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Bisphosphonates are considered an effective inhibitor of glutamine synthetase and thus can be used for treating tuberculosis (TB). However, its clinical benefit in TB remains unknown. We conducted a population-based cohort study by using the Taiwan National Health Insurance Research Database and TB databases of the Taiwan Centers for Disease Control. Patients with osteoporosis and a history of bone fracture from 2007 to 2014 were identified. Among them, bisphosphonate users and propensity score-matched nonusers were selected. A stratified multivariable Cox proportional hazard regression model was employed to investigate the independent predictors of TB. Among 218 908 patients with osteoporosis and bone fracture, 46 842 bisphosphonate users and 46 842 propensity score-matched nonusers were selected. Within the 2-year follow-up, 723 patients-348 in the user group and 375 in the nonuser group-developed TB. Bisphosphonate use was not an independent predictor of TB in the multivariable Cox proportional hazard model (adjusted hazard ratio, 0.86; 95%CI, 0.71-1.04); however, male sex, older age, being bedridden, and steroid use were independent risk factors. The real-world data revealed that bisphosphonate use did not protect patients with osteoporosis against TB.

Purpose Noninvasive ventilation (NIV) is often required for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), and it can significantly reduce the need for endotracheal intubation. Currently, there is no standard method for predicting successful weaning from NIV. Therefore, we aimed to evaluate whether a weaning index can predict NIV outcomes of patients with AECOPD. Methods This study was conducted at a single academic public hospital in northern Taiwan from February 2019 to January 2021. Patients with AECOPD admitted to the hospital with respiratory failure who were treated with NIV were included in the study. Univariate and multivariate logistic regression analyses were used to identify independent predictors of successful weaning from NIV. Receiver operating characteristic curve methodology was used to assess the predictive capacity. Results A total of 85 patients were enrolled, 65.9% of whom were successfully weaned from NIV. The patients had a mean age of 75.8 years and were mostly men (89.4%). The rapid shallow breathing index (RSBI) (P

BackgroundStudies comparing effectiveness of either adjuvant oral uracil-tegafur (UFT) or chemotherapy on early-stage non-small cell lung cancer (NSCLC) patients receiving complete surgical resection remain limited. MethodsFrom January 2011 to December 2017, patients with early-stage NSCLC (defined as tumor size >3 cm and no lymph node involvement) receiving either adjuvant UFT or chemotherapy after complete surgical resection were identified from the Taiwan Cancer Registry. Overall survival (OS) was the primary outcome and relapse-free survival (RFS) was the secondary outcome. Propensity matching was used for controlling confounders.ResultsA total of 840 patients receiving adjuvant therapy after surgery (including 595 UFT and 245 chemotherapy) were enrolled. Before matching, patients using oral UFT had significantly longer OS (p=0.0415) and RFS (p=0.0451) than those with chemotherapy. A 1:1 propensity score (PS)-matched cohort of 352 patients (176 for each group) was created. In the Cox regression analysis, the UFT and the matched chemotherapy groups had similar OS (HR: 0.96, 95% CI: 0.86–1.07, p=0.3865) and RFS (HR: 0.99, 95% CI: 0.72–1.35, p=0.9248). Among subgroup analysis, oral UFT use was associated with longer RFS among the subgroups of non-drinker (HR: 0.61, 95% CI: 0.38–0.99, p=0.0458) and patients with stage IB disease (HR: 0.63, 95% CI: 0.42–0.95, p=0.0261). ConclusionsOur large-scale, population-based real-world study reveals that the effect of oral UFT on clinical outcomes for patients with early-stage NSCLC after surgery is not different from conventional intravenous chemotherapy. Additionally, for patients with stage IB (AJCC 7th edition, equivalent to stage IB & IIA by AJCC 8th edition) disease and non-drinkers, oral UFT administration was significantly associated with longer RFS than those using chemotherapy as treatment.

Objective To determine serogroups, multilocus sequence typing (MLST) of Listeria monocytogenes isolates and analyze clinical characteristics of these clones focusing on non-perinatal cases. Methods From 2000 to 2015, we analyzed 123 human listeriosis cases at a medical center in northern Taiwan using PCR serogrouping, MLST, and clinical presentations. Results The annual incidence of listeriosis increased since 2005 with a peak in 2008 (0.2 per 1000 admission) and decreased thereafter. Of the 115 non-perinatal listeriosis cases, we found a male predominance (60%) with an average age of 63.9 years old (standard deviation: 15.3 years), and almost all patients had underlying conditions including malignancies (61.7%), steroid usage (39.1%), diabetes mellitus (31.3%), renal insufficiency (27.8%), and liver cirrhosis (17.4%). Clinical presentations included bacteremia (74.8%), neurolisteriosis (20.0%), and spontaneous bacterial peritonitis (5.2%). The most frequently identified serogroup-sequence types (ST) were IIB-ST87 (30.9%), followed by IIA-ST378 (16.3%) and IIA-ST155 (14.6%). The 30-day all-cause mortality of non-perinatal listeriosis was 25.2% and was associated with age (Hazard ratio: 1.04, 95% C.I. = 1.01–1.07, p = 0.021), steroid usage (Hazard ratio: 2.54, 95% C.I. = 1.06–6.11, p = 0.038) and respiratory distress at presentation (Hazard ratio: 2.59, 95% C.I. = 1.05–6.39, p = 0.038); while no association was found with serogroups (IIA, IIB, and IVB) or three major ST types by multivariable analysis. All 8 mothers of perinatal listeriosis patients survived and three neonates died (mortality, 37.5%), and IIB-ST87 was the major type (62.5%). Conclusion Predominant strains in Taiwan could cause significant morbidity and mortality. Further disease monitoring and source surveillance are warranted despite a declining trend of human listeriosis in Taiwan.

Background Poor control of diabetes mellitus (DM) increases active tuberculosis (TB) risk. Understanding risk factors for latent TB infection (LTBI) in this population and intervention completion rates is crucial for policy making. Methods Under a collaborative multidisciplinary team consisting of public health professionals, endocrinologists, and pulmonologists, patients aged >45 years with poorly controlled DM (pDM), defined as having a glycated hemoglobin level of ≥9% within the preceding year, were enrolled by endocrinologists from 2 hospitals; these patients underwent LTBI screening by using QuantiFERON (QFT). Once-weekly isoniazid and rifapentine for 12 weeks (3HP) or daily isoniazid for 9 months (9H) was administered by pulmonologists. QFT-positivity predictors were evaluated using logistic regression. Completion rates and safety were also investigated. Results Among 980 patients with pDM (age: 64.2 ± 9.7 years), 261 (26.6%) were QFT-positive. Age, DM duration, chronic kidney disease stage ≥3, and dipeptidyl peptidase-4 inhibitor use, not using metformin, were associated with QFT-positivity. Preventive therapy (3HP: 138; 9H: 62) was administered in 200 (76.6%) QFT-positive patients. The completion rates of 3HP and 9H were 84.1% and 79.0%, respectively (P = .494). Nine (6.5%) and zero patients in the 3HP and 9H groups, respectively, developed systemic drug reactions (P = .059); 78.3% and 45.2% had ≥1 adverse drug reactions (P, The latent tuberculosis infection prevalence exceeds 25% in elderly patients with poorly controlled diabetes mellitus (DM), particularly those with a long DM duration. The completion rate of preventive therapy, regardless of the regimen, approaches 80% in this population under a collaborative framework.

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, 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 may modulate host immunity relevant to TB susceptibility, and microbial signature might be a potential diagnostic biomarker and therapeutic target for LTBI in pDM patients.

Background Weekly rifapentine and isoniazid (3HP) is gaining popularity for latent tuberculosis infection treatment because of its short course and high completion rate. Prior to widespread use, comprehensive 3HP treatment assessment covering an all-age population is essential. Methods Participants receiving ≥1 3HP dose from September 2014 to December 2019 were stratified into elderly (≥65 years), middle-aged (>35 & Results Overall, 134 of 579 (23.1%) participants were elderly. The completion rate was 83.1% overall and was highest and lowest in the younger group (94.5%) and elderly (73.9%) group, respectively. However, the 3HP discontinuation rate was not significantly different among the 3 groups in multivariate logistic regression analysis. In total, 362 (62.5%) participants experienced 1 or more adverse drug reactions (ADRs), of which 38 (10.5%) and 98 (27.1%) required temporary and permanent treatment interruption, respectively. The SDR risk was 11.2% in overall and 17.1% in the middle-aged group, 3.04-fold higher than that in the elderly group (P = .025). This finding was consistently observed in different clinical settings. Hypertensive events accompanied with flu-like symptoms occurred in 11.2% of elderly participants, and accounted for 50% of grade ≥3 ADRs. Conclusions With proper medical support and programmatic follow-up, the 3HP completion rate is >70% even in elderly participants. In middle-aged and elderly individuals, 3HP should be employed with caution because of risk of SDRs and hypertensive events, respectively. Summary: Under programmatic medical support, widespread use of weekly rifapentine and isoniazid (3HP) for latent tuberculosis treatment is possible for its high completion rate. 3HP should be employed with caution for risk of systemic drug reactions and hypertensive events in middle-aged and elderly individuals, respectively.

Nontuberculous mycobacteria (NTM) are critical emerging global infectious pathogens. Though NTM can be mere colonizers when isolated from human specimens, NTM are also responsible for diverse human infections. NTM-lung disease (NTM-LD) is the most common human disease entity. The present review aims to provide general insight into NTM-LD epidemiology in Taiwan. In reviewing NTM epidemiology in Taiwan, we discovered three distinguishing features. First, NTM disease incidence has increased in Taiwan over the past decade. Second, the distribution of NTM varies geographically in Taiwan. Mycobacterium avium-intracellulare complex (MAC) is the dominant species in northern Taiwan, whereas Mycobacterium abscessus complex and MAC may be equally dominant in southern Taiwan. Third, researchers in Taiwan have published valuable research investigating NTM among special patient populations, including patients in intensive care units, with ventilator dependency, with pulmonary tuberculosis, and who are infected with specific NTM species. The largest obstacle to clarifying NTM epidemiology in Taiwan may be the lack of routine NTM species identification in laboratories. Increased awareness of NTM diseases and acknowledgment that NTM species identification is crucial and guides clinical management are essential steps for facilitating the identification of NTM species in laboratories.

Background Systemic drug reaction (SDR) is a major safety concern with weekly rifapentine plus isoniazid for 12 doses (3HP) for latent tuberculosis infection (LTBI). Identifying SDR predictors and at-risk participants before treatment can improve cost-effectiveness of the LTBI program. Methods We prospectively recruited 187 cases receiving 3HP (44 SDRs and 143 non-SDRs). A pilot cohort (8 SDRs and 12 non-SDRs) was selected for generating whole-blood transcriptomic data. By incorporating the hierarchical system biology model and therapy–biomarker pathway approach, candidate genes were selected and evaluated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Then, interpretable machine learning models presenting as SHapley Additive exPlanations (SHAP) values were applied for SDR risk prediction. Finally, an independent cohort was used to evaluate the performance of these predictive models. Results Based on the whole-blood transcriptomic profile of the pilot cohort and the RT-qPCR results of 2 SDR and 3 non-SDR samples in the training cohort, 6 genes were selected. According to SHAP values for model construction and validation, a 3-gene model for SDR risk prediction achieved a sensitivity and specificity of 0.972 and 0.947, respectively, under a universal cutoff value for the joint of the training (28 SDRs and 104 non-SDRs) and testing (8 SDRs and 27 non-SDRs) cohorts. It also worked well across different subgroups. Conclusions The prediction model for 3HP-related SDRs serves as a guide for establishing a safe and personalized regimen to foster the implementation of an LTBI program. Additionally, it provides a potential translational value for future studies on drug-related hypersensitivity.

Background Histologic diagnosis of granuloma is often considered clinically equivalent to a definite diagnosis of pulmonary tuberculosis (TB) in endemic areas. Optimal management of surgically resected granulomatous inflammation in lung with negative mycobacterial culture results, however, remains unclear. Methods From 7 medical institutions in northern, middle, and southern Taiwan between January 2010 and December 2018, patients whose surgically resected pulmonary nodule(s) had histological features suggestive of TB but negative microbiological study results and who received no subsequent anti-TB treatment were identified retrospectively. All patients were followed up for 2 years until death or active TB disease was diagnosed. Results A total of 116 patients were enrolled during the study period. Among them, 61 patients (52.6%) were clinically asymptomatic, and 36 (31.0%) patients were immunocompromised. Solitary pulmonary nodule accounted for 44 (39.6%) of all cases. The lung nodules were removed by wedge resection in 95 (81.9%), lobectomy in 17 (14.7%), and segmentectomy in 4 (3.4%) patients. The most common histological feature was granulomatous inflammation (n=116 [100%]), followed by caseous necrosis (n=39 [33.6%]). During follow-up (218.4 patient-years), none of the patients developed active TB. Conclusions In patients with surgically resected culture-negative pulmonary granulomas, the incidence rate of subsequent active TB is low. Watchful monitoring along with regular clinical, radiological, and microbiological follow-up, instead of routine anti-TB treatment, may also be a reasonable option., The incidence of active tuberculosis in patients with surgically resected culture-negative pulmonary granulomas was very low. Regular clinical, radiological, and microbiological follow-up, instead of routine immediate antituberculosis treatment, may be a reasonable option.

Background: Anti-tuberculous (TB) medications are common causes of drug-induced liver injury (DILI). Limited data are available on systemic inflammatory mediators as biomarkers for predicting DILI before treatment. We aimed to select predictive markers among potential candidates and to formulate a predictive model of DILI for TB patients. Methods: Adult active TB patients from a prospective cohort were enrolled, and all participants received standard anti-tuberculous treatment. Development of DILI, defined as ≥5× ULN for alanine transaminase or ≥2.6× ULN of total bilirubin with causality assessment (RUCAM, Roussel Uclaf causality assessment method), was regularly monitored. Pre-treatment plasma was assayed for 15 candidates, and a set of risk prediction scores was established using Cox regression and receiver-operating characteristic analyses. Results: A total of 19 (7.9%) in 240 patients developed DILI (including six carriers of hepatitis B virus) following anti-TB treatment. Interleukin (IL)-22 binding protein (BP), interferon gamma-induced protein 1 (IP-10), soluble CD163 (sCD163), IL-6, and CD206 were significant univariable factors associated with DILI development, and the former three were backward selected as multivariable factors, with adjusted hazards of 0.20 (0.07–0.58), 3.71 (1.35–10.21), and 3.28 (1.07–10.06), respectively. A score set composed of IL-22BP, IP-10, and sCD163 had an improved area under the curve of 0.744 (p &lt, 0.001). Conclusions: Pre-treatment IL-22BP was a protective biomarker against DILI development under anti-TB treatment, and a score set by additional risk factors of IP-10 and sCD163 employed an adequate DILI prediction.

Background: Comprehensive rehabilitation programs are recommended for patients with prolonged mechanical ventilation (PMV) to facilitate functional recovery and ventilator weaning, but whether the functional status after rehabilitation influences outcome has not been clearly evaluated. This study aimed to investigate the association between post-rehabilitation functional status and weaning and survival outcome in PMV patients.Methods: We retrospectively enrolled PMV patients admitted to the respiratory care center (RCC), a post-ICU weaning facility with protocolized rehabilitation program, from January 2016 through December 2017. Functional status was measured by the de Morton Mobility Index (DEMMI), with a cut-off value set at 20 points. The primary outcomes were the weaning status at RCC discharge and hospital survival. The secondary outcomes were overall survival and survival at 3 months after RCC discharge. We followed patients until 3 months after RCC discharge or death. Logistic and Cox regressions were performed to identify significant parameters associated with weaning success and survival.Results: In total, 320 patients were enrolled. The weaning success rate was 71.6%. The survival rate at RCC discharge, hospital discharge, and 3 months after RCC discharge was 89.1, 77.5, and 66.6%, respectively. Post-rehabilitation DEMMI ≥ 20 (odds ratio [OR], 3.514; 95% confidence interval [CI], 1.436–8.598; P = 0.006) was the most significantly associated with weaning success. The weaning success and higher post-rehabilitation DEMMI were the two most significant independent factors associated with both hospital survival (weaning success, OR, 12.272; 95% CI, 5.281–28.517; P < 0.001; post-rehabilitation DEMMI ≥ 20, OR, 6.298; 95% CI, 1.302–30.477; P = 0.022) and survival at 3 months after RCC discharge (weaning success, OR, 38.788; 95% CI, 11.505–130.762; P < 0.001; post-rehabilitation DEMMI ≥ 20, OR, 4.830; 95% CI, 1.072–21.756; P = 0.040). Post-rehabilitation DEMMI ≥ 20 remained significantly association with overall survival at 3 months after RCC discharge (hazard ratio, 0.237; 95% CI, 0.072–0.785; P = 0.018).Conclusions: Post-rehabilitation functional status of PMV patients was independently associated with weaning success, as well as hospital and 3-month overall survival after RCC discharge. Post-rehabilitation, but not pre-rehabilitation, functional status was a significant parameter associated with weaning success and survival in patients requiring PMV.

Background _The mitogen response in interferon-γ(IFN-γ) release assays(IGRAs) measures IFN-γ after binding to CD2, a surface adhesion marker found on T-cells and NK cells. A lower mitogen response implies either peripheral blood mononuclear cells have fewer adhesion molecules either in absolute numbers or per T-cells, or the pathway from adhesion molecules to IFN-γ production is not functioning well. To date, it remains poorly understood whether the mitogen response is associated with outcomes in tuberculosis patients. Methods _From 2012 to 2017, patients with culture-confirmed tuberculosis were tested for QuantiFERON-TB Gold In-Tube(QFT-GIT). The associations between patient outcomes and QFT-GIT as well as IFN-γ responses to the mitogen were investigated. Outcomes of interest included 1-year mortality after tuberculosis diagnosis and 2-month culture conversion. Results _In total, 466 culture-confirmed tuberculosis patients were enrolled and QFT-GIT was positive in 309(66%). Within 1 year of diagnosis, 20(4%) died and notably, 15(11%) out of 137 patients with a lower mitogen response did so. The multivariate Cox model showed that a lower mitogen response (hazard ratio, 8.789; 95% confidence interval, 3.074–25.129) was independently associated with 1-year mortality. Moreover, among 160 patients with smear-positive culture-confirmed pulmonary tuberculosis, multivariate logistic analysis indicated that a lower mitogen response (odds ratio, 3.966; 95% confidence interval, 1.182–13.303) was significantly associated with 2-month culture persistence. Conclusions _This study found that a lower mitogen response was associated with worse 1-year survival in tuberculosis patients and correlated with 2-month culture persistence in patients with sputum smear-positive culture-confirmed tuberculosis. These findings suggest another application of QFT-GIT for prognostication of tuberculosis patients.

The effects of cardiopulmonary resuscitation (CPR) on patients with advanced cancer remain to be elucidated. We identified a cohort of patients with stage-IV cancer who received in-hospital CPR from the Taiwan Cancer Registry and National Health Insurance claims database, along with a matched cohort without cancer who also received in-hospital CPR. The main outcomes were post-discharge survival and in-hospital mortality. In total, 3,446 stage-IV cancer patients who underwent in-hospital CPR after cancer diagnosis were identified during January 2009–June 2014. A vast majority of the patients did not survive to discharge (n = 2,854, 82.8%). The median post-discharge survival was 22 days; 10.1% (n = 60; 1.7% of all patients) of the hospital survivors received anticancer therapy after discharge. We created 1:1 age–, sex–, Charlson comorbidity index (CCI)–, and year of CPR–matched noncancer and stage-IV cancer cohorts (n = 3,425 in both; in-hospital mortality rate = 82.1% and 82.8%, respectively). Regression analysis showed that the stage-IV cancer cohort had shorter post-discharge survival than did the noncancer cohort. The outcome of patients with advanced cancer was poor. Even among the survivors, post-discharge survival was short, with only few patients receiving further anticancer therapy.

Animal studies have demonstrated that metformin exerts a renoprotective effect. Human studies of patients with diabetes mellitus (DM) regarding the association of metformin use with end-stage renal disease (ESRD) are lacking. Patients with type 2 DM and without a history of kidney disease who were enrolled under the pay-for-performance program of the National Health Insurance in Taiwan were identified. Those who received ≥90 cumulative defined daily doses of metformin within 1 year were selected (metformin users) and compared with a 1:1 propensity score-matched metformin nonuser cohort. Primary and secondary outcomes were development of ESRD and chronic kidney disease (CKD), respectively. Independent predictors were investigated using Cox regression analysis. A total of 24 158 pairs of metformin users and nonusers were enrolled, with an incidence of ESRD of 1908 and 1723 and CKD of 1095 and 1056 cases per 100 000 person-years, respectively. Metformin use was independently associated with increased risks of ESRD (adjusted hazard ratio, 1.22; 95% confidence interval, 1.12-1.32) and CKD (adjusted hazard ratio, 1.25; 95% confidence interval, 1.12-1.40) in a dose-response relationship. Patients with hypertension plus nonuse of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers potentiated kidney damage by metformin. In patients with DM, use of metformin may increase the risk of ESRD and CKD. Health care professionals should be alert and closely monitor renal function when prescribing metformin.

Background: The impact of intensive care unit (ICU) admission during life-threatening critical illness on survival of patients with advanced cancer remains unknown. Methods: We identified incident stage IV cancer patients from Taiwan Cancer Registry during 2009-2013 and ascertained the first episode of septic shock after cancer diagnosis. Patient was classified as ICU admission and no ICU admission during the index hospitalization. Primary outcome of interest was overall survival. Propensity score (PS) and proportional hazards regression were used to control potential confounders. Results: A total of 11,825 stage IV cancer patients with septic shock were identified. Among them, 6,089 (51.5%) patients were admitted to ICU during the index hospitalization and 3,626 (30.7%) patients survived the index hospitalization. A 1:1 propensity score (PS)-matched cohort of 7,186 patients were created for patients with/without ICU admission among the total study population. Both the PS-stratified analysis among the overall population (pooled hazard ratio [HR]: 0.78, 95% confidence interval [CI]: 0.74-0.81) and analysis among the PS-matched population (HR: 0.76, 95% CI: 0.72-0.79) showed association between ICU admission and better overall survival. ICU admission was also associated with a lower risk of in-hospital mortality in both PS-stratified analysis (pooled odds ratio [OR]: 0.69, 95% CI: 0.63-0.75) and PS-matched analysis (OR: 0.61, 95% CI: 0.55-0.68). In PS-stratified analysis for long-term survival after discharge among hospital survivors, ICU admission was associated with improved long-term survival after discharge (pooled HR: 0.73, 95% CI: 0.68-0.80). Also ICU admission was associated with better long-term survival after discharge (HR: 0.77, 95% CI: 0.70-0.85) in PS-matched analysis. Conclusions: Though ICU admission with aggressive treatment may be associated with improved survival, the majority (70%) of stage IV cancer patients with septic shock were unable to survive until hospital discharge.

Lung cancer remains the primary cause of cancer-related mortality worldwide. Several treatment modalities are available for lung cancer, including surgery, radiation, and chemotherapy. Among the chemotherapeutics available, afatinib has been shown to be effective for those with epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma. Herein, we analyzed the factors affecting the prognosis of patients who received afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma in the real-world setting. Patients who received afatinib as a first-line therapy and were reimbursed by the National Health Insurance were recruited in this study. Data on patient characteristics and treatment courses were collected. In total, 259 patients were enrolled (median follow-up, 22.0 months). Of them, 82 (31.7%) were identified to have brain metastases at baseline, which were associated with poor Eastern Cooperative Oncology Group performance status, high incidence of central nervous system progression, and short overall survival. However, the results of our analysis showed that overall survival was not affected by reductions in the afatinib dosage or any upfront local treatments for brain tumors. Multivariate analyses showed that brain metastases at diagnosis and treatment response to afatinib are two important prognostic factors for the overall survival of patients with EGFR mutation-positive lung adenocarcinoma.

Tuberculosis (TB) remains a devastating disease, yet despite its enormous toll on global health, tools to control TB are insufficient and often outdated. TB Biomarkers (TB-BM) would constitute extremely useful tools to measure infection status and predict outcome of infection, vaccination or therapy. There are several types of TB-BM: Correlate of Infection; Correlate of TB Disease; Correlate of Increased Risk of Developing Active TB Disease; Correlate of the Curative Response to Therapy; and Correlate of Protection (CoP). Most TB-BM currently studied are host-derived BM, and consist of transcriptomic, proteomic, metabolomic, cellular markers or marker combinations ('signatures'). In particular, vaccine-inducible CoP are expected to be transformative in developing new TB vaccines as they will de-risk vaccine research and development (R&D) as well as human testing at an early stage. In addition, CoP could also help minimizing the need for preclinical studies in experimental animals. Of key importance is that TB-BM are tested and validated in different well-characterized human TB cohorts, preferably with complementary profiles and geographically diverse populations: genetic and environmental factors such as (viral) coinfections, exposure to non-tuberculous mycobacteria, nutritional status, metabolic status, age (infants vs children vs adolescents vs adults) and other factors impact host immune set points and host responses across different populations. In this study, we review the most recent advances in research into TB-BM for the diagnosis of active TB, risk of TB development and treatment-induced TB cure.

In countries with low and moderate incidence of tuberculosis (TB), the disease tends to concentrate in specific high-risk populations such as people with diabetes mellitus (DM). We review the updated evidence on the association between 1) DM and active TB, and 2) DM and latent tuberculous infection (LTBI), and 3) we summarize the findings on the population-level impact of DM on TB epidemiology, with particular focus on low- and moderate-incidence settings. We conducted an updated review of studies on DM and active TB, and found 11 more cohort studies published after the previous systematic review from 2008. The updated pooled relative risk (RR) (2.03, 95%CI 1.62-2.55) of all the studies was substantially lower than the three-fold risk increase in the previous review. Substantial heterogeneity of RR across studies was found. Possible reasons for such heterogeneity include different levels of residual confounding, the effect of modification by age, and different levels of glycemic control in the population. In a recently published systematic review on DM and LTBI, one cohort study and 12 cross-sectional studies were identified. The results from cross-sectional studies suggest a significant but modestly increased risk of LTBI among patients with DM (pooled odds ratio 1.18, 95%CI 1.06-1.30). We reviewed evidence on the population-level impact of DM on TB epidemiology in studies using population-attributable fraction analysis and infectious disease modelling. Those studies revealed that DM accounted for a substantial TB burden in low- and moderate-incidence countries. Finally, we discussed the complex association of obesity, DM and TB risk and the impact of the global obesity pandemic on TB epidemiology.

Objectives: Aspergillus-specific IgG (Asp-IgG) cut-off level in diagnosing chronic pulmonary aspergillosis (CPA) remains unknown. Methods: We prospectively recruited participants with clinical suspicion of CPA in three centers in Taiwan during 2019 June to 2020 August. Serum Aspergillus fumigatus-specific IgG (Asp-IgG) (Phadia, Uppsala, UPPS, Sweden) was examined. Optimal cut-off level was determined by Youden’s index and validated. Results: A total of 373 participants were recruited. In the derivation cohort (n = 262), Asp-IgG had an area under the receiver-operating-characteristic curve (AUC) of 0.832. The optimal cut-off level was 40.5 mgA/L. While applying this cut-off level to the validation cohort (n = 111), the sensitivity and specificity were 86.7% and 80.2%. Lowering the cut-off level from 40.5 to 27 mgA/L, the sensitivity was steady (30/36, 83.3% to 31/36, 86.1%) while specificity dropped from 81.9% (276/337) to 63.5% (214/337). Restricting CPA diagnosis to only chronic cavitary pulmonary aspergillosis (CCPA) and chronic fibrosing pulmonary aspergillosis (CFPA) yielded a cut-off level of 42.3 mgA/L in the derivation cohort with a sensitivity of 100% and specificity of 84.4% in the validation cohort. Conclusions: Serum Asp-IgG performs well for CPA diagnosis and provides a low false-positive rate when using a higher cut-off level (preferably around 40 mgA/L).

// Sheng-Kai Liang 1 , Min-Shu Hsieh 2 , Meng-Rui Lee 1 , Li-Ta Keng 1 , Jen-Chung Ko 1 and Jin-Yuan Shih 3 1 Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan 2 Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan Correspondence to: Jin-Yuan Shih, email: jyshih@ntu.edu.tw Keywords: afatinib, EGFR mutation-positive, first-line therapy, lung adenocarcinoma, real-world study Received: March 15, 2017 Accepted: July 19, 2017 Published: July 26, 2017 ABSTRACT We evaluated the real-world efficacy and side effects of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. The medical records of patients receiving afatinib as a first-line therapy after National Health Insurance reimbursement between May 2014 and January 2016 were reviewed, and information on patient characteristics and treatment courses were collected consecutively. Rebiopsy tissue was collected for EGFR mutation and MET amplification analyses. MET amplification was detected by fluorescence in situ hybridization and immunohistochemistry. In total, 140 patients were enrolled (median follow-up, 18.0 months). No significant differences in side effects, treatment responses, progression-free survival, or brain metastasis control were observed between patients receiving 40 mg versus 10.0% in 6 months) had a shorter median progression-free survival. Patients with brain metastases had a poorer Eastern Cooperative Oncology Group performance status and were associated with a shorter median progression-free survival. Nine patients (32.1%) had a p.T790M mutation and only 1 patient gained MET amplifications after disease progression. Afatinib is effective as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. Afatinib dosage does not affect clinical efficacy and drug-related side effects.

Advanced molecular typing methods have greatly expanded the taxonomy of Mycobacterium avium complex (MAC) species; however, little is known about the epidemiology and clinical features of bacteraemia caused by different MAC species. In this study, the clinical characteristics of patients treated for MAC bacteraemia in a tertiary-care centre in northern Taiwan during 2008–2014 were investigated. Isolates were identified to species level by rpoB gene and 16S–23S rRNA internal transcribed spacer region sequencing. Among 30 patients with bacteraemia due to MAC, the majority ( n = 26) had concomitant human immunodeficiency virus (HIV) infection. Of the 30 blood isolates obtained from patients, 24 were M. avium subsp. hominissuis , 4 were Mycobacterium colombiense and 2 were Mycobacterium intracellulare . All four M. colombiense isolates were from HIV-infected patients. Bacteraemia due to M. colombiense was associated with higher 30-day mortality than bacteraemia due to M. avium subsp. hominissuis [2/4 (50%) vs. 1/24 (4%); P = 0.045, Fisher's exact test]. All four M. colombiense isolates were susceptible to clarithromycin, moxifloxacin and linezolid. Among the five patients who received ethambutol treatment and four patients who received fluoroquinolone treatment for various durations between positive MAC cultures, two and three patients, respectively, had isolates with significantly increased (≥4-fold) ethambutol and fluoroquinolone minimum inhibitory concentrations. M. colombiense was the second leading causative pathogen of MAC bacteraemia, comprising 15% of all MAC isolates obtained from HIV-positive patients. Monitoring the susceptibility of MAC isolates to ethambutol and fluoroquinolones is warranted in patients with persistent MAC bacteraemia.

BackgroundThe protective effect of metformin against active tuberculosis (TB) among TB close contacts is unknown.MethodsTB close contacts with diabetes mellitus (DM) and normal renal function were selected from the National Health Insurance Research Database of Taiwan. Metformin users were patients who received ≥90 cumulative defined daily doses within 1 year before the index date. For each metformin user, a propensity-score matched metformin nonuser and an age- and sex-matched healthy TB close contact were selected. The outcome was incident TB, identified using previously validated diagnostic criteria. Independent predictors were investigated using stratified Cox regression analysis. Interaction analysis was also performed.ResultsA total of 5846 TB close contacts who were metformin users, metformin non-users, and healthy contacts were analysed. The incidence of active TB was 755 (600–938), 1117 (927–1335), and 526 (393–689) cases per 100,000 person-years in each group, respectively. Multivariate analysis revealed that healthy contacts had the lowest risk of developing active TB (adjusted hazard ratio [aHR]: 0.42 [0.30–0.60]) and metformin use partially reversed the risk associated with DM (aHR: 0.73 [0.54–0.98]). Subpopulation analysis revealed a significant interaction between insulin use and metformin use.ConclusionsMetformin use is associated with a lower risk of developing active TB among TB close contacts with DM, especially for insulin users. It may be an alternative choice for primary prevention against active TB if no contraindications exist. However, prospective studies are needed to confirm the findings.

Objectives A single isolate of nontuberculous mycobacterium (NTM) from bronchoscopic samples satisfies the microbiological criterion for diagnosing NTM-pulmonary disease (PD). Studies investigating patients with NTM-PD and multiple culture-negative sputum samples but culture-positive bronchoscopic samples are lacking. We investigated the clinical characteristics, outcome, and predictors of radiographic progression in this special population. Methods Patients with negative NTM culture from ≥2 expectorated sputum samples within the 3 months prior to bronchoscopy diagnosis of NTM-PD between 2009 and 2017 were included. Patient characteristics and clinical course were described. Predictors for radiographic progression of NTM-PD within 2 years were analysed by using multivariate logistic regression. Results Among 66 patients with bronchoscopy-diagnosed NTM-PD, radiographic progression occurred within 2 years in 17 (26%). Of the 60 patients not initially treated, radiographic progression occurred in 17 (28%). Among them, 10 never received treatment, with 6 deteriorating and 3 dying. Of the 6 and 7 patients who received treatment immediately after NTM-PD diagnosis and after radiographic progression, respectively, none had further radiographic progression. The independent predictors of radiographic progression were male sex, body mass index Conclusions Among patients with bronchoscopy-diagnosed NTM-PD, one fourth experienced radiographic progression within 2 years. The risk was even higher in those with the aforementioned predictors, immediate treatment or close monitoring is recommended. For others, conservative management by regular microbiological monitoring for sputum samples and image follow-up may be the optimal choice.