Search

Online video learning has been gaining substantial attention in medical education. The purpose of the study was to evaluate medical students’ online video-viewing patterns as well as to identify features associated with their class style preferences in precision medicine courses. A mixed methods research design was used. Part of the cognitive load of the class content of “acute liver failure” was shifted to a 10-minute pre-class online video learning which was further reduced using threshold concept strategy. In the 2019 academic year, all fifth-year medical students who had viewed the pre-class video were invited to take a survey on their learning process and four class style expectations for the upcoming in-person class. For each round of medical students, teaching assistants helped collect anonymous survey data before the class. The teacher then adjusted the in-person class as part of precision medical education. Furthermore, the researchers coded the video-viewing patterns through an action log transformation, along with the questionnaire results, for analysis. Mann–Whitney U and Kruskal–Wallis tests were employed to compare group differences. Qualitative data were content-coded through a descriptive approach using thematic analysis. Of the 130 medical students, 114 (87.7%) joined the pre-class video learning, 113 (86.9%) responded to the questionnaires, and 87 (66.9%) provided their comments. Most medical students preferred the class styles of a thorough introduction (42.5%) and concept orientation (44.2%). High-engagement viewing patterns were associated with difficult concepts and the provision of comments. Class style expectation and video-viewing patterns did not demonstrate significant linkages. A majority of the substantial comments initiated thought-provoking questions after the online video learning. Association between medical students’ preferred class styles and online video-viewing patterns was not necessarily linked. However, medical teachers are recommended to modify class styles based on medical students’ expectations after pre-class learning, thereby providing precision medical education.KEY MESSAGEImplementing precision medical education in the blended class is feasible.Online video learning is an ideal platform for balancing the dilemma between increasing the cognitive load of class content and the practice of precision medical education.The association between medical students’ preferred class styles and online video-viewing patterns was not clearly seen. Implementing precision medical education in the blended class is feasible. Online video learning is an ideal platform for balancing the dilemma between increasing the cognitive load of class content and the practice of precision medical education. The association between medical students’ preferred class styles and online video-viewing patterns was not clearly seen.

BackgroundSurvival after post-transplant recurrence of HCC is dismal, and almost all treatments for recurrent HCC are off-labeled, without an extensive large-scale analysis. We aimed to delineate their post-recurrence courses and define benchmarks for comparing future treatment effectiveness.MethodsThree national databases, including health insurance, catastrophic illness, and the cause of death, were linked for cohort establishment and data collection during the period from 2005 to 2016. Patients with HCC recurrence ≥6 months after transplant surgery and under treatment were recruited for survival analysis. Selection of treatment strategies for HCC recurrence after liver transplant was based on the same criteria for those without liver transplant.ResultsOf 2,123 liver transplant recipients, 349 developed HCC recurrence ≥6 months after liver transplant, and the median recurrence time was 17.8 months post-transplant. Within 2 years of treatment, 61% patients showed recurrence (early recurrence group), and survival in these patients was poorer than in the late recurrence group. According to a multivariable analysis, the transplant era before 2008 and radiofrequency ablation were associated with good prognosis, whereas receiving sorafenib and radiotherapy was associated with poor prognosis. The effect of transplant era became insignificant after stratification by recently receiving pretransplant transarterial chemoembolization.ConclusionTiming of recurrence and interventions used were associated with the outcomes of patients with post-transplant HCC recurrence. These data provide the benchmark and indicate the critical period and high-risk factors for further therapeutic trial consideration.

BackgroundHypertension induces systemic inflammation, but its impact on the outcome of infectious diseases like tuberculosis (TB) is unknown. Calcium channel blockers (CCB) improve TB treatment outcomes in pre-clinical models, but their effect in patients with TB remain unclear.MethodsThis retrospective cohort study, including all patients > 18 years receiving treatment for culture-confirmed, drug-sensitive TB from 2000 to 2016 at the National Taiwan University Hospital, assessed the association of hypertension and CCB use with all-cause and infection-related mortality during the first 9 months of TB treatment, as well as sputum-smear microscopy and sputum-culture positivity at 2 and 6 months.Results1052 of the 2894 patients (36.4%) had hypertension. Multivariable analysis revealed that hypertension was associated with increased mortality due to all causes (HR 1.57, 95% confidence interval[CI], 1.23-1.99) and infections (HR 1.87, 95%CI, 1.34-2.6), but there was no statistical difference in microbiological outcomes when stratified based on hypertensive group. Dihydropyridine-CCB (DHP-CCB) use was associated with reduced all-cause mortality (HR 0.67, 95%CI: 0.45-0.98) only by univariate Cox regression. There was no association between DHP-CCB use and infection-related mortality (HR 0.78, 95%CI: 0.46-1.34) or microbiological outcomes in univariate or multivariate regression analyses.ConclusionsPatients with hypertension have increased all-cause mortality and infection-related mortality during the 9 months following TB treatment initiation. DHP-CCB use may lower all-cause mortality in TB patients with hypertension. The presence of hypertension or the use of CCB did not result in a significant change in microbiological outcomes.

Additional file 1 Table S1. Demographics of study population according to development of tuberculosis (TB). Table S2. Incidence rates of tuberculosis (TB) if we excluded patients lost to follow up < 30 days. Table S3. Incidence rates of tuberculosis (TB) if we excluded patients lost to follow up < 180 days.

Background Undiagnosed tuberculosis (TB) patients hospitalized because of comorbidities constitute a challenge to TB control in hospitals. We aimed to assess the impact of introducing highly sensitive fluorescent microscopy for examining sputum smear to replace conventional microscopy under a high TB risk setting. Methods We measured the impact of switch to fluorescent microscopy on the smear detection rate of culture-confirmed pulmonary TB, timing of respiratory isolation, and total non-isolated infectious person-days in hospital at a high-caseload medical center (approximately 400 TB cases annually) in Taipei. Multivariable Cox regression was applied to adjust for effects of covariates. The effect attributable to the improved smear detection rate was determined using causal mediation analysis. Results After switch to fluorescence microscopy, median non-isolated infectious duration decreased from 12.5 days to 3 days (P

Background The outcome of lung nodule(s) with histopathological findings suggestive of tuberculosis (TB) but lack of microbiologic confirmation remains unclear. Whether these patients require anti-TB treatment remains unknown. The aim of the study was to compare the risk of active TB within 4 years in untreated patients with histological findings but no microbiological evidences suggestive of TB. Methods From January 2008 to June 2013, patients with either solitary or multiple lung nodules having histological findings but no microbiological evidences suggestive of TB were identified from a medical center in Taiwan and were followed for 4 years unless they died or developed active TB. Results A total of 107 patients were identified. Among them, 54 (51%) were clinical asymptomatic. Biopsy histology showed granulomatous inflammation in 106 (99%), and caseous necrosis was present in 55 (51%) cases. Forty (37%) patients received anti-TB treatment, and 21 (53%) of them had adverse events, including 13 initially asymptomatic patients. Anti-TB treatment was favored in patients with caseous necrosis, whereas observation was preferred in subjects whose nodules were surgically removed. Only 1 case in the untreated group developed culture-confirmed active pulmonary TB during 4-year follow-up (1 case per 251.2 patient-years). None of the 16 cases having co-existing histologic finding of malignancy became incident TB case within a follow-up of 56.7 patient-years. Conclusions In patients having lung nodules with only histologic features suggestive of TB, the incidence rate of developing active TB was low. Risk of adverse events and benefit from immediate treatment should be carefully considered.

Treatment of latent tuberculosis (TB) infection (LTBI) effectively prevents its progression to active TB. However, long treatment duration and drug-related hepatotoxicity limit the effectiveness of the 9-month daily isoniazid (9H). Data on the 3-month weekly rifapentine plus isoniazid (3 HP) in Asian populations are currently unavailable. We prospectively randomised the LTBI contacts aged ≥12 years with positive tuberculin skin test into 9H and 3 HP groups in four hospitals between January 2014 and May 2016 in Taiwan. The primary and secondary outcomes were treatment completion rate and adverse drug reactions (ADRs), respectively. Overall, 263 participants with LTBI were randomised into the 3 HP (n = 132) and 9H groups (n = 131); 14 (10.6%) and 29 (22.1%) participants in the 3 HP and 9H groups, respectively, discontinued therapy (p = 0.011). Discontinuation rates owing to ADRs were 9.1% (3 HP) and 5.3% (9H) (p = 0.241). Clinically relevant hepatotoxicity was more common in the 9H than in the 3 HP group (5.3% vs. 1.5%; p = 0.103), whereas systemic drug reaction was more common in the 3 HP than in the 9H group (3.8% vs. 0%; p = 0.060). Women had a significantly higher rate of Grade II fever than men (13.7% vs. 1.2%; p = 0.003). Compared with the 9H regimen, the 3 HP regimen had a higher completion rate with lower hepatotoxicity and well-tolerated ADR. Clinical trials registration number NCT02208427.

Background Mycobacterium avium complex (MAC)-lung disease (LD) is increasing in patients without human immunodeficiency virus infection. However, data on host vulnerability to MAC-related immune responses, and in particular the interleukin (IL)-23/IL-17 axis, are lacking. Methods We enrolled 50 patients with MAC-LD, 25 age-matched patients with tuberculosis (TB) and 25 controls. We measured levels of plasma cytokines, and studied IL-12/IL-17 responses in macrophage and lymphocyte activation to MAC. Results The plasma level of IL-17 in the MAC group was higher than in the TB and control groups. In in-vitro macrophage stimulation, the expression of IL-23 in macrophages was similar in the patients with MAC-LD and controls, although the expression of IL-12 p40 was lower in the patients with MAC-LD. In assays of lymphocyte activation, IL-17 was induced by MAC-primed macrophages, but its level was lower in the patients with MAC-LD and TB than in the controls. The expression of programmed death (PD)-1 receptor was higher in CD4+IL17A+ lymphocytes in the patients with MAC-LD, and the production of IL-17 was significantly increased by blockade of PD-1 and PD-ligand 1. Conclusions MAC induced a similar expression of IL-23 from macrophages in the patients with MAC-LD compared to the controls, but a lower expression of IL-17 from lymphocytes, which may be through an increased expression of PD-1. The macrophage response of IL-12 p40 was stronger than that of IL-12 p70, and higher in the controls during MAC disease, which may suggest another kind of MAC-related immune evasion.

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.

Objective Anti-interferon- γ (IFN-γ) autoantibodies (anti-IFN-γ Abs) have been increasingly recognized as an important cause of disseminated nontuberculous mycobacterial (DNTM) infection, and identification of this immunodeficiency impacts clinical management. However, the protean disease manifestations and inaccessibility to diagnostic tests in clinical settings hamper its early diagnosis. Here, we sought to determine whether QuantiFERON-TB Gold In-tube (QFT-GIT), a commercialized IFN-γ release assay, could be used to screen for neutralizing anti-IFN-γ Abs among previously healthy adults with DNTM infection. Methods Non-HIV patients with DNTM infection were prospectively enrolled for the QFT-GIT assays. We measured their plasma concentration of anti-IFN-γ Abs and their neutralizing capacity through enzyme-linked immunosorbent assay and flow cytometry. We then analysed the correlation between QFT-GIT results and the presence of neutralizing anti-IFN-γ Abs among patients with and without previously recognized immunosuppression, respectively. Results Irrespective of the autoantibody concentration or disease activity, all patients with neutralizing anti-IFN-γ Abs (100%, 30/30) had indeterminate QFT-GIT results because of extremely low or undetectable IFN-γ levels in the mitogen tubes. None of the four DNTM patients who were previously healthy and tested negative of anti-IFN-γ Abs had an indeterminate QFT-GIT result, and their IFN-γ levels in the mitogen tube were significantly higher than those of the patients with anti-IFN-γ Abs (8.28 IU/mL vs. 0.05 IU/mL, p 0.001). Conclusion An indeterminate QFT-GIT result because of undetectable or extremely low IFN-γ level in the mitogen tube suggests the presence of neutralizing anti-IFN-γ Abs in a previously healthy patient with DNTM infection.

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).

Among treatment modalities for lung cancer, the most promising therapy is the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs). Both erlotinib and gefitinib, the two first‐generation EGFR‐TKIs, exhibit significant clinical responses for patients with lung adenocarcinoma. However, few studies have compared the effects of these two drugs, and results have been inconclusive because of the small sample sizes in these studies. Therefore, this study was conducted to investigate this issue. This retrospective nationwide cohort study enrolled NSCLC patients who received EGFR‐TKIs after previous chemotherapy in Taiwan between 1996 and 2010 from the National Health Insurance Research Database. Clinical response and survival after receiving erlotinib and gefitinib were compared using logistic and Cox regression analyses, respectively. Inverse propensity score weighting and a sensitivity analysis in the EGFR‐TKI responder (clinical improvement by taking EGFR‐TKIs for 90 days), adherent patients (receiving EGFR‐TKI on a daily basis), adenocarcinoma, and adenocarcinoma with second‐line TKIs subgroup were performed for bias adjustment. A total of 7222 patients, including 4592 (63.6%) who received gefitinib, were identified. In the survival analysis, erlotinib was associated with a decline in 1‐year progression‐free survival (PFS) (hazard ratio, HR: 1.15 [1.09–1.21]) and overall survival (OS) (HR: 1.10 [1.03–1.18]). The effects of various TKIs were consistent in the 4939 EGFR‐TKI responders, adherent subgroup, adenocarcinoma subgroup, and adenocarcinoma with second‐line TKIs subgroup. In previously treated EGFT‐TKI‐naive NSCLC patients, those receiving gefitinib exhibited a longer PFS and OS than those receiving erlotinib. Additional large‐scale randomized controlled trials are warranted to confirm this finding.

Background Persistent growth of Mycobacterium avium complex (MAC) in the lungs indicates continuous infection in MAC lung disease (MAC-LD), but its clinical significance has not been investigated. We aimed to evaluate the predictors of persistent culture-positivity for MAC (MAC-PP) and its impact on radiographic deterioration in MAC-LD. Methods Patients with MAC-LD at multiple medical centers from 2011 to 2016 were enrolled retrospectively. Microbiological persistence of MAC-LD was defined as MAC-PP exceeding 1 year, in contrast with the negative-conversion group. The outcome was radiographic progression, namely, increased number of involved lung areas or cavitary formation. Results Among 126 patients with MAC-LD, 75 (60%) were in the MAC-PP group; these patients had a higher proportion of radiographic progression (54%) than patients in the negative-conversion group (odds ratio [OR], 3.318; 95% confidence interval, 1.146-9.612). Independent predictors of MAC-PP were low body mass index (BMI), radiographic nodular-bronchiectatic (NB) pattern, and increase in the highest grade of acid-fast bacilli smear (AFS). Patients with BMI

How host genetic factors affect Mycobacterium tuberculosis (Mtb) infection outcomes remains largely unknown. SP110b, an IFN-induced nuclear protein, is the nearest human homologue to the mouse Ipr1 protein that has been shown to control host innate immunity to Mtb infection. However, the function(s) of SP110b remains unclear.To elucidate the role of SP110b in controlling host immunity and susceptibility to tuberculosis (TB), as well as to identify the fundamental immunological and molecular mechanisms affected by SP110b.Using cell-based approaches and mouse models of Mtb infection, we characterized the function(s) of SP110b/Ipr1. We also performed genetic characterization of patients with TB to investigate the role of SP110 in controlling host susceptibility to TB.SP110b modulates nuclear factor-κB (NF-κB) activity, resulting in downregulation of tumor necrosis factor-α (TNF-α) production and concomitant upregulation of NF-κB-induced antiapoptotic gene expression, thereby suppressing IFN-γ-mediated monocyte and/or macrophage cell death. After Mtb infection, TNF-α is also downregulated in Ipr1-expressing mice that have alleviated cell death, less severe necrotic lung lesions, more efficient Mtb growth control in the lungs, and longer survival. Moreover, genetic studies in patients suggest that SP110 plays a key role in modulating TB susceptibility in concert with NFκB1 and TNFα genes.These results indicate that SP110b plays a crucial role in shaping the inflammatory milieu that supports host protection during infection by fine-tuning NF-κB activity, suggesting that SP110b may serve as a potential target for host-directed therapy aimed at manipulating host immunity against TB.

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.

The incidence of nontuberculous mycobacteria lung disease (NTM-LD) is increasing in patients without human immunodeficiency virus. Mycobacterium avium complex (MAC) is one of the most common pathogenic species. The presence of MAC has a clinical relevance of around 35~42%, indicating the possibility of host susceptibility. Previous studies have shown that interleukin (IL)-1β and IL-1-receptor knock-out mice are susceptible to mycobacterial infections; however, the role of inflammasome-driven interleukin (IL)-1β has not been studied in MAC-LD. We enrolled patients with MAC-LD and healthy controls. Peripheral blood mononuclear cells (PBMCs), monocytes, and monocyte-derived macrophages were stimulated by MAC bacilli. The responses of interleukin(IL)-1β and the expression of inflammasome and toll-like receptors (TLRs) were measured. Single nucleotide polymorphisms (SNPs) were also examined for NLRP3 and TLR2 genes. In the patients with MAC-LD, the IL-1β responses decreased in PBMCs, monocytes, and macrophages assayed by MAC bacilli in comparison to the healthy controls. In addition, the level of caspase-1 after stimulation was lower in the MAC-LD group, although the mRNA level of IL-1β was not significantly lower. In surveying the activation of IL-1β, the MAC-LD group had an attenuated mRNA level of NLRP3 but similar levels of AIM2 and ASC compared with the controls. The SNPs rs3806268 and rs34298354 in NLRP3 for females and rs3804100 in TLR2 for males were associated with MAC-LD. In conclusion, our patients with MAC-LD had attenuated IL-1β production, which may have been due to lower activation of the NLRP3-caspase-1 axis. Two SNPs of NLRP3 and one of TLR2 were correlated with MAC-LD, possibly indicating host susceptibility.

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.

Background Practical barriers exist in applying threshold-concept–based clinical teaching. We applied the practice model to the subject of acute liver failure and reported the experiences in teaching and learners’ reactions. Methods The course comprised a 10-min online preclass video and a 1-h class with in-depth discussion. The video explained six extracted threshold concepts, which were labelled TC1–TC6. Three sets of feedback questionnaires were given to students. Questionnaires were provided after they watched the online video (Q1), after class (Q2), and before the end of the curriculum section (Q3). All the feedback questionnaires were analysed. Results Of the 136 attendees in the academic year 2018, 127 (93.4%), 69 (50.7%), and 112 (82.4%) completed the Q1, Q2, and Q3 questionnaires, respectively, and 48 (42.6%) provided comments. The degree of comprehension varied among threshold concepts and individual students. TC1 and TC2 were viewed as transformative for all three surveys. The threshold-concept-based learning process was satisfactory, and students could auto-reflect on the defining features of a threshold concept. Students became aware of their deficiencies in knowledge and acknowledged room for development with regard to their mindset for future patient management. Conclusion Threshold-concept–based clinical teaching is a feasible strategy. Students' reflections indicate that thresholds were crossed, which does not guarantee that students’ mindsets are ready for future clinical practice.

While evidence is accumulating that platelets contribute to tissue destruction in tuberculosis (TB) disease, it is still not known whether antiplatelet agents are beneficial to TB patients. We performed this retrospective cohort study and identified incident TB cases in the Taiwan National Tuberculosis Registry from 2008 to 2014. These cases were further classified into antiplatelet users and non-users according to the use of antiplatelet agents prior to the TB diagnosis, and the cohorts were matched using propensity scores (PSs). The primary outcome was survival after a TB diagnosis. In total, 74,753 incident TB cases were recruited, 9497 (12.7%) were antiplatelet users, and 7764 (10.4%) were aspirin (ASA) users. A 1:1 PS-matched cohort with 8864 antiplatelet agent users and 8864 non-users was created. After PS matching, antiplatelet use remained associated with a longer survival (adjusted hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.88&ndash, 0.95, p &lt, 0.0001). The risk of major bleeding was not elevated in antiplatelet users compared to non-users (p = 0.604). This study shows that use of antiplatelet agents has been associated with improved survival in TB patients. The immunomodulatory and anti-inflammatory effects of antiplatelet agents in TB disease warrant further investigation. Antiplatelets are promising as an adjunct anti-TB therapy.

Background: Increasing expression of programmed death-1 (PD-1) in patients with nontuberculous mycobacteria lung disease (NTM-LD) has been reported, but its role in clinical characteristics and outcomes remains unclear. Methods: We enrolled 96 participants, including 46 with Mycobacterium avium complex (MAC)-LD, 23 with M. abscessus (MAB)-LD, and 27 controls. We measured expressions of PD-1, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and regulatory T (Treg) cells on CD4+ lymphocytes and myeloid-derived suppressor cells (MDSCs) and analyzed their association with clinical features and radiographic outcomes. Results: The percentage of PD-1 on CD4+(PD-1+CD4+) lymphocytes and MDSCs were higher in the MAC-LD group than the controls. There were no intergroup differences regarding CTLA-4+CD4+ lymphocytes. Higher PD-1+CD4+ lymphocytes were found in M. intracellulare- and M. avium-LD than in other MAC-LD. Positive sputum acid-fast stains and fibrocavitary radiographic lesions were correlated with elevated PD-1+CD4+ lymphocytes and Treg cells. The percentage of PD-1+CD4+ lymphocytes at the initial and 2 months of follow-up significantly predicted subsequent radiographic progression. Conclusion: As markers of immune tolerance, PD-1+CD4+ lymphocytes and MDSCs were higher in MAC-LD patients. The levels of PD-1+CD4+ and Treg cells were correlated with high mycobacteria bacilli burden in NTM-LD. Monitoring the expressions of PD-1+CD4+ lymphocytes may predict radiographic progression.

Background The prevalence and incidence of latent tuberculosis infection (LTBI) in patients with kidney transplantation remain unclear. Methods In this prospective study, we enrolled kidney transplantation candidates (KTCs) and recipients (KTRs) from 2014 to 2018. We defined LTBI as a positive result of QuantiFERON-TB Gold In-tube (QFT). We analyzed the predictors for LTBI acquisition and followed up on QFT assay test for 2 years among those initially without LTBI. Results Of 425 patients enrolled, 305 (71.8%) patients belonged to the KTC group and 120 (28.2%) to the KTR group. The initial QFT showed positive results in 32 (10.5%) and 24 (20.0%) patients in the KTC and KTR groups, respectively (P = .009). The QFT response value in patients with LTBI was higher in the KTR group than in the KTC group (1.85 vs 1.06 IU/mL, P = .046). Multivariate logistic regression showed that old age, absence of bacillus Calmette–Guérin (BCG) scar, presence of donor-specific antibody, and KTR group were independent factors for positive LTBI. For participants with initial negative QFT, positive QFT conversion within a 2-year follow-up was higher after kidney transplantation (20%) than in KTCs (5.5%) (P = .034). Conclusions This study is the first cohort to follow up LTBI status in patients with kidney transplantation and shows its higher prevalence and incidence in KTRs. It indicates that surveillance of LTBI after renal transplantation is important. In addition to status of kidney transplantation, old age, no BCG vaccination, and positive donor-specific antibody are also positive predictors for LTBI., The present study found a higher prevalence and incidence of latent tuberculosis infection (LTBI) in kidney transplantation recipients than in kidney transplantation candidates. This indicates that surveillance and control of LTBI after kidney transplantation are important.

Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 h after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 7.00 [2.03–24.1]) and CYP2E1 rs2070673 (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02–12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 h after 3HP administration (OR [95% CI]: 1.61 [1.15–2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs. CC+CT, OR [95% CI]: 4.43 [1.30–15.1]). Conclusions: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection.

Background/Purpose: Little remains known regarding whether newer FQ with less anti-mycobacterial activity (gemifloxacin) would reduce treatment delay. Methods: We identified one hospital-based cohort (HBC) and one population-based cohort (PBC) including patients receiving amoxicillin/clavulanate acid (Beta-lactam), gemifloxacin (Gemi), and fluoroquinolones other than gemifloxacin (Non-Gemi FQ) prior to TB treatment. Results: A total of 201 patients in the HBC and 3544 patients in the PBC were recruited. After 1:1 propensity score matching, TB treatment delay was statistically insignificant between Beta-lactam, Gemi group, and Non-Gemi FQ group in HBC (Beta-lactam vs Gemi: 22.3 ± 21.4 d vs 28.6 ± 27.9 d, p = 0.292; Beta-lactam vs Non-Gemi FQ: 33.3 ± 26.5 d vs 50.3 ± 47.3 d, p = 0.135) and PBC (Beta-lactam vs Gemi: 26.4 ± 29.1 vs 25.0 ± 28.1, p = 0.638; Beta-lactam vs Non-Gemi FQ: 29.4 ± 36.0 d vs 32.7 ± 35.0 d, p = 0.124, Non-Gemi FQ vs Gemi: 28.4 ± 33.0 d vs 25.0 ± 28.1 d, p = 0.29). Conclusion: While limited by relatively low case number, our study showed that use of gemifloxacin neither results in nor reduces delay in TB treatment. The issue of FQ use on TB treatment delay was also not observed in our study. Early survey and maintaining high clinical alertness remains the key to reducing TB treatment delay. Keywords: Gemifloxacin, Fluoroquinolone, Beta-lactam, Tuberculosis, Treatment delay

Summary at a Glance The diagnosis and progression of nontuberculous mycobacteria lung disease (NTN-LD) are important for clinical judgement but cannot easily be predicted. The immunological response of mono- and poly-functional T cells, a representative of host reactivity to NTM, could be a surrogate biomarker for disease and progression prediction. Background Mycobacterium avium complex (MAC) and M. abscessus (MAB) induced lung disease (LD) have become a clinical concern. Predicting clinical disease relevance and progression is important, but suitable biomarkers are lacking. The host immune response of mono- and poly-functional T cells might aid in clinical judgement. Methods We enrolled 140 participants, including 42 MAC-LD, 25 MAB-LD, 31 MAC airway colonization (MAC-Co), 15 MAB-Co patients, and 27 healthy controls. Their blood mono- and poly-functional T cells were measured and analyzed after in-vitro stimulation. Results Patients with MAC-LD generally had lower total IFN-γ+, total TNF-α+ and triple-positive T cells but higher mono-IL-2+ expression than the controls and MAC-Co group. The MAB-LD group had lower total IL-2 and triple positive cells than the controls and colonization group. Multivariate analysis revealed that body mass index (BMI), mono-IL2+ CD4+ and triple positive-CD8+ cells (PMA stimulation) significantly predicted MAC-LD from the controls. By contrast, male gender and triple positive-CD4+ cells predicted MAC-LD from colonization. On the other hand, the triple positive-CD4+ cells (PMA stimulation) alone or together with the mock/MAB ratio of IL-2+/TNF-α+ CD4 cells could predict MAB-LD in the MAB-Co group or the controls. Among MAC/MAB-LD patients without anti-mycobacterial treatment, MAC-specific mono-IFN-γ+ CD4+ cells and PMA-induced triple positive-CD4+ cells were correlated with progression, with an area under the ROC curve of 0.875. Conclusions The patients with MAC/MAB-LD had attenuated poly-functional T cells. The triple-positive CD4+ cells could be useful in diagnosing disease from colonization. MAC-specific mono-IFN-γ+ CD4+ cells and triple positive-CD4+ might predict radiographic progression, which could be useful in making treatment decisions.

Background. The difference of macrophage-specific interleukin-1 beta (IL-1b) response between latent tuberculosis infection (LTBI) and active tuberculosis (TB) remains less studied. Method. We performed this prospective study and recruited active TB patients, contacts with LTBI, and uninfected contacts. The gene and protein expression of human monocyte-derived macrophage (hMDM) after ex vivo stimulation by early secretory antigenic target-6KD (ESAT-6) and tuberculin purified protein derivatives (PPD) was studied by real-time PCR and flow cytometry. The effect of caspase-1 inhibitor was also studied. Result. The IL-1b gene expression after 6 hr ESAT-6 1 μg/ml stimulation was different among active TB patients (n=12), LTBI cases (n=12), and uninfected contacts (n=23) (log fold change: 0.98±1.26 vs. 2.20±0.96 vs. 2.20±0.96, P=0.013). The IL-1b gene expression at 24 hours was higher than that at 6 hours in LTBI cases (n=4) and uninfected contacts (n=6). After 24 hr ESAT-6 1 μg/ml stimulation, the percentage of IL-1b-expressed hMDM was borderline lower in the active TB patients (n=9) than in the LTBI cases (n=10) (14.0±11.2% vs. 31.6±22.5%, P=0.065). Compared with ESAT-6 1 μg/ml stimulation but without the addition of caspase-1 inhibitor (CasI) (55.6±16.3%), the percentage of IL-1b-positive hMDMs decreased after addition of CasI (50 μg/ml CasI: 49.8±18.2%, P=0.078; 100 μg/ml CasI: 46.6±20.8%, P=0.030; 150 μg/ml CasI: 33.7±15.5%, P=0.016). Conclusions. This study revealed that macrophage-specific IL-1b response differed among different stages of Mycobacterium tuberculosis infection. The role of IL-1b and inflammasome in the process of LTBI progressing to active TB warrants further investigation.

Additional file 1. Supplemental methods and results. This file includes definitions of co-morbidities, list of drugs and anatomic therapeutic chemical codes, E-Table S1, E-Table S2, E-Table S3, E-Table S4 and E-Table S5.

The clinical significance of a single Mycobacterium kansasii (MK) isolation in multiple sputum samples remains unknown. We conducted this study to evaluate the outcome and predictors of developing MK-pulmonary disease (PD) within 1 year among these patients. Patients with a single MK isolation from ≥3 sputum samples collected within 3 months and ≥2 follow-up sputum samples and chest radiography in the subsequent 9 months between 2008 and 2016 were included. The primary outcome was development of MK-PD within 1 year, with its predictors explored using multivariate logistic regression analysis. A total of 83 cases of a single MK isolation were identified. The mean age was 68.9 ± 17.9, with a male/female ratio of 1.96. Within 1 year, 16 (19%) cases progressed to MK-PD; risk factors included high acid-fast smear (AFS) grade (≥3), elementary occupation workers, and initial radiographic score >6, whereas coexistence with other nontuberculous mycobacterium species was protective. Among patients who developed MK-PD, all experienced radiographic progression, and 44% died within 1 year. Although a single MK isolation does not fulfil the diagnostic criteria of MK-PD, this disease may develop if having above-mentioned risk factors. Early anti-MK treatment should be considered for high-risk patients.

One-fourth of the human population is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) and carries the infection in its latent form. This latent infection presents a lifelong risk of developing active tuberculosis (TB) disease, and persons with latent TB infection (LTBI) are significant contributors to the pool of active TB cases. Genetic polymorphisms among hosts have been shown to contribute to the outcome of Mtb infection. The SP110 gene, which encodes an interferon-induced nuclear protein, has been shown to control host innate immunity to Mtb infection. In this study, we provide experimental data demonstrating the ability of the gene to control genetic susceptibility to latent and active TB infection. Genetic variants of the SP110 gene were investigated in the Taiwanese population (including 301 pulmonary TB patients, 68 LTBI individuals, and 278 healthy household contacts of the TB patients), and their association with susceptibility to latent and active TB infection was examined by performing an association analysis in a case-control study. We identified several SNPs (rs7580900, rs7580912, rs9061, rs11556887, and rs2241525) in the SP110 gene that are associated with susceptibility to LTBI and/or TB disease. Our studies further showed that the same SNPs may have opposite effects on the control of susceptibility to LTBI versus TB. In addition, our analyses demonstrated that the SP110 rs9061 SNP was associated with tumor necrosis factor-α (TNFα) levels in plasma in LTBI subjects. The results suggest that the polymorphisms within SP110 have a role in controlling genetic susceptibility to latent and active TB infection in humans. To the best of our knowledge, this is the first report showing that the SP110 variants are associated with susceptibility to LTBI. Our study also demonstrated that the identified SP110 SNPs displayed the potential to predict the risk of LTBI and subsequent TB progression in Taiwan.

Objective Disease progression is a strong indicator of treatment for Mycobacterium avium complex lung disease (MAC-LD). The impact of MAC subspecies on the risk of disease progression remains uncertain in MAC-LD patients. Methods In this cohort study, we included MAC-LD patients from 2013 to 2018 and classified them into M. intracellulare, M. avium, M. chimaera and other subspecies groups by genotype. We observed the disease progression of MAC-LD, indicated by antibiotic initiation and/or radiographic progression. We used Cox regression analysis to assess predictors for disease progression. Results Of 105 MAC isolates from unique MAC-LD patients, 35 (33%) were M. intracellulare, 41 (39%) M. avium, 16 (15%) M. chimaera and 13 (12%) other subspecies. After a mean follow-up time of 1.3 years, 56 (53%) patients developed disease progression: 71% (25/35), 54% (22/41), 31% (4/13) and 31% (5/16) in patients with M. intracellulare, M. avium, others and M. chimaera, respectively. The independent predictors for disease progression were M. chimaera subspecies (HR 0.356, 95% CI (0.134–0.943)), compared with the reference group of M. intracellulare, body mass index ≤20 kg/m2 (HR 1.788 (1.022–3.130)) and initial fibrocavitary pattern (HR 2.840 (1.190–6.777)) after adjustment for age, sex and sputum smear positivity. Among patients without fibrocavitary lesions (n = 94), the risk of disease progression significantly decreased in patients with other subspecies (HR 0.217 (0.050–0.945)) and remained low in those with M. chimaera (HR 0.352 (0.131–0.947)). Conclusions Mycobacterium chimaera was not uncommon in this study; unlike M. intracellulare, it was negatively correlated with disease progression of MAC-LD, suggesting a role of MAC subspecies identification in prioritizing patients.

Pulmonary tuberculosis (TB) is caused by Mycobacterium tuberculosis. The protein composition of sputum may reflect the immune status of the lung. This study aimed to evaluate the protein profiles in spontaneous sputum samples from patients with active pulmonary TB. Sputum samples were collected from patients with pulmonary TB and healthy controls. Western blotting was used to analyze the amount of interleukin 10 (IL-10), interferon-gamma (IFN-γ), IL-25, IL-17, perforin-1, urease, albumin, transferrin, lactoferrin, adenosine deaminase (also known as adenosine aminohydrolase, or ADA), ADA-2, granzyme B, granulysin, and caspase-1 in sputum. Results of detection of IL-10, IFN-γ, perforin-1, urease, ADA2, and caspase-1, showed relatively high specificity in distinguishing patients with TB from healthy controls, although sensitivities varied from 13.3% to 66.1%. By defining a positive result as the detection of any two proteins in sputum samples, combined use of transferrin and urease as markers increased sensitivity to 73.2% and specificity to 71.1%. Furthermore, we observed that the concentration of transferrin was proportional to the number of acid-fast bacilli detected in sputum specimens. Detection of sputum transferrin and urease was highly associated with pulmonary TB infection. In addition, a high concentration of transferrin detected in sputum might correlate with active TB infection. This data on sputum proteins in patients with TB may aid in the development of biomarkers to assess the severity of pulmonary TB.

Objectives Chronic pulmonary aspergillosis (CPA) is an emerging global disease with tuberculosis (TB) being the most important risk factor. Epidemiologic data on the seroprevalence of Aspergillus IgG and prevalence of CPA in different areas, especially in country with intermediate burden of TB, are lacking. Methods We prospectively recruited healthy volunteers, TB close contacts, active TB patients and participants with old pulmonary TB in Taiwan during 2012–2019. We measured serum Aspergillus fumigatus and niger-specific IgG levels and assessed if the participants were having CPA. Results A total of 1242 participants (including 200 healthy volunteers, 326 TB close contacts, 524 active TB patients and 192 old TB cases) were recruited. Using 27 mgA/L (milligrams of antigen-specific antibodies per liter) as cut-off level, the seropositive rate of A. fumigatus-specific IgG was 33.0% (66/200), 37.7% (123/326), 26.5% (139/524) and 43.2% (83/192) among the four groups, respectively. In multivariate logistic regression, pulmonary cavitation (OR 1.73; 95% CI 1.07–2.80), female sex (OR 1.49; 95% CI 1.14–1.95), old TB (OR 1.59; 1.05–2.42) were independent risk factors for Aspergillus IgG positivity. One (0.2%) active TB patient and four (2.1%) old TB patients developed CPA. Correlation between A. fumigatus and A. niger-specific IgG was high (Spearman correlation coefficient: 0.942). Discussion Geographic variation in Aspergillus IgG seroprevalence and CPA prevalence exists. A universal cut-off value for Aspergillus IgG may not exist. In areas and populations in which background Aspergillus IgG level is unknown, Aspergillus IgG may be better used as a test of exclusion for CPA using prespecified cut-off level.

Summary Background Clinical application of the CD8 response as measured by the newer interferon gamma release assay, QuantiFERON-TB Gold-Plus (QFT-Plus), remains to be investigated. Method We performed this prospective study and recruited active TB patients, contacts with latent tuberculosis infection (LTBI) and contacts without LTBI in two centres in northern Taiwan in 2017. Subjects were tested with both QuantiFERON-TB Gold In-Tube (QFT-GIT) and QFT-Plus. LTBI was defined by positive result by QFT-GIT and exclusion of active TB. Results A total of 336 participants (118 uninfected contacts, 105 LTBI, 113 active TB) were included. The concordance rate of QFT-GIT and QFT-Plus was high (n = 300, 89.3%). The kappa value was 0.811 among contacts and 0.708 among active TB. While TB1 and TB2 quantitative responses were not different between active TB and LTBI (TB1: 1.74 ± 2.73 IU/ml vs. 2.03 ± 2.28 IU/ml, p = 0.403; TB2: 2.21 ± 3.09 IU/ml vs. 2.15 ± 2.40 IU/ml, p = 0.867), CD8 response was higher in active TB than LTBI (0.47 ± 1.53 IU/ml vs. −0.06 ± 1.47 IU/ml, p = 0.011). Culture-confirmed TB had a higher CD8 response compared with LTBI (0.63 ± 1.74 IU/ml vs. −0.05 ± 1.47 IU/ml, p = 0.004). Conclusions This study demonstrated specific CD8 responses among uninfected contacts, LTBI as well as active TB.

Background Liver recipients may develop various diseases after transplant. However, because of inadequate study of liver transplant during undergraduate education, the quality of post-transplant care provided to these patients remains suboptimal. Herein, we introduce an innovative and integrated multimodal pedagogical approach to effectively disseminate key information regarding liver transplant to undergraduate students. The goal is to examine this approach through students’ assessment in multiple dimensions. Methods This prospective observational study evaluated student reactions to our pedagogical approach. Fifth-year medical students during the academic year 2015–2016 attended a 2-h session on what nontransplant doctors should know about liver transplants. The pedagogical strategy consisted of an online preclass self-learning exercise, an in-class interactive discussion (facilitated by the class teacher who is a liver transplant specialist to avoid distractions within the short-time frame), and a postclass essay assignment (to integrate and apply concepts). After the class, questionnaires were distributed to individual students to collect data, if returned, concerning the students’ learning experience and feedback to improve teaching quality. Descriptive statistics, Mann-Whitney U tests, chi-squared tests, and McNemar’s tests were used to analyze quantitative data. Qualitative data were content-coded through a descriptive approach using thematic analysis. Results Of the 266 attendees, 263 (98.9%) completed the questionnaires and 182 (69.2%) provided comments. Student feedback indicated they “felt better” and “more satisfied” compared with problem-based learning (PBL) (51.0 and 63.1%, respectively) or large-lecture class (92.0 and 88.6%, respectively) approaches. Regarding confidently managing liver transplant patients in future, 80 (30.4%) and 246 (93.5%) students expressed preclass and postclass confidence, respectively (p

Background Research has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated. Methods From 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders. Results Among the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81–1.16) and 0.96 (0.80–1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46–14.1). Conclusion Compared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe. Electronic supplementary material The online version of this article (10.1186/s12885-018-4292-y) contains supplementary material, which is available to authorized users.

Funding: World Health Organization and Canadian Institutes of Health Research. Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1–3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. Findings: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8–9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1–7·3), but no significant effect on mortality (aOR 0·7, 0·4–1·1) or acquired rifampicin resistance (aOR 0·1, 0·0–1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2–0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. Interpretation: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. Funding World Health Organization and Canadian Institutes of Health Research. Postprint

Background Tuberculosis (TB) remains one of the major infectious diseases worldwide. Adverse reactions are common during TB treatment. Few reports, however, are available on treatment-related acute biliary events (ABEs), such as cholelithiasis, biliary obstruction, acute cholecystitis, and cholangitis. Methods We first report four pulmonary TB patients who developed ABEs during anti-TB treatment. Abdominal sonography revealed multiple gall stones with dilated intrahepatic ducts in three patients and cholecystitis in one patient. To investigate the incidence of and risk factors for ABEs during anti-TB treatment, we subsequently conducted a nationwide cohort study using the National Health Insurance Research Database of Taiwan. Results A total of 159,566 pulmonary TB patients were identified from the database between 1996 and 2010, and among them, 195 (0.12%) developed ABEs within 180 days after beginning anti-TB treatment. Logistic regression analysis revealed that the risk factors associated with ABEs are older age (relative risk [RR]: 1.32 [1.21–1.44] per 10-year increment) and diabetes mellitus (RR: 1.59 [1.19–2.13]). Conclusions Although infrequently encountered, ABEs should be considered among patients with TB who experience abdominal discomfort with hyperbilirubinemia, especially patients who have older age or diabetes.

Table S2. Descriptive details of qualitative feedback of studentsâ comments. (DOCX 28 kb)

Table S1. Feedback questionnaire form after class of liver transplantation. (DOCX 17 kb)

Table S1. Anatomical Therapeutic Chemical codes and generic names of the chemoprevention drugs available in Taiwan during the study period. (DOCX 16Â kb)

Background: Weekly rifapentine and isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Little, however, is known regarding the predictors of 3HP-related SDRs. Methods: We prospectively recruited 2 LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the NAT2, CYP2E1, and AADAC SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 hours after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. Findings: A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, NAT2 rs1041983 (TT vs CC CT, odds ratio [OR] [95% CI]: 7.38 [2.17-25.1]) and CYP2E1 rs2070673 (AA vs TT TA, OR [95% CI]: 3.49 [1.02-12.0]) were associated with SDR development. In the PK cohort, isoniazid level 24 hours after 3HP administration (OR [95% CI]: 1.61 [1.15-2.25]) was associated with SDRs. Additionally, the association between the NAT2 SNP and SDRs was validated in the PK cohort (rs1041983 TT vs CC CT, OR [95% CI]: 4.14 [1.24-13.8]). Interpretations: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection. Funding: The study was supported by grants from the Ministry of Health and Welfare (MOHW106-CDC-C-11400104 and MOHW107-CDC-C-114-000105) and the Ministry of Science and Technology (MOST106-2314-B-002-055, MOST107-2314-B-002-191 and MOST107-2314-B-037-106-MY3). Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: The study was approved by the institutional ethics committees of both medical centres (NTUH REC 201609044RINB and KMUHIRB-G[II]-20170033).

Table S2. Antihypertensive medications (other than ACEIs and ARBs) for patients with HBV and HCV within 6Â months after antihypertensive treatment, as grouped according to ACEI or ARB use within 6Â months after the index date. (DOCX 20Â kb)

Table S3. Duration and amount of HBV medications and interferons in patients who received them in the study period, as grouped according to the use of ACEIs or ARBs within 6Â months after the index date. (DOCX 17Â kb)