reactivation or latent TB infection (LTBI). METHODS: To determine the risk of TB reactivation in patients with lung cancer who use ICIs or tyrosine kinase inhibitors (TKIs), we conducted a retrospective study using a hospital-based cancer registry. In addition, we monitored patients with cancer using ICI or TKI in a multicenter prospective study to check the incidence of LTBI. RESULTS: In the retrospective study, several demographic factors were imbalanced between the ICI and TKI groups: the ICI group was younger, had more males, exhibited more squamous cell carcinoma in histology rather than adenocarcinoma, had fewer EGFR mutations, and received more chemotherapy. Propensity score matching was used to control for confounding factors, and we found that the incidence of TB was higher among patients with lung cancer who received ICIs than among those who received TKIs (2298 vs 412 per 100 000 person-years, P = .0165). Through multivariable analysis, group (ICI vs TKI) was the independent risk factor for TB development (adjusted hazard ratio (aHR): 6.29, 95% CI, 1.23-32.09, P = .0269). In the prospective cohort, which included 72 patients receiving ICIs and 50 receiving TKIs, we found that the incidence of positive seroconversion of LTBI by interferon gamma release assay (IGRA) was significantly higher in patients receiving ICIs (18% vs 0%, aHR: 9.88, P = 0.035) under multivariable Cox regression. CONCLUSION: The use of ICIs may be linked to a higher likelihood of TB reactivation and LTBI than individuals solely receiving TKIs as anticancer therapy. Consequently, the implementation of a screening program for TB reactivation and LTBI among patients undergoing ICI treatment could prove advantageous by enabling early detection and prompt treatment of the infection.

The impact of nontuberculous mycobacterial lung disease in critically ill patients: Significance for survival and ventilator use.

BACKGROUND: This study investigates the impact of nontuberculous mycobacterial lung disease (NTM-LD) on mortality and mechanical ventilation use in critically ill patients. METHODS: We enrolled patients with NTM-LD or tuberculosis (TB) in intensive care units (ICU) and analysed their association with 30-day mortality and with mechanical ventilator-free survival (VFS) at 30 days after ICU admission. RESULTS: A total of 5996 ICU-admitted patients were included, of which 541 (9.0 %) had TB and 173 (2.9 %) had NTM-LD. The overall 30-day mortality was 22.2 %. The patients with NTM-LD had an adjusted hazard ratio (aHR) of 1.49 (95 % CI, 1.06-2.05), and TB patients had an aHR of 2.33 (95 % CI, 1.68-3.24), compared to ICU patients with negative sputum mycobacterial culture by multivariable Cox proportional hazard (PH) regression. The aHR of age<65 years, obesity, idiopathic pulmonary fibrosis, end-stage kidney disease, active cancer and autoimmune disease and diagnosis of respiratory failure were also significantly positively associated with ICU 30-day mortality. In multivariable Cox PH regression for VFS at 30 days in patients requiring invasive mechanical ventilation, NTM-LD was negatively associated with VFS (aHR 0.71, 95 % CI: 0.56-0.92, p = 0.009), while TB showed no significant association. The diagnosis of respiratory failure itself predicted unfavourable outcome for 30-day mortality and a negative impact on VFS at 30 days. CONCLUSIONS: NTM-LD and TB were not uncommon in ICU and both were correlated with increasing 30-day mortality in ICU patients. NTM-LD was associated with a poorer outcome in terms of VFS at 30 days.

Corticosteroids for COVID-19-induced olfactory dysfunction: A comprehensive systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Olfactory dysfunction is a common manifestation in COVID-19 patients and can significantly impact their quality of life. Corticosteroids have been proposed as a potential treatment, but their efficacy remains controversial. This systematic review and meta-analysis aims to comprehensively analyze the efficacy of corticosteroid therapy for treating COVID-19-related olfactory dysfunction. METHODS: A literature search was conducted in PubMed, Cochrane Library, and Embase databases up to March 1, 2023. Randomized controlled trials investigating the effects of corticosteroids on olfactory dysfunction in patients with COVID-19 were included. The primary outcome was the olfactory score at the end of follow-up, and the secondary outcomes were the duration and the rate of recovery from olfactory dysfunction. RESULTS: Seven randomized controlled trials with 999 participants were included in the meta-analysis. Compared with the control group, corticosteroid treatment resulted in a statistically significant improvement in olfactory score with a standardized mean difference of 0.55 (95% CI: 0.15 to 0.95). Topical corticosteroids were found to be effective, but systemic corticosteroids were not. In addition, longer durations and higher dosages of corticosteroids treatment may also be associated with significant improvements in olfactory scores. No significant effect was observed on the duration or recovery rate of olfactory dysfunction. CONCLUSIONS: Our findings suggest that topical corticosteroid treatment is a viable option for improving COVID-19-related olfactory dysfunction, but further research is needed to investigate optimal treatment protocols and safety profiles.

Deep learning with test-time augmentation for radial endobronchial ultrasound image differentiation: a multicentre verification study.

PURPOSE: Despite the importance of radial endobronchial ultrasound (rEBUS) in transbronchial biopsy, researchers have yet to apply artificial intelligence to the analysis of rEBUS images. MATERIALS AND METHODS: This study developed a convolutional neural network (CNN) to differentiate between malignant and benign tumours in rEBUS images. This study retrospectively collected rEBUS images from medical centres in Taiwan, including 769 from National Taiwan University Hospital Hsin-Chu Branch, Hsinchu Hospital for model training (615 images) and internal validation (154 images) as well as 300 from National Taiwan University Hospital (NTUH-TPE) and 92 images were obtained from National Taiwan University Hospital Hsin-Chu Branch, Biomedical Park Hospital (NTUH-BIO) for external validation. Further assessments of the model were performed using image augmentation in the training phase and test-time augmentation (TTA). RESULTS: Using the internal validation dataset, the results were as follows: area under the curve (AUC) (0.88 (95% CI 0.83 to 0.92)), sensitivity (0.80 (95% CI 0.73 to 0.88)), specificity (0.75 (95% CI 0.66 to 0.83)). Using the NTUH-TPE external validation dataset, the results were as follows: AUC (0.76 (95% CI 0.71 to 0.80)), sensitivity (0.58 (95% CI 0.50 to 0.65)), specificity (0.92 (95% CI 0.88 to 0.97)). Using the NTUH-BIO external validation dataset, the results were as follows: AUC (0.72 (95% CI 0.64 to 0.82)), sensitivity (0.71 (95% CI 0.55 to 0.86)), specificity (0.76 (95% CI 0.64 to 0.87)). After fine-tuning, the AUC values for the external validation cohorts were as follows: NTUH-TPE (0.78) and NTUH-BIO (0.82). Our findings also demonstrated the feasibility of the model in differentiating between lung cancer subtypes, as indicated by the following AUC values: adenocarcinoma (0.70; 95% CI 0.64 to 0.76), squamous cell carcinoma (0.64; 95% CI 0.54 to 0.74) and small cell lung cancer (0.52; 95% CI 0.32 to 0.72). CONCLUSIONS: Our results demonstrate the feasibility of the proposed CNN-based algorithm in differentiating between malignant and benign lesions in rEBUS images.

Oral uracil-tegafur compared with intravenous chemotherapy as adjuvant therapy for resected early-stage non-small cell lung cancer patients.

BACKGROUND: Studies comparing the effectiveness of either adjuvant oral uracil-tegafur (UFT) or intravenous chemotherapy on early-stage (stage I and II) non-small cell lung cancer (NSCLC) patients treated with complete surgical treatment remain limited. METHODS: From January 2011 to December 2017, patients with early-stage NSCLC (defined as tumor size >3 cm without mediastinal lymph node involvement or any distant metastasis) receiving either adjuvant oral UFT or intravenous chemotherapy after surgical resection were identified from the Taiwan Cancer Registry. Overall survival (OS) and relapse-free survival (RFS) were the primary and secondary outcomes, respectively. Propensity matching was used for controlling confounders. RESULTS: A total of 840 patients receiving adjuvant therapy after surgery (including 595 oral UFT and 245 intravenous chemotherapy) were enrolled. Before matching, patients using oral UFT had significantly longer OS (HR: 0.69, 95% CI: 0.49-0.98, p = 0.0387) and RFS (HR: 0.79, 95% CI: 0.61-0.97, p = 0.0392) than those with intravenous chemotherapy. A matched cohort of 352 patients was created using 1:1 propensity score-matching. In the Cox regression analysis, the UFT and the matched chemotherapy groups had similar OS (HR: 0.80, 95% CI: 0.48-1.32, p = 0.3753) and RFS (HR: 0.98, 95% CI: 0.72-1.34, p = 0.9149). Among subgroup analysis, oral UFT use was associated with longer RFS among the subgroups of non-drinker (HR: 0.66, 95% CI: 0.34-0.99, p = 0.0478) and patients with stage IB disease (HR: 0.67, 95% CI: 0.42-0.97, p = 0.0341). CONCLUSIONS: This population-based study in the real-world setting of Taiwan demonstrates comparable effectiveness between oral UFT and intravenous chemotherapy in terms of clinical outcomes for early-stage NSCLC patients after surgery.

Serial electrocardiogram recordings revealed a high prevalence of QT interval prolongation in patients with tuberculosis receiving fluoroquinolones.

BACKGROUND: Fluoroquinolones, crucial components of treatment regimens for drug-resistant tuberculosis (TB), are associated with QT interval prolongation and risks of fatal cardiac arrhythmias. However, few studies have explored dynamic changes in the QT interval in patients receiving QT-prolonging agents. METHODS: This prospective cohort study recruited hospitalized patients with TB who received fluoroquinolones. The study investigated the variability of the QT interval by using serial electrocardiograms (ECGs) recorded four times daily. This study analyzed the accuracy of intermittent and single-lead ECG monitoring in detecting QT interval prolongation. RESULTS: This study included 32 patients. The mean age was 68.6 ± 13.2 years. The results revealed mild-to-moderate and severe QT interval prolongation in 13 (41%) and 5 (16%) patients, respectively. The incremental yields in sensitivity of one to four daily ECG recordings were 61.0%, 26.1%, 5.6%, and 7.3% in detecting mild-to-moderate QT interval prolongation, and 66.7%, 20.0%, 6.7%, and 6.7% in detecting severe QT interval prolongation. The sensitivity levels of lead II and V5 ECGs in detecting mild-to-moderate and severe QT interval prolongation exceeded 80%, and their specificity levels exceeded 95%. CONCLUSION: This study revealed a high prevalence of QT interval prolongation in older patients with TB who receive fluoroquinolones, particularly those with multiple cardiovascular risk factors. Sparsely intermittent ECG monitoring, the prevailing strategy in active drug safety monitoring programs, is inadequate owing to multifactorial and circadian QT interval variability. Additional studies performing serial ECG monitoring are warranted to enhance the understanding of dynamic QT interval changes in patients receiving QT-prolonging anti-TB agents.

Omadacycline pharmacokinetics/pharmacodynamics in the hollow fiber model and clinical validation of efficacy to treat pulmonary Mycobacterium abscessus disease.

BACKGROUND: Guideline-based therapy (GBT) for pulmonary Mycobacterium abscessus (Mab) disease achieves sustained sputum culture conversion (SSCC) rates of 30%; this is reflected by poor efficacy of GBT in the hollow fiber system model of Mab (HFS-Mab), which killed ∼1.22 log10 CFU/mL. This study was performed to determine which clinical dose of omadacycline, a tetracycline antibiotic, should be used in combination therapy to treat pulmonary Mab disease for relapse-free cure. METHODS: First, omadacycline intrapulmonary concentration-time profiles of seven daily doses were mimicked in the HFS-Mab model and exposures associated with optimal efficacy were identified. Second, 10,000 subject Monte-Carlo simulations were performed to determine whether oral omadacycline 300 mg/day achieved these optimal exposures. Third, a retrospective clinical study on omadacycline vs. primarily tigecycline-based salvage therapy was conducted to assess rates of SSCC and toxicity. Fourth, a single patient was recruited to validate the findings. RESULTS: Omadacycline efficacy in the HFS-Mab was 2.09 log10 CFU/mL at exposures achieved in >99% of patients on 300 mg/day omadacycline. In the retrospective study of omadacycline 300 mg/day-based combinations vs. comparators, SSCC was achieved in 8/10 vs. 1/9 (P=0.006), symptom improvement in 8/8 vs. 5/9 (P=0.033), toxicity in 0 vs. 9/9 (P<0.001), and therapy discontinuation due to toxicity in 0 vs. 3/9 (P<0.001) cases, respectively. In one prospectively recruited patient, omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months. CONCLUSION: Based on the preclinical and clinical data, omadacycline 300 mg/day in combination regimens could be appropriate for testing in Phase III trials in patients with Mab pulmonary disease.

Prevention and management of tuberculosis in solid organ transplantation: A consensus statement of the transplantation society of Taiwan.

Solid organ transplant recipients have an increased risk of tuberculosis (TB). Due to the use of immunosuppressants, the incidence of TB among solid organ transplant recipients has been consistently reported to be higher than that among the general population. TB frequently develops within the first year after transplantation when a high level of immunosuppression is maintained. Extrapulmonary TB and disseminated TB account for a substantial proportion of TB among solid organ transplant recipients. Treatment of TB among recipients is complicated by the drug-drug interactions between anti-TB drugs and immunosuppressants. TB is associated with an increased risk of graft rejection, graft failure and mortality. Detection and management of latent TB infection among solid organ transplant candidates and recipients have been recommended. However, strategy to mitigate the risk of TB among solid organ transplant recipients has not yet been established in Taiwan. To address the challenges of TB among solid organ transplant recipients, a working group of the Transplantation Society of Taiwan was established. The working group searched literatures on TB among solid organ transplant recipients as well as guidelines and recommendations, and proposed interventions to strengthen TB prevention and care among solid organ transplant recipients.

A deep learning model using chest X-ray for identifying TB and NTM-LD patients: a cross-sectional study.

BACKGROUND: Timely differentiating between pulmonary tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD), which are radiographically similar, is important because infectiousness and treatment differ. This study aimed to evaluate whether artificial intelligence could distinguish between TB or NTM-LD patients by chest X-rays (CXRs) from suspects of mycobacterial lung disease. METHODS: A total of 1500 CXRs, including 500 each from patients with pulmonary TB, NTM-LD, and patients with clinical suspicion but negative mycobacterial culture (Imitator) from two hospitals, were retrospectively collected and evaluated in this study. We developed a deep neural network (DNN) and evaluated model performance using the area under the receiver operating characteristic curves (AUC) in both internal and external test sets. Furthermore, we conducted a reader study and tested our model under three scenarios of different mycobacteria prevalence. RESULTS: Among the internal and external test sets, the AUCs of our DNN model were 0.83 ± 0.005 and 0.76 ± 0.006 for pulmonary TB, 0.86 ± 0.006 and 0.64 ± 0.017 for NTM-LD, and 0.77 ± 0.007 and 0.74 ± 0.005 for Imitator. The DNN model showed higher performance on the internal test set in classification accuracy (66.5 ± 2.5%) than senior (50.8 ± 3.0%, p < 0.001) and junior pulmonologists (47.5 ± 2.8%, p < 0.001). Among different prevalence scenarios, the DNN model has stable performance in terms of AUC to detect TB and mycobacterial lung disease. CONCLUSION: DNN model had satisfactory performance and a higher accuracy than pulmonologists on classifying patients with presumptive mycobacterial lung diseases. DNN model could be a complementary first-line screening tool.

Completion, safety, and efficacy of tuberculosis preventive treatment regimens containing rifampicin or rifapentine: an individual patient data network meta-analysis.

BACKGROUND: 3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R. METHODS: We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs. FINDINGS: We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found. INTERPRETATION: In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment. FUNDING: None. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Linking the choice of the class format and preclass learning experiences sheds light on a step further in blended medical education.

BACKGROUND: The core principle of HyFlex ('hybrid' and 'flexible') learning is to maintain learning equity under most circumstances. Within a blended framework in precision medical education, how different preferences of synchronous learning environment influence learning process and outcome is limited. We investigated students' preclass online video learning experiences and their choices toward synchronous class formats. METHODS: This was a mixed-methods study. During the 2021 academic year, all 5th-year medical students who had viewed online video clips presenting core concepts were asked to complete a survey on their preference for future synchronous class format (face-to-face, online, or HyFlex) and asked to provide reflective comments on their self-learning. Anonymous survey data, online records, and summative assessment scores (short-term learning outcomes) were collected. Kruskal - Wallis or Chi-square tests were used to compare differences between groups, and multiple linear regression was managed to select the factors associated with various choices. The students' comments were coded in a descriptive thematic analysis. RESULTS: Among 152 medical students, 150 responded to the questionnaires, and 109 provided comments. Medical students spent a median of 32 min online, significantly shorter in the face-to-face group than in the online and HyFlex groups. The online group had a lower preclass video completion rate for certain concepts. The choice was not associated with short-term learning outcomes. Student feedback revealed a higher frequency of multiple themes for each student in the face-to-face and HyFlex groups, and these themes fell into the categories of learning efficiency, focus concentration, and course attractiveness. CONCLUSIONS: Linking the choice of the class format and learning experiences of preclass online videos sheds light on a step further within a blended framework of precision medical education. Supplement of online interactive elements may help secure learning engagement among students choosing 'online only' class format of HyFlex learning.

Incidence of and Risk Factors for Acute Kidney Injury During Antituberculosis Treatment: A Prospective Cohort Study and Literature Review.

INTRODUCTION: Acute kidney injury (AKI) is occasionally detected in patients receiving anti-tuberculosis (TB) treatment. This prospective cohort study is the first to investigate the incidence, risk factors, and renal outcomes of AKI during anti-TB treatment. METHODS: This study was conducted from January 1, 2016, to May 31, 2018. Patients with a new diagnosis of TB and on standard anti-TB treatment were enrolled, and the patients received regular laboratory monitoring. AKI was defined according to the Kidney Disease: Improving Global Outcome (KDIGO) criteria. Urinalysis, renal ultrasonography, blood erythrocyte morphology, and fractional excretion of sodium were performed at AKI onset. The TB treatment regimen was adjusted by the primary physician if necessary. Risk factors for AKI were identified through Cox regression. RESULTS: In total, 106 patients were recruited (mean age 52.6 years, 71.7% men). Eleven (10.3%) patients experienced AKI. Increased serum uric acid and hemoglobin levels were noted at AKI onset. All patients with AKI achieved renal recovery and completed anti-TB treatment containing rifampin. Age [hazard ratio (HR) 1.06 (1.02-1.11)], a higher baseline estimated glomerular filtration rate [eGFR; HR 1.04 (1.02-1.06)], and a blood eosinophil count > 350 (109/L) [HR 10.99 (2.28-53.02)] were associated with a higher risk of AKI during TB treatment. CONCLUSION: Regular pharmacovigilant monitoring revealed an incidence of renal impairment during anti-TB treatment that was higher than expected. AKI was more common in older patients with a higher eGFR and blood eosinophil count. However, the complications had no influence on TB treatment completion, and no permanent renal impairment occurred.

Gut microbiota composition can reflect immune responses of latent tuberculosis infection in patients with poorly controlled diabetes.

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB). Evidence has linked the DM-related dysbiosis of gut microbiota to modifiable host immunity to Mycobacterium tuberculosis infection. However, the crosslinks between gut microbiota composition and immunological effects on the development of latent TB infection (LTBI) in DM patients remain uncertain. METHODS: We prospectively obtained stool, blood samples, and medical records from 130 patients with poorly-controlled DM (pDM), defined as ever having an HbA1c > 9.0% within previous 1 year. Among them, 43 had LTBI, as determined by QuantiFERON-TB Gold in-Tube assay. The differences in the taxonomic diversity of gut microbiota between LTBI and non-LTBI groups were investigated using 16S ribosomal RNA sequencing, and a predictive algorithm was established using a random forest model. Serum cytokine levels were measured to determine their correlations with gut microbiota. RESULTS: Compared with non-LTBI group, the microbiota in LTBI group displayed a similar alpha-diversity but different beta-diversity, featuring decrease of Prevotella_9, Streptococcus, and Actinomyces and increase of Bacteroides, Alistipes, and Blautia at the genus level. The accuracy was 0.872 for the LTBI prediction model using the aforementioned 6 microbiome-based biomarkers. Compared with the non-LTBI group, the LTBI group had a significantly lower serum levels of IL-17F (p = 0.025) and TNF-α (p = 0.038), which were correlated with the abundance of the aforementioned 6 taxa. CONCLUSIONS: The study results suggest that gut microbiome composition maybe associated with host immunity relevant to TB status, and gut microbial signature might be helpful for the diagnosis of LTBI.

Isoniazid level and flu-like symptoms during rifapentine-based tuberculosis preventive therapy: A population pharmacokinetic analysis.

AIM: A population pharmacokinetic (PPK) study of the correlation of adverse drug reactions (ADRs) with the 3HP regimen (weekly high-dose rifapentine plus isoniazid for 12 doses) for latent tuberculosis infection (LTBI) remains lacking. The purpose of this study is to determine the association of rifapentine or isoniazid concentration and ADRs. METHODS: This prospective, multicentre, observational study enrolled LTBI contacts receiving 3HP treatment between January 2017 and August 2020. The concentrations of rifapentine, isoniazid and their metabolites (25-desacetyl-rifapentine and acetyl-isoniazid) in plasma samples collected monthly after 3HP treatment were determined. A PPK model was constructed to predict the maximum concentration (Cmax ) and area under the concentration-time curve from 0 to 24 h (AUC). Their association with ADRs was evaluated by applying three multivariate logistic regression models with adjustment for various covariates. RESULTS: A total of 415 LTBI cases were ultimately enrolled; 355 (85.5%) completed the 3HP treatment. Among them, 47 (11.3%) experienced systemic drug reactions and 291 (70.0%) experienced one or more flu-like symptom. The plasma concentration-time profiles of isoniazid, rifapentine and their metabolites were adequately described by the developed models. A higher Cmax of isoniazid was significantly correlated with a higher risk of any ADR (adjusted odds ratio and 95% confidence interval: 3.04 [1.07-8.65]) and any or at least two flu-like symptoms (all severity grades) (2.76 [1.06-7.17]). CONCLUSIONS: Isoniazid may be responsible for ADRs, especially flu-like symptoms, during 3HP treatment.

Nouveau short-course therapy and morphism mapping for clinical pulmonary Mycobacterium kansasii.

Standard therapy [isoniazid, rifampin, ethambutol], with or without a macrolide, for pulmonary Mycobacterium kansasii lasts more than a year. Therefore, shorter treatment duration regimens are required. We used data from 32 Taiwanese patients treated with standard therapy who were followed using repetitive sampling-based sputum Mkn time-to-positivity in liquid cultures to calculate kill slopes [γ] based on ordinary differential equations and time-to-extinction of each patient's bacterial burden. The γ was 0.18 [95% Confidence Interval (CI): 0.16-0.20] log10 CFU/mL/day on standard therapy. Next, we identified Mkn time-to-extinction in the hollow fiber system model of pulmonary M. kansasii disease [HFS-Mkn] treated with standard therapy, which was a γ of 0.60 [95% CI: 0.45-0.69) log10 CFU/mL/day. The γs and time-to-extinctions between the two datasets formed structure-preserving maps based on category theory: thus, we could map them from one to the other using morphisms. This mapping identified a multistep non-linear transformation-factor for time-to-extinction from HFS-Mkn to patients. Next, a head-to-head study in the HFS-Mkn identified median time-to-extinction for standard therapy of 38.7 [95% CI: 29.1-53.2) days, isoniazid-rifampin-ethambutol-moxifloxacin of 21.7 [95% CI: 19.1-25) days, isoniazid-rifampin-moxifloxacin of 22 [96% CI: 20.1-24.5) days, and rifampin-moxifloxacin-tedizolid of 20.7 [95% CI:18.5-29) days. Our transformation-factor based translation predicted the proportion of patients of 90.7 [88.74-92.35)% achieving cure with standard therapy at 12 months, and 6-months cure rates of 99.8 [95% CI: 99.27-99.95)% for isoniazid-rifampin-ethambutol-moxifloxacin, 92.2 [90.37-93.71)% for isoniazid-rifampin-moxifloxacin, and 99.9 [99.44-99.99)% for rifampin-moxifloxacin-tedizolid. Thus, rifampin-moxifloxacin-tedizolid and isoniazid-rifampin-ethambutol-moxifloxacin are predicted to be short-course chemotherapy regimens for pulmonary M. kansasii disease.

Sex-Specific Associations Between Susceptibility to Mycobacterium avium Complex Lung Disease and Programmed Cell Death 1 Gene Polymorphisms.

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) preferentially occurs in postmenopausal women and may have immune exhaustion involving the programmed cell death 1 (PD-1) pathway. It is still unknown whether sex-specific associations between susceptibility to MAC-LD and programmed cell death 1 gene (PDCD1) polymorphisms exist. METHODS: Adult patients with MAC-LD (n = 152) and controls (n = 167) were included at 2 medical centers in Taiwan. Five single-nucleotide polymorphisms in PDCD1 genes were genotyped, and their associations with MAC-LD and soluble PD-1 protein were analyzed, especially in sex subgroups. RESULTS: PDCD1 rs2227982 polymorphism was associated with increased risk of MAC-LD in women (adjusted odds ratio for AA vs AG vs GG, 2.205 [95% confidence interval, 1.108-4.389]; P = .02), and the rs10204525 TT genotype was associated with low risk in men (TT vs TC and CC, 0.396 [.176-.890]; P = .02). Compared with men with rs10204525 TT, women with rs2227982 AG and with AA had 2.7- and 5.0-fold increased risks, respectively. Soluble PD-1 levels were lower in the female subgroup with rs2227982 AG and AA than in the remainder (median level [interquartile range], 46.7 [33.7-71.5] pg/mL vs 66.2 [48.6-101.5] pg/mL; P < .001). CONCLUSIONS: PDCD1 genetic polymorphisms were associated with the risk of MAC-LD in a sex-specific pattern, possibly through regulation of PD-1 expression.

Association of pulmonary nontuberculous mycobacteria with the outcomes of patients with lung cancer: A retrospective matched cohort study with a special emphasis on the impact of chemotherapy.

INTRODUCTION: Nontuberculous mycobacteria (NTM) may be present in the respiratory tract of patients with lung cancer. We investigated the association of pulmonary NTM with the clinical features and outcomes of patients with lung cancer. METHODS: Between 2015 and 2019, the data of patients diagnosed with lung cancer at a medical center in northern Taiwan were analyzed. Patients whose respiratory specimens were culture-positive for NTM were identified (NTM group). For each patient in the NTM group, a matched control was selected (control group). The survival of the two groups was compared using the Kaplan-Meier method and Cox proportional hazards regression analysis. RESULTS: Among 8718 patients with lung cancer, 5418 (62.1%) underwent a sputum mycobacterial culture. At least one NTM species was isolated from 138 (2.5%) patients. The median age was 72 years (range: 64-80). In the NTM group, 19.8% fulfilled both the microbiological and radiographic criteria for the diagnosis of NTM lung disease. Compared with the control group, the NTM group exhibited a lower body mass index (22.4 vs. 23.6, p = 0.025) and a higher prevalence of structural lung disease (38.9% vs. 22.2%, p = 0.004). The two-year survival was not significantly different between the two groups (hazard ratio [HR]: 1.110; 95% confidence interval [CI]: 0.702-1.754, p = 0.656). In patients receiving chemotherapy, pulmonary NTM was associated with worse survival (HR: 2.497, 95% CI: 1.262-4.943, p = 0.009). CONCLUSIONS: Except in patients receiving chemotherapy, pulmonary NTM may not be clinically relevant in patients with lung cancer.

Characteristics and local risk factors of community-acquired and health-care-associated Staphylococcus aureus pneumonia.

This study aims at identifying characteristics, risk factors and mortality of community-acquired (CAP) and health-care-associated pneumonia (HCAP) by Staphylococcus aureus (S. aureus). We retrieved adults with S. aureus CAP or HCAP diagnosed by blood or pleural effusion culture in 2.6 years, and compared with those of Streptococcus pneumoniae (S. pneumoniae) CAP or HCAP diagnosed by blood or respiratory culture, or urine antigen. We found 18 patients with CAP and 9 HCAP due to S. aureus (female 33%, 66.6 ± 12.4 years-old), and 48 patients with CAP and 15 HCAP due to S pneumoniae (female 41%, 69.5 ± 17.5 years). Diabetes mellitus (52% vs. 24%, p = 0.019), hemodialysis (11% vs. 0%, p = 0.046), skin lesions (44% vs. 0%, p < 0.001), cavitary nodules (37% vs. 1.6%, p < 0.001) and pleural effusions (48% vs. 18%, p = 0.007) were more common in staphylococcal than pneumococcal group. Three patients with staphylococcal pneumonia had acute myocardial infarction. Pneumonia severity index (139 ± 52 vs. 109 ± 43, p = 0.005) and 30-day mortality (41% vs. 9.5%, p = 0.001) were higher in staphylococcal group. Multivariate analysis showed underlying disease (especially cancer and cirrhosis), risk class 4/5, altered mentality, shock and bilateral pneumonia were risk factors for 30-day mortality.