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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: Findings on the association of statin use with delirium risk are inconsistent. We performed an up-to-date systematic review and meta-analysis to elucidate this association among critically ill and surgical patients.Materials and Methods: We searched PubMed, the Cochrane Library, and the EMBASE database, limiting the search to human patients and articles in English published until December 31, 2021. The odds ratio (OR) and 95% confidence interval (CI) were used to indicate the difference in the incidence of delirium between statin use and nonuse groups. A random-effects model was selected in the case of high heterogeneity of study populations. We used funnel plots, Egger’s test, Duval and Tweedie’s trim-and-fill approach, and the classic fail-safe N to assess publication bias.Findings: Of a total of 264 identified studies, 13 were selected for the qualitative review—4 RCTs and 9 observational cohort studies. Statin use was not associated with low delirium risk (pooled OR, 0·82; 95% CI, 0·64 to 1·04; p = 0·09). Substantial statistical heterogeneity was observed (I2, 90%). Visual inspection of the funnel plot of ORs from the studies revealed symmetry.Conclusions: Statin use is not associated with delirium risk. More comprehensive RCTs are required to confirm the results.

Background : Previous studies have indicated that statins can reduce the severity of depressive symptoms. However, the optimal choice of statin remains unclear. Therefore, we conducted a network meta-analysis to determine the optimal statin for treating depression. Method : We performed a pairwise and network meta-analysis by searching the PubMed, Embase, and Cochrane Library databases on October 29th, 2020. Eligible studies were randomized controlled trials that reported on changes in depressive symptoms. The Cochrane Collaboration tool was used to assess risk of bias. We tested for possible inconsistency globally by using a χ2-test and locally by calculating inconsistency factors for each comparison in closed loops. The ranking probabilities of being at each possible rank for each intervention were estimated. Comparison-adjusted funnel plots were obtained to assess publication bias. Sensitivity analysis was also performed. Results : We identified 13 studies that matched our inclusion criteria. The risks of bias were mostly low. None of the global or local tests found significance. Compared with placebo, atorvastatin significantly reduced the severity of depressive symptoms (mean difference −3.46, 95% confidence interval −5.26 to −1.67). Atorvastatin had the first and second rank with probabilities of 44.9% and 39.0%, respectively. Comparison-adjusted funnel plots revealed no significant publication bias. Limitations : Low similarity of included studies and a relative large treatment effect of a single study were observed. Conclusions : In this first network meta-analysis, atorvastatin, with high intensity and a lipophilic effect, was identified as the optimal choice of statin for treating depression.

A population pharmacokinetic (PPK) study of the correlation of adverse drug reactions (ADRs) with the 3HP regimen (weekly high-dose rifapentine plus isoniazid for 12 doses) for latent tuberculosis infection (LTBI) remains lacking. The purpose of this study is to determine the association of rifapentine or isoniazid concentration and ADRs.This prospective, multicentre, observational study enrolled LTBI contacts receiving 3HP treatment between January 2017 and August 2020. The concentrations of rifapentine, isoniazid and their metabolites (25-desacetyl-rifapentine and acetyl-isoniazid) in plasma samples collected monthly after 3HP treatment were determined. A PPK model was constructed to predict the maximum concentration (CA total of 415 LTBI cases were ultimately enrolled; 355 (85.5%) completed the 3HP treatment. Among them, 47 (11.3%) experienced systemic drug reactions and 291 (70.0%) experienced one or more flu-like symptom. The plasma concentration-time profiles of isoniazid, rifapentine and their metabolites were adequately described by the developed models. A higher CIsoniazid may be responsible for ADRs, especially flu-like symptoms, during 3HP treatment.

Lysine-specific demethylase 1 (Lsd1) plays a key role in balancing cell proliferation and differentiation. Lsd1 has been recently reported to associate with specific long noncoding RNAs (lncRNAs) to account for oncogenic gene expression in cancer cells. However, how lncRNA-Lsd1 interplay affects cell-specific differentiation remains elusive in vivo. Here, through Lsd1 specific RNA immunopecipitation sequencing (RIP-seq) experiments, we identify three long hairpin RNAs as Lsd1-interacting non-coding RNAs (LINRs) from fly ovaries. Knocking out LINR-1 and LINR-2 affects fly egg production, while each of the LINR deletion mutant females produce eggs with reduced hatch rate, indicating important functions of LINRs in supporting oogenesis. At the cellular level, LINR-2 regulates the differentiation of germline stem cells and follicle progenitors likely though modulating the expression and function of Lsd1 in vivo. Our identification of ovarian LINRs presents a physiological example of dynamic lncRNA-Lsd1 interplay that regulates stem cell/progenitor differentiation.

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.

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.

The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is an essential lipid A biosynthetic enzyme that is conserved in the majority of gram-negative bacteria. It has emerged as an attractive novel antibiotic target due to the recent discovery of an LpxH-targeting sulfonyl piperazine compound (referred to as AZ1) by AstraZeneca. However, the molecular details of AZ1 inhibition have remained unresolved, stymieing further development of this class of antibiotics. Here we report the crystal structure of Klebsiella pneumoniae LpxH in complex with AZ1. We show that AZ1 fits snugly into the L -shaped acyl chain-binding chamber of LpxH with its indoline ring situating adjacent to the active site, its sulfonyl group adopting a sharp kink, and its N -CF 3 –phenyl substituted piperazine group reaching out to the far side of the LpxH acyl chain-binding chamber. Intriguingly, despite the observation of a single AZ1 conformation in the crystal structure, our solution NMR investigation has revealed the presence of a second ligand conformation invisible in the crystalline state. Together, these distinct ligand conformations delineate a cryptic inhibitor envelope that expands the observed footprint of AZ1 in the LpxH-bound crystal structure and enables the design of AZ1 analogs with enhanced potency in enzymatic assays. These designed compounds display striking improvement in antibiotic activity over AZ1 against wild-type K. pneumoniae , and coadministration with outer membrane permeability enhancers profoundly sensitizes Escherichia coli to designed LpxH inhibitors. Remarkably, none of the sulfonyl piperazine compounds occupies the active site of LpxH, foretelling a straightforward path for rapid optimization of this class of antibiotics.

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.

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.

The Drosophila melanogaster ovarian follicle cell lineage provides a powerful system for investigating how epigenetic changes contribute to differentiation. Downstream from an epithelial stem cell, follicle progenitors undergo nine mitotic cell cycles before transitioning to the endocycle and initiating differentiation. During their proliferative phase, follicle progenitors experience Lsd1-dependent changes in epigenetic stability that can be monitored using GAL4::UAS variegation. Eventually, follicle progenitors acquire competence to respond to Delta, a Notch ligand present in the environment, which signals them to cease division and initiate differentiation. The time required to acquire competence determines the duration of mitotic cycling and hence the final number of follicle cells. We carried out a screen for dominant modifiers of variegation spanning nearly 70% of Drosophila euchromatin to identify new genes influencing follicle progenitor epigenetic maturation. The eight genes found include chromatin modifiers, but also cell cycle regulators and transcription factors. Five of the modifier genes accelerate the acquisition of progenitor competence and reduce follicle cell number, however, the other three genes affect follicle cell number in an unexpected manner.

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.

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.

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.

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

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)

Background and objective This retrospective national surveillance study investigated the burden of and risk factors for nosocomial exposure of pulmonary tuberculosis (TB) in intensive care units. Methods Patients admitted to intensive care units were identified from the National Health Insurance Research Database. During 2004–2009, there were 1 387 707 intensive care unit admissions of 900 562 adult patients. Pulmonary tuberculosis association was considered if the patient was diagnosed with pulmonary tuberculosis during admission or within 3 months after discharge. Nosocomial transmissible period was calculated based on the length of anti-tuberculosis treatment and negative-pressure isolation during admission. Results Pulmonary tuberculosis was associated with 1.20% of all intensive care unit admissions and 6731 (38.9%) started anti-TB treatment during admission. For the other 10 583 admissions, the diagnosis was made after discharge and anti-TB treatment was not prescribed during admission. The probability paralleled the regional tuberculosis incidence. On average, 2794 pulmonary tuberculosis associated intensive care unit admissions contributed to 42 999–44 062 days of nosocomial exposure per year. The length of nosocomial transmissible period decreased with the gradual implementation of Mycobacterium tuberculosis nucleic acid amplification tests in intensive care practice. Multivariate linear regression analysis revealed that the length of nosocomial transmissible period was inversely associated with male gender, airway symptoms prior to admission and performing M. tuberculosis nucleic acid amplification tests and mycobacterial culture. Conclusions Nosocomial tuberculosis exposure is not uncommon in intensive care units. Performing rapid molecular diagnostic tests in those suspected of tuberculosis is recommended to reduce the risk of nosocomial exposure.

Despite its excellent activity against Mycobacterium tuberculosis [1], empirical fluoroquinolone (FQ) therapy has been associated with delayed initiation of appropriate treatment [2–4] and acquired resistance [5, 6] in tuberculosis (TB) patients presenting as community-acquired pneumonia (CAP). A previous study conducted in intensive care unit revealed immediate mycobacteriology study may possibly prevent the delay in anti-TB treatment [7]. However, this hypothesis has not been confirmed. Empirical fluoroquinolone use for ≥7 days delays antituberculosis treatment despite immediate mycobacteriology study The authors thank the National Health Research Institute of Taiwan for providing the NHIRD. Details of the computer code for statistical analyses are available from the corresponding author.

BACKGROUND Diabetes mellitus (DM) increases the risk of TB recurrence. This study investigated whether 9-month anti-TB treatment is associated with a lower risk of TB recurrence within 2 years after complete treatment than 6-month treatment in patients with DM with an emphasis on the impact of directly observed therapy, short course (DOTs). METHODS Patients with pulmonary but not extrapulmonary TB receiving treatment of 173 to 277 days between 2002 and 2010 were identified from the National Health Insurance Research Database of Taiwan. Patients with DM were then selected and classified into two groups based on anti-TB treatment duration (9 months vs 6 months). Factors predicting 2-year TB recurrence were explored using Cox regression analysis. RESULTS Among 12, 688 patients with DM and 43, 195 patients without DM, the 2-year TB recurrence rate was 2.20% and 1.38%, respectively ( P P CONCLUSIONS The 2-year TB recurrence rate is higher in a diabetic population in Taiwan and can be reduced by treatment supervision. Extending the anti-TB treatment by 3 months may also decrease the recurrence rate when treatment is not supervised.

Progenitors are early lineage cells that proliferate before the onset of terminal differentiation. Although widespread, the epigenetic mechanisms that control the progenitor state and the onset of differentiation remain elusive. By studying Drosophila ovarian follicle cell progenitors, we identified lysine-specific demethylase 1 (lsd1) and CoRest as differentiation regulators using a GAL4∷GFP variegation assay. The follicle cell progenitors in lsd1 or CoRest heterozygotes prematurely lose epigenetic plasticity, undergo the Notch-dependent mitotic-endocycle transition, and stop dividing before a normal number of follicle cells can be produced. Simultaneously reducing the dosage of the histone H3K4 methyltransferase Trithorax reverses these effects, suggesting that an Lsd1/CoRest complex times progenitor differentiation by controlling the stability of H3K4 methylation levels. Individual cells or small clones initially respond to Notch; hence, a critical level of epigenetic stabilization is acquired cell-autonomously and initiates differentiation by making progenitors responsive to pre-existing external signals.

There are still several unanswered research questions regarding tuberculosis (TB) contact investigations [1–4]. For example, up-to-date epidemiological studies regarding TB contacts in the area of intermediate incidence are not readily available [5]. The long-term risk of TB, especially beyond 5 years, remains undetermined [6]. Risk factors for TB development among contacts are also not well defined [2]. To expand current understanding and knowledge of TB contact investigation, we recruited a population-based TB contacts cohort utilising the National Health Insurance Research Database of Taiwan, which included medical care claims data of 99% Taiwan residents [7]., Taiwan TB contact cohort: 0.5% 1-year yield, age ≥65 as significant risk factor and elevated TB risk at 5th year http://ow.ly/9ZGr30dpkMc

Purpose Diabetic mellitus (DM) is a well-known risk factor of tuberculosis (TB). However, there is paucity of reports on the impact of diabetic control and adherence to anti-diabetic treatment on the risk of TB. This nationwide cohort study aimed to address these issues. Methods In the Longitudinal Health Insurance Database 2005 of Taiwan, DM cases and matched control subjects were selected. Potential risk factors for developing TB were investigated using the Cox proportional hazards regression analysis. Time-dependent variables were used to measure drug prescription, adherence, and number of DM-associated admissions from 360 to 90days prior to each outcome event. Results The 49903 DM patients identified (52.5% males) had a mean age of 61.9±14.2years. Among DM patients and control subjects, the independent risk factors of TB were age, male sex, chronic obstructive pulmonary disease (COPD), autoimmune disease, and DM (hazard ratio [HR] 1.293 [1.154–1.449]). Among DM patients, time-dependent Cox analysis revealed that age, male sex, COPD, endstage renal disease, maximum average daily dose of oral hypoglycemic agent (HR 1.13 [1.071–1.193]), insulin use during admission (HR 1.462 [1.087–1.966]), adherence to anti-diabetic medication (0.577 [0.429–0.776]), and number of DM-associated admissions (1.789 [1.231–2.601]) were independent factors associated with the development of TB. Conclusions The risk of TB parallels DM severity. Some cases of TB can be prevented by fostering adherence to anti-diabetic medication. Copyright © 2013 John Wiley & Sons, Ltd. key words—adherence; cohort study; diabetes mellitus; National Health Insurance Database; tuberculosis; pharmacoepidemiology

Human studies on the use of metformin as host-directed therapy (HDT) for tuberculosis (TB) are rare. We performed a nationwide cohort study to evaluate the effect of metformin on mitigating the risk of active TB among patients with diabetes mellitus (DM). Among newly diagnosed DM patients identified in the Taiwan National Health Insurance Research Database, metformin users, defined on the basis of >90 cumulative defined daily doses within 1 year, and propensity-score-matched metformin nonusers were selected. The primary outcome was incident TB, identified using diagnostic criteria validated by real patient data at a medical center. Independent predictors were investigated using Cox regression analysis. Similar analysis was performed in a subpopulation without a history of hypertensive nephropathy and renal replacement therapy. A total of 88,866 metformin users and 88,866 propensity-score-matched nonusers were selected. Validation results showed that the TB diagnostic criteria had a sensitivity of 99.13% and specificity of 99.90%. During follow-up, 707 metformin users and 807 nonusers developed active TB. Metformin use was independently associated with a lower risk of incident TB (hazard ratio [HR]: 0.84 [0.74–0.96]). TB risk was lower in high-dose metformin users than in low-dose users (HR: 0.83 [0.72–0.97]). The effect of metformin remained when analysis was restricted in the subpopulation without renal function impairment. Newly diagnosed diabetic patients without contraindication should receive metformin as an anti-diabetic medication, with potential additional benefit against TB.

SummaryOptimal function of neuronal networks requires interplay between rapid forms of Hebbian plasticity and homeostatic mechanisms that adjust the threshold for plasticity, termed metaplasticity. Numerous forms of rapid synapse plasticity have been examined in detail. However, the rules that govern synaptic metaplasticity are much less clear. Here, we demonstrate a local subunit-specific switch in NMDA receptors that alternately primes or prevents potentiation at single synapses. Prolonged suppression of neurotransmitter release enhances NMDA receptor currents, increases the number of functional NMDA receptors containing NR2B, and augments calcium transients at single dendritic spines. This local switch in NMDA receptors requires spontaneous glutamate release but is independent of action potentials. Moreover, single inactivated synapses exhibit a lower induction threshold for both long-term synaptic potentiation and plasticity-induced spine growth. Thus, spontaneous glutamate release adjusts plasticity threshold at single synapses by local regulation of NMDA receptors, providing a novel spatially delimited form of synaptic metaplasticity.

The association of inhaled corticosteroids (ICS) and pneumonia in patients with chronic obstructive pulmonary disease (COPD) is still controversial. From the National Health Insurance Database of Taiwan, COPD cases with history of acute exacerbation (AE) were identified (COPD cohort). Time-dependent Cox regression analysis was applied to investigate the risk factors for pneumonia with COPD severity controlled by surrogate variables. Among the COPD cohort, those who continuously used ICS for more than 360 days without interruption were selected (ICS cohort). The incidence rate of pneumonia during ICS use was compared with those before ICS use and after ICS discontinuation by using pair t test. A total of 6034 and 842 cases were identified as the COPD and ICS cohorts, respectively. In the COPD cohort, recent ICS use was independently associated with pneumonia (hazard ratio: 1.06 [1.02–1.11] for per 80 mg of budesonide). Other independent risk factors included age, male, diabetes mellitus, malignancy, low income, baseline pneumonia event, and recent use of oral corticosteroids and aminophylline. In the ICS cohort, while AE rate gradually decreased, the incidence rate of pneumonia significantly increased after ICS use (from 0.10 to 0.21 event/person-year, P = 0.001). This study demonstrates the association between ICS use and pneumonia in patients with COPD and history of AE. ICS should be judiciously used in indicated COPD patients.

During apoptosis, phosphatidylserine, which is normally restricted to the inner leaflet of the plasma membrane, is exposed on the surface of apoptotic cells and has been suggested to act as an “eat-me” signal to trigger phagocytosis. It is unclear how phagocytes recognize phosphatidylserine. Recently, a putative phosphatidylserine receptor (PSR) was identified and proposed to mediate recognition of phosphatidylserine and phagocytosis. We report thatpsr-1, theCaenorhabditis eleganshomolog of PSR, is important for cell corpse engulfment. In vitro PSR-1 binds preferentially phosphatidylserine or cells with exposed phosphatidylserine. InC. elegans, PSR-1 acts in the same cell corpse engulfment pathway mediated by intracellular signaling molecules CED-2 (homologous to the human CrkII protein), CED-5 (DOCK180), CED-10 (Rac GTPase), and CED-12 (ELMO), possibly through direct interaction with CED-5 and CED-12. Our findings suggest that PSR-1 is likely an upstream receptor for the signaling pathway containing CED-2, CED-5, CED-10, and CED-12 proteins and plays an important role in recognizing phosphatidylserine during phagocytosis.

Diabetes mellitus (DM) increases the risk of TB recurrence. This study investigated whether 9-month anti-TB treatment is associated with a lower risk of TB recurrence within 2 years after complete treatment than 6-month treatment in patients with DM with an emphasis on the impact of directly observed therapy, short course (DOTs).Patients with pulmonary but not extrapulmonary TB receiving treatment of 173 to 277 days between 2002 and 2010 were identified from the National Health Insurance Research Database of Taiwan. Patients with DM were then selected and classified into two groups based on anti-TB treatment duration (9 months vs 6 months). Factors predicting 2-year TB recurrence were explored using Cox regression analysis.Among 12,688 patients with DM and 43,195 patients without DM, the 2-year TB recurrence rate was 2.20% and 1.38%, respectively (P.001). Of the patients with DM, recurrence rate decreased from 3.54% to 1.19% after implementation of DOTs (P.001). A total of 4,506 (35.5%) were classified into 9-month anti-TB treatment group. Although a 9-month anti-TB treatment was associated with a lower recurrence rate (hazard ratio, 0.76 [95% CI, 0.59-0.97]), the benefit disappeared (hazard ratio, 0.69 [95% CI, 0.43-1.11]) under DOTs. Other predictors of recurrence included older age, male sex, malignancy, earlier TB diagnosis year, culture positivity after 2 months of anti-TB treatment, and anti-TB treatment being ≤ 80% consistent with standard regimen.The 2-year TB recurrence rate is higher in a diabetic population in Taiwan and can be reduced by treatment supervision. Extending the anti-TB treatment by 3 months may also decrease the recurrence rate when treatment is not supervised.

To report a case of suspected caspofungin-induced toxic epidermal necrolysis (TEN).An 86-year-old man had a right femur intertrochanteric fracture and right proximal humerus fracture due to an accidental fall. Disseminated Candida krusei infection complicated the postoperative course. Candidemia persisted despite 25 days of treatment with parenteral fluconazole. The antifungal agent was changed to intravenous caspofungin. Immediately after administration of a caspofungin 70-mg loading dose, a transient skin rash developed, which resolved after discontinuation of the drug and immediate treatment with intravenous diphenhydramine 30 mg and methylprednisolone 40 mg. Six days later, a caspofungin 70-mg loading dose was given again due to increasing sepsis. Erythematous and purpuric macules and plaques developed the next day and rapidly progressed to extensive erythema, exfoliation, blisters, and skin erosions. A dermatologist was consulted and TEN was diagnosed. The patient was treated with intravenous hydrocortisone 100 mg every 8 hours and diphenhydramine 30 mg every 8 hours. The skin lesions progressed unrelentingly and the patient died of refractory shock 6 days later.TEN is a rare but life-threatening systemic and cutaneous disease that is most often the result of an adverse drug reaction. It usually manifests as fever and influenza-like symptoms 1-3 days before the development of mucocutaneous lesions, namely erythema and erosions of the buccal, ocular, and genital mucosa and characteristic epidermal detachment. The precise pathogenesis is not fully understood. Several models have been described, including immunopathology, genetic susceptibility, Fas-Fas ligand, perforin/granzyme, and cytokine dysregulation. Use of the Naranjo probability scale indicated a probable relationship between caspofungin and the development of TEN in this patient.This is the first report of caspofungin-induced TEN. Health-care professionals are advised to be aware of the early presentations of TEN in patients receiving caspofungin.

In this paper, we demonstrated the optical properties of grating-coupled reflection type SPR sensor which made by the commercial compact disk with the heterodyne interferometry. Based on the measurement results, the sensitivity of these two type sensors with phase measurement are higher than intensity measurement at resonance angle.

Listeria meningitis, a rare but life-threatening infection in patients with systemic lupus erythematosus, often represents a diagnostic and therapeutic challenge because of its rarity and non-representative manifestations. L. monocytogenes is an intracellular pathogen capable of spreading directly from cell to cell without exposure to the extracellular humoral immune system. With the evolving trend of intense immunosuppressive therapy, patients with SLE usually have abnormal cell-mediated immunity and are susceptible to L. monocytogenes infections. The gastrointestinal tract is usually the portal of entry, and a transient gastroenteritis may precede the full-blown meningitides. Ampicillin and penicillin G are the drugs of choice. For patients who are allergic to penicillin, trimethoprim-sulfamethoxazole is an eligible alternative. Delay in diagnosis and inappropriate antibiotics are detrimental to the outcome. Herein, we report a young woman with systemic lupus erythematosus who developed listeria meningitis. Clinicians are advised to be aware of the clinical presentations of this disease.