Comparison of networks of loneliness, depressive symptoms, and anxiety symptoms in at-risk community-dwelling older adults before and during COVID-19.

Network analysis provides an innovative approach to examining symptom-to-symptom interactions in mental health, and adverse external conditions may change the network structures. This study compared the networks of common risk factors and mental health problems (loneliness, depressive symptoms, and anxiety symptoms) in community-dwelling older people before and during COVID-19. Older adults (aged ≥ 60) at risk for depression were recruited through non-governmental organizations. Loneliness, depressive symptoms and anxiety symptoms were measured using the three-item Loneliness Scale (UCLA-3), nine-item Patient Health Questionnaire (PHQ-9), and seven-item Generalized Anxiety Disorder Scale (GAD-7), respectively. Data from 2549 (before) and 3506 (during COVID-19) respondents were included using propensity score matching. Being restless (GAD-7-item5) was most central, indicated by Expected Influence, in both pre and during COVID-19 networks despite low severity (mean score). The network during COVID-19 had higher global strength and edge variability than the pre-pandemic network, suggesting easier symptom spread and potentially more complex symptom presentation. In addition, feeling isolated from others (UCLA-3-item3) had stronger connections with feeling worthless/guilty (PHQ-9-item6) and anticipatory anxiety (GAD-7-item7) during COVID-19 than before. These findings may enhance our knowledge of the symptom structure of common mental health problems and the impacts of the pandemic. Targeting central symptoms may offer novel preventive strategies for older people.

Deficiency of ADAR2 ameliorates metabolic-associated fatty liver disease via AMPK signaling pathways in obese mice.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.

Xanthine oxidase inhibition study of isolated secondary metabolites from Dolichandrone spathacea (Bignoniaceae): In vitro and in silico approach.

Xanthine oxidase (XO) has been widely recognized as a pivotal enzyme in developing hyperuricemia, primarily contributing to the excessive production of uric acid during purine metabolism in the liver. One of the standard treatment approaches involves reducing uric acid levels by inhibiting XO activity. In this study, the leaf extract of Dolichandrone spathacea, traditionally used in folk medicine, was found to inhibit XO activity in the ethyl acetate and butanol fractions at a concentration of 100 µg/mL, their values were 78.57 ± 3.85 % (IC50 = 55.93 ± 5.73 µg/ml) and 69.43 ± 8.68 % (IC50 = 70.17 ± 7.98 µg/ml), respectively. The potential XO inhibitory components were isolated by bioactivity assays and the HR-ESI-MS and NMR spectra system. The main constituents of leaf extracts of Dolichandrone spathacea, six compounds, namely trans-4-methoxycinnamic acid (3), trans-3,4-dimethoxycinnamic acid (4), p-coumaric acid (5), martynoside (6), 6-O-(p-methoxy-E-cinnamoyl)-ajugol (7), and scolymoside (17), were identified as potent XO inhibitors with IC50 values ranging from 19.34 ± 1.63 µM to 64.50 ± 0.94 µM. The enzyme kinetics indicated that compounds 3-5, 7, and 17 displayed competitive inhibition like allopurinol, while compound 6 displayed a mixed-type inhibition. Computational studies corroborated these experimental results, highlighting the interactions between potential metabolites and XO enzyme. The hydrogen bonds played crucial roles in the binding interaction, especially, scolymoside (17) forms a hydrogen bond with Mos3004, exhibited the lowest binding energy (-18.3286 kcal/mol) corresponding to the lowest IC50 (19.34 ± 1.63 µM). Furthermore, nine compounds were isolated for the first time from this plant. In conclusion, Dolichandrone spathacea and its constituents possess the potential to modulate the xanthine oxidase enzyme involved in metabolism.

Non-invasive evaluation of liver steatosis with imaging modalities: New techniques and applications.

In the world, nonalcoholic fatty liver disease (NAFLD) accounts for majority of diffuse hepatic diseases. Notably, substantial liver fat accumulation can trigger and accelerate hepatic fibrosis, thus contributing to disease progression. Moreover, the presence of NAFLD not only puts adverse influences for liver but is also associated with an increased risk of type 2 diabetes and cardiovascular diseases. Therefore, early detection and quantified measurement of hepatic fat content are of great importance. Liver biopsy is currently the most accurate method for the evaluation of hepatic steatosis. However, liver biopsy has several limitations, namely, its invasiveness, sampling error, high cost and moderate intraobserver and interobserver reproducibility. Recently, various quantitative imaging techniques have been developed for the diagnosis and quantified measurement of hepatic fat content, including ultrasound- or magnetic resonance-based methods. These quantitative imaging techniques can provide objective continuous metrics associated with liver fat content and be recorded for comparison when patients receive check-ups to evaluate changes in liver fat content, which is useful for longitudinal follow-up. In this review, we introduce several imaging techniques and describe their diagnostic performance for the diagnosis and quantified measurement of hepatic fat content.

Specific Pandemic-Related Worries Predict Higher Attention-Related Errors and Negative Affect Independent of Trait Anxiety in UK-Based Students.

Background: The COVID-19 pandemic has resulted in many individuals experiencing increased symptoms of anxiety. We predict that this increase may be underpinned by pandemic-related worry (PRW), characterised by repetitive negative thinking about pandemic-specific outcomes; and that this relationship is mediated through reduced attentional capacity required to regulate negative affect. Methods: We developed a novel scale to measure the contents of PRW in an initial sample of 255 participants, and explored its relationship with cognitive functioning and negative affect in a sample of 382 UK-based university students, whilst controlling for recalled pre-pandemic trait anxiety. Results: A five-factor model of PRW was identified, with factors reflecting worry about decline in quality of life (QoL) and probability of infection correlating with attention and memory-related errors. Importantly, attention-related errors partially mediated the positive relationship between PRW and negative affect, even when controlling for pre-pandemic trait anxiety. Conclusion: PRW's relationship with negative affect was partially mediated through attentional function, consistent with models of anxiety and attentional control. In UK-based students PRW may be predominantly focused on the decline in QoL; therefore, interventions targeting worry about the decline in QoL caused by COVID-19 are especially important in this population in the wake of the pandemic. Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-022-10336-7.

Factorial validity, reliability, and measurement invariance of the Negative Physical Self Scale in a sample of men residing in North America.

The Negative Physical Self Scale (NPSS) is a measure of body dissatisfaction that was developed for administration within an Asian sample and has recently been translated to English and validated for use in North American female samples. The aim of the present study was to examine the factor structure and measurement invariance of the English-translated version of the NPSS across three ethnic groups (i.e., Caucasian, Asian, and other) using a sample of men residing in North America. Additionally, the internal consistency, convergent validity, and incremental validity of the NPSS were examined. A sample of 534 young (aged between 18 and 25) North American men completed self-report measures of the NPSS, the Body Shape Questionnaire, the Eating Disorder Examination Questionnaire, and the Male Body Attitudes Scale. Confirmatory factor analysis was conducted on two hypothesized models. The results supported the second-order factor structure (four factors with three subdimensions). Overall, we found that the factor structure and factor loadings of the NPSS were equal in participants across three broad ethnic categories (i.e., Caucasian, Asian, and other). Likewise, the NPSS displayed first-order scalar invariance. Further, the NPSS test scores demonstrated high internal consistency, strong convergent validity, and incremental validity over and above the existing measures of body dissatisfaction, body attitudes, and disordered eating. In sum, the English version of the NPSS is a valid and appropriate measure to assess body dissatisfaction in men residing in North America. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Association between proton pump inhibitor use and risk of pneumonia in children: nationwide self-controlled case series study in Sweden.

OBJECTIVE: To evaluate the association between use of proton pump inhibitors (PPIs) and risk of pneumonia in children. DESIGN: Nationwide register-based self-controlled case series study. SETTING: Sweden, July 2006 to December 2016. PARTICIPANTS: Children aged <18 years who were treated with PPIs and had a hospitalisation or hospital emergency care visit for pneumonia within 1 year before and 2 years after PPI initiation. MAIN OUTCOMES AND MEASURES: The primary analysis examined the risk of pneumonia during the risk period (ongoing PPI treatment), the pre-exposure period (≤30 days preceding PPI treatment) and the postexposure period (days 1-365 after PPI discontinuation), comparing to the unexposed period. Conditional Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% CIs. RESULTS: A total of 2356 cases of pneumonia were included. Compared with the unexposed period, the risk of pneumonia was significantly increased during ongoing PPI treatment, with an adjusted IRR of 1.40 (95% CI 1.21 to 1.62). The risk of pneumonia was also increased in the pre-exposure period (adjusted IRR, 1.80, 95% CI 1.51 to 2.13), but not in the postexposure period (adjusted IRR 0.98, 95% CI 0.89 to 1.08). Dividing the risk period by time since treatment initiation, the increased risk of pneumonia was highest in the first 30 days (adjusted IRR 1.63, 95% CI 1.35 to 1.97), remained during days 31-90 (adjusted IRR 1.32, 95% CI 1.04 to 1.69), but waned in days ≥91 (IRR 1.06, 95% CI 0.79 to 1.41). CONCLUSIONS AND RELEVANCE: An increased risk of pneumonia was observed both immediately before and immediately after PPI initiation. This pattern of association can likely be explained by an underlying risk of pneumonia due to factors transiently present at the time around PPI initiation. Thus, our findings do not support a causal relationship between PPI use and risk of pneumonia.

Proton pump inhibitor use and risk of depression and anxiety in children: nationwide cohort study.

Although some data have linked proton pump inhibitor (PPI) use to risk of depression and anxiety, there are no studies investigating this safety issue in children. This study investigated the association between PPI use and risk of depression and anxiety in children. We conducted a nationwide register-based cohort study in Sweden, July 1, 2007, to December 31, 2016. Following matching on age and propensity score, we included 29,320 pairs of PPI initiators and noninitiators among children aged 7-17 years old. The primary analysis examined the risk of incident depression and anxiety, a composite outcome defined as a diagnosis of depression, anxiety, or a prescription for an antidepressant. Children who initiated PPI use had higher hazards for risk of depression and anxiety compared with noninitiators (hazard ratios [HRs], 2.61; 95% confidence interval [CI], 2.32-2.94). In analyses of the timing of depression and anxiety onset after PPI initiation, the HRs were 3.71 (95% CI, 2.17-6.34) for 1-30 days, 3.47 (95% CI, 2.33-5.18) for 31-90 days, 2.71 (2.04-3.60) for 91-180 days, 2.52 (2.00-3.16) for 181-365 days, and 2.34 (1.94-2.82) for 366-730 days. Significant associations were observed across all age groups. The magnitude of the association increased with longer duration of PPI use (p for trend < 0.0001). The association was consistent through all sensitivity analyses, including high-dimensional propensity score matching (HR, 2.31, 95% CI, 2.05-2.61). PPI use was associated with increased risk of depression and anxiety in children. Further investigation is warranted to confirm or refute this potential association.

Gypenosides regulate autophagy through Sirt1 pathway and the anti-inflammatory mechanism of mitochondrial autophagy in systemic lupus erythematosus.

To study the mechanism of gynostemma pentaphyllum saponins (GpS) regulating mitochondrial autophagy and anti-inflammatory through Sirtuin 1 (Sirt1) pathway in systemic lupus erythematosus (SLE). JURKAT cells were cultured in vitro, RT-PCR and western blotting (WB) were utilized to identify the expression of related-proteins in Sirt1 pathway and global autophagy and mitochondrial autophagy markers in JURKAT before and after GpS treatment induced by ultraviolet B (UVB), and the related-mechanism of GpS regulation of autophagy was analyzed. The SLE model was established to analyze the alleviating effects of GpS on various symptoms of lupus mice. Sirt1/AMPK/mTOR pathway was activated in UVB induced JURKAT cells. After the addition of GpS, WB revealed that the phosphorylation of AMPK decreased, the phosphorylation of mTOR increased, the expression of Sirt1 protein decreased, and the activation of the pathway was inhibited. Moreover, autophagy of JURKAT cells wasinhibited. In order to further verify the role of Sirt1 pathway, we activated Sirt1 expression in cells by constructing lentiviral vectors, and the therapeutic effect of GpS was significantly reduced. These results indicate GpS can exert autophagy regulation by inhibiting the activity of Sirt1 pathway. To treat SLE. GpS can significantly reduce the level of autoantibodies, kidney inflammation, immune complex deposition and urinary protein excretion, improve kidney function in lupus-prone mice. GpS can regulate autophagy and mitochondrial autophagy through Sirt1 pathway, which may be a potential mechanism for GpS to reduce the level of autoantibodies, kidney inflammation, immune complex deposition and urinary protein excretion, improve kidney function in lupus-prone mice.

Association Between Proton Pump Inhibitor Use and Risk of Asthma in Children.

Importance: The use of proton pump inhibitors (PPIs) in children has increased substantially in recent years, concurrently with emerging concerns that these drugs may increase the risk of asthma. Whether PPI use in the broad pediatric population is associated with increased risk of asthma is not known. Objective: To investigate the association between PPI use and risk of asthma in children. Design, Setting, and Participants: This nationwide cohort study collected registry data in Sweden from January 1, 2007, to December 31, 2016. Children and adolescents 17 years or younger were matched by age and propensity score into 80 870 pairs of those who initiated PPI use and those who did not. Data were analyzed from February 1 to September 1, 2020. Exposures: Initiation of PPI use. Main Outcomes and Measures: The primary analysis examined the risk of incident asthma with a median follow-up to 3.0 (interquartile range, 2.1-3.0) years. Cox proportional hazards regression was used to estimate hazard ratios (HRs). Results: Among the 80 870 pairs (63.0% girls; mean [SD] age, 12.9 [4.8] years), those who initiated PPI use had a higher incidence rate of asthma (21.8 events per 1000 person-years) compared with noninitiators (14.0 events per 1000 person-years), with an HR of 1.57 (95% CI, 1.49-1.64). The risk of asthma was significantly increased across all age groups and was highest for infants and toddlers with an HR of 1.83 (95% CI, 1.65-2.03) in the group younger than 6 months and 1.91 (95% CI, 1.65-2.22) in the group 6 months to younger than 2 years (P < .001 for interaction). The HRs for individual PPIs were 1.64 (95% CI, 1.50-1.79) for esomeprazole, 1.49 (95% CI, 1.25-1.78) for lansoprazole, 1.43 (95% CI, 1.35-1.51) for omeprazole, and 2.33 (95% CI, 1.30-4.18) for pantoprazole. In analyses of the timing of asthma onset after PPI initiation, the HRs were 1.62 (95% CI, 1.42-1.85) for 0 to 90 days, 1.73 (95% CI, 1.52-1.98) for 91 to 180 days, and 1.53 (95% CI, 1.45-1.62) for 181 days to end of follow-up. The association was consistent through all sensitivity analyses, including high-dimensional propensity score matching (HR, 1.48; 95% CI, 1.41-1.55). Conclusions and Relevance: In this cohort study, initiation of PPI use compared with nonuse was associated with an increased risk of asthma in children. Proton pump inhibitors should be prescribed to children only when clearly indicated, weighing the potential benefit against potential harm.

Use of antidiabetic medications and risk of chronic obstructive pulmonary disease exacerbation requiring hospitalization: a disease risk score-matched nested case-control study.

BACKGROUND: Exacerbation of chronic obstructive pulmonary disease (COPD) severely impacts the quality of life and causes high mortality and morbidity. COPD is involved with systemic and pulmonary inflammation, which may be attenuated with antidiabetic agents exerting anti-inflammatory effects. Real-world evidence is scant regarding the effects of antidiabetic agents on COPD exacerbation. Accordingly, we conducted a disease risk score (DRS)-matched nested case-control study to systemically assess the association between each class of oral hypoglycemic agents (OHAs) and risk of severe COPD exacerbation in a nationwide COPD population co-diagnosed with diabetes mellitus (DM). METHODS: We enrolled 23,875 COPD patients receiving at least one OHA for management of DM by analyzing the Taiwan National Health Insurance claims database between January 1, 2000, and December 31, 2015. Cases of severe exacerbation were defined as those who had the first hospital admission for COPD. Each case was individually matched with four randomly-selected controls by cohort entry date, DRS (the estimated probability of encountering a severe COPD exacerbation), and COPD medication regimens using the incidence density sampling approach. Conditional logistic regressions were performed to estimate odds ratios (OR) of severe COPD exacerbation for each type of OHAs. RESULTS: We analyzed 2700 cases of severe COPD exacerbation and 9272 corresponding controls after DRS matching. Current use of metformin versus other OHAs was associated with a 15% (adjusted OR [aOR], 0.85; 95% confidence interval [CI] 0.75-0.95) reduced risk of severe COPD exacerbation, whereas the reduced risk was not observed with other types of antidiabetic agents. When considering the duration of antidiabetic medication therapy, current use of metformin for 91-180 and 181-365 days was associated with a 28% (aOR, 0.72; 95% CI 0.58-0.89) and 37% (aOR, 0.63; 95% CI 0.51-0.77) reduced risk of severe COPD exacerbation, respectively. Similarly, 91-180 days of sulfonylureas therapy led to a 28% (aOR, 0.72; 95% CI 0.58-0.90) lower risk, and longer treatments consistently yielded 24-30% lower risks. Current use of thiazolidinediones for more than 181 days yielded an approximately 40% decreased risk. CONCLUSIONS: Duration-dependent beneficial effects of current metformin, sulfonylurea, and thiazolidinedione use on severe COPD exacerbation were observed in patients with COPD and DM.

Use of antipsychotics and the risk of acute respiratory failure among adults: A disease risk score-matched nested case-control study.

AIMS: Evidence on acute respiratory failure (ARF) from antipsychotics is scant, and only 1 population-based study examined this drug safety issue in chronic obstructive pulmonary disease patients. Antipsychotics have been frequently prescribed off-label in adults, but whether antipsychotic use carries an increased ARF risk among adult patients is uncertain. METHODS: We adopted a nested case-control study analysing 716 493 adults aged ≥20 years, identified from the Taiwan nationwide healthcare claims records between January 2000 and December 2013. Among the study cohort, 7084 adults with ARF and 12,785 disease risk scored-matched randomly selected controls were analysed. Multivariable logistic regression models were employed to estimate odds ratios of ARF with antipsychotic usages. RESULTS: Current, recent, and recent past use of antipsychotics was associated with a 2.33-fold (95% confidence interval [CI] = 2.06-2.64), 1.79-fold (95% CI = 1.43-2.25) and 1.41-fold (95% CI = 1.20-1.66) increased risk of ARF, respectively, compared with nonuse, while antipsychotics discontinued >90 days carried no risk. A dose-dependent association was observed with current therapy of antipsychotics (test for trend, P < .001), in which antipsychotic use at >1 defined daily dose yielded the highest risk of 6.53-fold (95% CI = 3.33-12.79). The findings were robust to using carbamazepine as an active comparator. CONCLUSION: Antipsychotic use was associated with an increased risk of ARF in adult patients. The risk was dose-dependent and markedly higher with current use of antipsychotic agents at doses of 1 defined daily dose and above, <10% of this cohort. Physicians should be vigilant about any respiratory symptoms in patients currently receiving antipsychotics at such dose.

[Advances in the clinical research on acupuncture in treatment of respiratory diseases].

This article reviews the clinical studies on acupuncture in the treatment of asthma, chronic bronchitis, and acute exacerbation and stable phase of chronic obstructive pulmonary disease in China over the past 10 years, and the results suggest that acupuncture has a good clinical effect. At present, there are still several problems in related clinical studies, including lacking of standard operation procedure for acupuncture, unreasonable design of control group, and low quality of clinical research. Therefore, in the future, top-level design should be standardized and large-sample multicenter clinical studies should be conducted to provide stronger evidence of evidence-based medicine for acupuncture in the treatment of respiratory diseases.

Association Between Proton Pump Inhibitor Use and Risk of Fracture in Children.

Importance: Proton pump inhibitor (PPI) use has been linked to increased risk of fracture in adults. Despite a trend in prescription of PPIs in children, there is scarce evidence regarding this safety concern in pediatric patients. Objective: To evaluate the association between PPI use and risk of fracture in children. Design: This nationwide register-based cohort study included data from Sweden from July 2006 to December 2016. Children younger than 18 years who initiated PPI use were matched on propensity score and age with those who did not initiate PPI use. Exposure: Initiation of PPI use. Main Outcomes and Measures: Cox regression was adopted to estimate hazard ratios (HRs) for a first fracture of any type and 5 subtypes of fracture, with follow-up for up to 5 years. To address potential residual confounding, high-dimensional propensity score matching and a direct comparison with histamine-2 receptor antagonists were performed. Results: There were a total of 115 933 pairs of children included. During a mean (SD) of 2.2 (1.6) years of follow-up, 5354 and 4568 cases of any fracture occurred among those who initiated PPIs vs those who did not, respectively (20.2 vs 18.3 events per 1000 person-years; hazard ratio [HR], 1.11 [95% CI, 1.06-1.15]). Use of PPIs was associated with increased risk of upper-limb fracture (HR, 1.08 [95% CI, 1.03-1.13]), lower-limb fracture (HR, 1.19 [95% CI, 1.10-1.29]), and other fractures (HR, 1.51 [95% CI, 1.16-1.97]) but not head fracture (HR, 0.93 [95% CI, 0.76-1.13]) or spine fracture (HR, 1.31 [95% CI, 0.95-1.81]). The HRs for fracture according to cumulative duration of PPI use were 1.08 (95% CI, 1.03-1.13) for 30 days or less, 1.14 (95% CI, 1.09-1.20) for 31 to 364 days, and 1.34 (95% CI, 1.13-1.58) for 365 days or more. The association was consistent in most sensitivity analyses, including high-dimensional propensity score matching (HR, 1.10 [95% CI, 1.06-1.15]), although the analysis of PPI vs histamine-2 receptor antagonist did not reach statistical significance (HR, 1.06 [95% CI, 0.97-1.15]). Conclusions and Relevance: In this large pediatric cohort, PPI use was associated with a small but significant increased risk of any fracture. Risk of fracture should be taken into account when weighing the benefits and risks of PPI treatment in children.

Risk of Severe Cardiovascular Events From Add-On Tiotropium in Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To examine the risk of cardiovascular disease (CVD) from tiotropium added to inhaled long-acting ß2 agonists (LABAs) and inhaled corticosteroids (ICSs) in a nationwide population with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: This nested case-control study included 65,966 patients with COPD treated with LABAs and ICSs identified from the Taiwan nationwide health care claims database from January 1, 2007, through June 30, 2011. Cases were all patients with a first primary diagnosis of ischemic heart disease, heart failure, stroke, or arrhythmia from inpatient or emergency care settings during follow-up, and each was matched with 4 disease risk score-matched controls from risk sets. The use of tiotropium in the year before the index/event date was measured, stratified by duration since therapy initiation, concomitant COPD medications, and dosage form. Conditional logistic regression models were used to estimate odds ratios of the CVD risk from add-on tiotropium therapy. RESULTS: From the study cohort, with a mean age of 70.3 years (interquartile range, 61.8-79.4 years), 3188 CVD cases (incidence rate, 6.2 [95% CI, 6.0-6.4] cases per 100 person-years) and 12,349 matched controls were identified. The new use of tiotropium was associated with a 1.88-fold (95% CI, 1.44-2.46) increased CVD risk within 30 days of therapy initiation, and the association was sustained up to 60 days after treatment initiation (adjusted odds ratio, 1.71; 95% CI, 1.08-2.70). The risk persisted across all tiotropium regimens, with a case-crossover analysis, and in comparison with new add-on theophylline therapy. CONCLUSION: Tiotropium newly added to LABA/ICS combination therapy was associated with an increased cardiovascular risk in patients with COPD.

Association of Cardiovascular Risk With Inhaled Long-Acting Bronchodilators in Patients With Chronic Obstructive Pulmonary Disease: A Nested Case-Control Study.

Importance: The associations between cardiovascular disease (CVD) and inhaled long-acting ß2-agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) in chronic obstructive pulmonary disease (COPD) are greatly debated. Pivotal and relevant randomized clinical trials included prior LABA or LAMA users and excluded patients with baseline CVD; therefore, cardiovascular events arising from first-time LABA or LAMA use, if any, could not be observed. There is an urgent need to examine whether new use of and duration since initiating LABAs and LAMAs could act as important determinants of cardiovascular events. Objective: To investigate risk of CVD associated with LABAs and LAMAs, focusing on the initiation and duration of LABA and LAMA therapies. Design, Setting, and Participants: This nested case-control study included 284 220 LABA-LAMA-naïve patients with COPD at least 40 years old (mean age, 71.4 years; 68.9% men), retrieved from the Taiwan National Health Insurance Research Database for health care claims from 2007 to 2011. Exposure: LABA or LAMA use was measured in the year preceding the event or index date, stratified by duration since initiation of LABA or LAMA treatment, new and prevalent users, concomitant COPD medications, and individual agents. Main Outcomes and Measures: Cases with inpatient or emergency care visits for coronary artery disease, heart failure, ischemic stroke, or arrhythmia were identified and individually matched to 4 randomly selected controls. Conditional logistic regressions were performed to estimate odds ratios of CVD from LABA and LAMA treatment. Results: During a mean follow-up of 2.0 years, 37 719 patients with CVD (mean age, 75.6 years; 71.6% men) and 146 139 matched controls (mean age, 75.2 years; 70.1% men) were identified. New LABA and LAMA use in COPD was associated with a 1.50-fold (95% CI, 1.35-1.67; P < .001) and a 1.52-fold (95% CI, 1.28-1.80; P < .001) increased cardiovascular risk within 30 days of initiation, respectively, whereas the risk was absent, or even reduced with prevalent use. Individual LABA agents, LAMA dosage forms, and concomitant COPD regimens did not differ in the CVD risks. The risk persisted in an alternative case-crossover study and remained across subgroups without CVD history or prior exacerbations. Conclusions and Relevance: New initiation of LABAs or LAMAs in patients with COPD is associated with an approximate 1.5-fold increased severe cardiovascular risk, irrespective of prior CVD status and history of exacerbations.

Benzodiazepine and Z-drug use and risk of pneumonia in patients with chronic kidney disease: A population-based nested case-control study.

BACKGROUND: Concerns were raised about pneumonia development from benzodiazepines (BZDs) and Z-drugs, but direct evidence is limited, conflicting and without examining the highly susceptible patients with chronic kidney disease (CKD) nor specifying the risk for different drug utilizations. This study aimed to investigate whether use of BZDs and Z-drugs was each associated with an increased risk of pneumonia in a CKD population. METHODS: We performed a nested case-control study of 36,880 CKD patients analyzing the Taiwan National Health Insurance Database between 01/1/2000 and 12/31/2011. Among the study cohort, we identified 4,533 cases of pneumonia based on validated disease codes, chest x-ray examination, and prescriptions of respiratory antibiotics, and randomly selected 16,388 controls from risk sets, matched by sex, age, and number of CKD-related hospitalizations. All prescription filling records of BZDs and Z-drugs in the year before the event/index date were analyzed for cases and controls. Conditional logistic regressions were performed to estimate the odds ratios (ORs). RESULTS: Current use of BZDs was associated with a 1.31-fold (95% CI, 1.18-1.26) increased risk of pneumonia compared to nonuse, but not for recent and past use. The risk from current BZD use was confined to new initiation (adjusted OR, 2.47; 95% CI, 2.02-3.03) or use for ≤ 30 days, and elevated to 2.88-fold (95% CI, 1.87-4.42) with parenteral administration. New initiation and current short-term use of Z-drugs was associated with a 2.94-fold (95% CI, 1.65-5.26) and 1.75-fold (95% CI, 1.13-2.72) increased risk of pneumonia, respectively. The findings were robust to adoption of a case-crossover study that analyzed cases only. CONCLUSIONS: Use of BZRAs is associated with an increased risk of pneumonia in CKD patients, especially for patients newly initiating BZDs or Z-drugs or those injected with BZDs. Physicians should exercise cautions for signs of pneumonia when prescribing BZDs or Z-drugs to CKD patients.

Association between leukoaraiosis and hemorrhagic transformation after cardioembolic stroke due to atrial fibrillation and/or rheumatic heart disease.

Cardioembolic stroke due to atrial fibrillation (AF) and/or rheumatic heart disease (RHD) often involves hemorrhagic transformation (HT), and we examined whether leukoaraiosis (LA) was associated with HT in these cases. We prospectively enrolled 251 patients who were admitted to two hospitals within one month of experiencing cardioembolic stroke due to AF/RHD. LA severity was assessed using three visual rating scales. HT was identified in 99 patients (39.4%) based on baseline computed tomography (CT) and post-admission magnetic resonance imaging or second CT. Univariate analysis identified risk of HT as higher in the presence of frontal LA based on the age-related white matter changes scale and in the presence of anterior LA based on the VSS scale. Multivariate analysis confirmed that moderate to severe LA was independently associated with higher HT risk. Of the various sites affected in LA, frontal LA correlated with highest risk of HT (OR 3.199, 95%CI 1.555-6.580). These results suggest that moderate to severe LA, especially at periventricular and anterior sites, is associated with HT after cardioembolic stroke due to AF/RHD. These findings suggest the need to take LA into account as a HT risk factor when considering the use of anticoagulation and thrombolysis in these patients.