Protein degradation of Lsd1 is mediated by Bre1 yet opposed by Lsd1-interacting lncRNAs during fly follicle development.

Tissue development, homeostasis, and repair all require efficient progenitor expansion. Lysine-specific demethylase 1 (Lsd1) maintains plastic epigenetic states to promote progenitor proliferation while overexpressed Lsd1 protein causes oncogenic gene expression in cancer cells. However, the precise regulation of Lsd1 protein expression at the molecular level to drive progenitor differentiation remains unclear. Here, using Drosophila melanogaster oogenesis as our experimental system, we discovered molecular machineries that modify Lsd1 protein stability in vivo. Through genetic and biochemical analyses, an E3 ubiquitin ligase, Bre1, was identified as required for follicle progenitor differentiation, likely by mediating Lsd1 protein degradation. Interestingly, specific Lsd1-interacting long non-coding RNAs (LINRs) were found to antagonize Bre1-mediated Lsd1 protein degradation. The intricate interplay discovered among the Lsd1 complex, LINRs and Bre1 provides insight into how Lsd1 protein stability is fine-tuned to underlie progenitor differentiation in vivo.

The effects of incretin-based therapies on weight reduction and metabolic parameters in children with obesity: A systematic review and meta-analysis.

BACKGROUND: Growing evidence indicates that incretin-based therapies (IBTs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP4is) are effective and safe for treating pediatric obesity patients with or without type 2 diabetes. Therefore, we aimed to perform a systematic review and meta-analysis for updating current evidence. METHODS: We searched the PubMed, the Cochrane Library, and the EMBASE database for articles published until September 15, 2023, and limited to randomized control trials. The primary outcomes were changed from baseline in weight metrics and the cardiometabolic profile. A random effects model will be used, as high heterogeneity is expected. All analyses were performed using STATA 17.0. RESULTS: Fifteen trials with a total number of 1286 participants were included in our meta-analysis. Overall, the mean difference in weight change between the IBTs group and the control group was -2.89 kg (95% confidence interval, -5.12 to -0.65, p = 0.011). Additionally, IBTs significantly reduced the HbA1c level and fasting plasma glucose by 0.37% and 6.99 mg/dl, compared with control groups. IBTs showed a little increased risk of GI side effects and hypoglycemia events, but none of the severe hypoglycemia events were occurred in IBTs group. CONCLUSIONS: Our study results have proved that GLP-1 RAs are safe, acceptable, and effective in weight reduction and sugar control for children with obesity. In addition, DPP-4is seems to have no effect on glycemic control and weight loss in childhood obesity. Further research is needed to confirm these findings, especially in younger children.

The association between tocilizumab and the secondary bloodstream infection maybe nonsignificant in hospitalized patients with SARS-CoV-2 infection: A cohort study.

BACKGROUND: Immunomodulatory agents, such as tocilizumab (TCZ), exert promising effects against SARS-CoV-2 infection. However, growing evidence indicates that using TCZ may carry higher risks of secondary bloodstream infection (sBSI). This study determined whether TCZ is associated with an increased risk of sBSI. METHODS: We retrospectively collected the demographic and clinical data of hospitalized patients with SARS-CoV-2 infection from two Taiwanese hospitals. The time-to-incident sBSI in the TCZ users and nonusers was compared using the log-rank test. A multivariate Cox proportional hazards model was performed to identify independent risk factors for sBSI. RESULTS: Between May 1 and August 31, 2021, among 453 patients enrolled, 12 (2.65 %) developed sBSI. These patients were in hospital for longer duration (44.2 ± 31.4 vs. 17.6 ± 14.3 days, p = 0.014). Despite sBSI being more prevalent among the TCZ users (7.1 % vs. 1.6 %, p = 0.005), Kaplan-Meier survival analysis and multivariate Cox proportional hazards model both revealed no significant difference in risks of sBSI between the TCZ users and nonusers [adjusted HR (aHR) = 1.32 (95 % confidence interval (CI) = 0.29-6.05), p = 0.724]. Female sex [aHR = 7.00 (95 % CI = 1.45-33.92), p = 0.016], heavy drinking [aHR = 5.39 (95 % CI = 1.01-28.89), p = 0.049], and mechanical ventilation [aHR = 5.65 (95 % CI = 1.67-19.30), p = 0.006] were independently associated with a higher sBSI risk. CONCLUSION: This real-world evidence indicates that in hospitalized patients with SARS-CoV-2 infection, TCZ does not significantly increase the risk of sBSI.

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

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

Statin Use and Delirium Risk: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Findings on the association of statin use with delirium risk are inconsistent. THE STUDY QUESTION: Is statin use associated with delirium risk? STUDY DESIGN: 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 effect size and 95% confidence interval (CI) were defined as the odds ratio (OR) and 95% CI, respectively, 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 test, Duval and Tweedie trim-and-fill approach, and the classic fail-safe N to assess publication bias. RESULTS: 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, 0·64-1·04; P = 0·09). Substantial statistical heterogeneity was observed ( I2 , 90%). Visual inspection of the funnel plot of ORs from the studies revealed symmetry. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, we assigned the evidence a rating of C and a weak recommendation for this review. CONCLUSIONS: Statin use is not associated with delirium risk. More comprehensive RCTs are required to confirm the results.

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

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

Identification of Lsd1-interacting non-coding RNAs as regulators of fly oogenesis.

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.

Bisphosphonate Use Is Not Associated With Tuberculosis Risk Among Patients With Osteoporosis: A Nationwide Cohort Study.

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.

Advantages of short-course rifamycin-based regimens for latent tuberculosis infection: an updated network meta-analysis.

OBJECTIVES: We conducted an updated network meta-analysis to elucidate the best regimen for latent tuberculosis infection (LTBI). METHODS: We searched the PubMed, Embase, and Cochrane Library databases on 16 August 2021 to perform an updated network meta-analysis. Only randomised controlled trials on populations with LTBI that reported the efficacy for preventing incident tuberculosis or the completion rates of treatment regimens were included. The Cochrane Collaboration tool was used to assess the risk of bias. We tested for possible global inconsistency with a χ2 test and local inconsistency by calculating inconsistency factors for each comparison in closed loops. The probability of each regimen being at each possible rank was estimated. Comparison-adjusted funnel plots were obtained to assess publication bias, and sensitivity analysis was performed. The major outcomes were the efficacy for preventing incident tuberculosis and the completion rates of treatment regimens. RESULTS: We identified 27 studies that matched our inclusion criteria; the risk of bias was mostly low. Rifampicin for four months (RFMP-4) was the most likely to be effective (probability: 56.3%) and the second most likely treatment to be completed (probability: 22.4%). By applying a multidimensional scaling approach for ranking based on a scatterplot with the surface under the cumulative ranking values for efficacy and completion rates, RFMP-4 was deemed the best choice for treating LTBI. Similar results were demonstrated after sensitivity analysis. CONCLUSION: This updated network meta-analysis revealed RFMP-4 to be the best choice for treating LTBI, per simultaneous consideration of efficacy and completion rates.

Effects of various statins on depressive symptoms: A network meta-analysis.

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.

Statin use and depression risk: A systematic review and meta-analysis.

BACKGROUND: Evidence regarding whether statin use is associated with depression is inconsistent. Therefore, we performed a meta-analysis to investigate this association. METHODS: We searched PubMed, the Cochrane Library, and the EMBASE database, limiting the search to human patients and articles written in English and published by March 31, 2020. The Newcastle-Ottawa scale for observational studies was used to assess study quality. All included studies were evaluated by 2 reviewers independently; any discrepancies were resolved through discussion. Because of the heterogeneity of study populations, a random effects model was used to calculate the pooled effect size. Statistical heterogeneity across studies was assessed using the I2 statistic. All analyses were performed using RevMan5 and Comprehensive Meta-Analysis software. RESULTS: A total of 13 observational (9 cohort, 3 case-control, and 1 cross-sectional) studies conducted in 11 countries and enrolling 5 035 070 participants were included. Substantial statistical heterogeneity was discovered (I2, 83%). Overall, use of statins was not associated with depression after trim and fill analysis (adjusted pooled odds ratio [OR], 0.87; 95% CI, 0.74-1.02). The finding was consistent in the subgroup analysis, except for studies published before 2013, showing statin use was associated with a lower risk of depression. LIMITATIONS: High heterogeneity and asymmetry funnel plot of ORs from these studies were observed. CONCLUSIONS: This meta-analysis revealed statin use was not associated with depression. However, high heterogeneity was observed between identified studies, and results were inconsistent in the subgroups of studies published before 2013.

Effect of ß-Blocker in Treatment-Naïve Patients With Advanced Lung Adenocarcinoma Receiving First-Generation EGFR-TKIs.

BACKGROUND: Through activation of adrenergic receptors, chronic stress can trigger the secretion of neurotransmitters and hormones that enhance tumor growth, increase angiogenesis, and promote drug resistance. This study aimed to evaluate the effect of ß-blockers in patients receiving first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for lung adenocarcinoma. METHODS: This retrospective cohort study enrolled patients with advanced lung adenocarcinoma under first-line EGFR-TKIs between 2011 and 2014 in the National Health Insurance Research Database of Taiwan. The effects of ß-blockers use, defined as ≥60 defined daily doses within 180 days before initiation of EGFR-TKI therapy, on the 2-year time-to-discontinuation (TTD) of EGFR-TKIs and 4-year overall survival (OS) were investigated using Cox regression analyses with inverse propensity score weighting and sensitivity analysis in subgroup with either hypertension or ischemic heart diseases. RESULTS: Among 4988 enrolled patients, 552 (11.1%) were in the ß-blocker group. Patients in the ß-blocker group were more likely to be older than 75 and had diabetes mellitus and cardiovascular comorbidities. In Cox regression analysis, ß-blocker usage was associated with a longer TTD (hazard ratio, HR: 0.91 [0.86-0.96]) and OS (HR: 0.68 [0.64-0.72]). The results also favored ß-blocker group in sensitivity analysis. CONCLUSIONS: In treatment-naïve patients with advanced lung adenocarcinoma under first-line EGFR-TKIs, prior use of ß-blocker was associated with a better outcome. The findings encourage further prospective clinical study to validate the possibility of ß-blockers as adjuvant anticancer therapy.

Survival After Treatable Hepatocellular Carcinoma Recurrence in Liver Recipients: A Nationwide Cohort Analysis.

BACKGROUND: Survival 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. METHODS: Three 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. RESULTS: Of 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. CONCLUSION: Timing 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.

Impact of metformin use among tuberculosis close contacts with diabetes mellitus in a nationwide cohort study.

BACKGROUND: The protective effect of metformin against active tuberculosis (TB) among TB close contacts is unknown. METHODS: TB 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. RESULTS: A 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. CONCLUSIONS: Metformin 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.

Use of Antiplatelet Agents and Survival of Tuberculosis Patients: A Population-Based Cohort Study.

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): 0.88-0.95, p < 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.

Association of Metformin Use With End-Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay-for-Performance Program.

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.

Metformin use is associated with a low risk of tuberculosis among newly diagnosed diabetes mellitus patients with normal renal function: A nationwide cohort study with validated diagnostic criteria.

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.

Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study.

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.

Acute biliary events during anti-tuberculosis treatment: hospital case series and a nationwide cohort study.

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.