Bioinformatic and functional analysis of OsDHN2 under cadmium stress.

As a toxic heavy metal, cadmium (Cd) is one of the principal pollutants influencing rice productivity and food security. Despite several studies, the underlying mechanism of Cd response in plants remains largely unclear. Dehydrins are part of the late embryogenesis abundant (LEA) family which protect plants against abiotic stresses. In this study, a Cd-responsive LEA gene, OsDHN2, was functionally characterized. The chromosome localization results indicated that OsDHN2 was located on chromosome 2 of rice. Meanwhile, cis-acting elements, such as MBS (MYB binding site involved in drought-inducibility), ARE (anaerobic induction), and ABRE (abscisic acid), were present in the OsDHN2 promoter region. Expression pattern analysis also showed that OsDHN2 expression was induced in both roots and shoots under Cd stress. Overexpression of OsDHN2 improved Cd tolerance and reduced Cd concentration in yeast. Moreover, increased expression levels of SOD1, CTA1, GSH1, or CTT1 were found in transgenic yeast under Cd stress, suggesting the increased antioxidant enzymatic activities. These results suggested that OsDHN2 is a Cd-responsive gene that has the potential to improve resistance to Cd in rice.

Cubane-type tungsten-iron-sulfur clusters with a nitrogen atom in the core: terminal ligand substitutions and redox behaviors.

The lack of M-Fe-S (M = Mo or W) clusters incorporating a second period (2p) atom in the core has resulted in limited investigations and poor understanding of the physical and chemical properties of the M-Fe-S clusters closely related to the FeMo cofactor. In this work, systematic studies have been carried out to explore the chemical reactivities at the terminal ligand sites and the redox properties of a series of clusters comprising a [WFe3S3N] cubane core, based on the previously developed cluster [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]1-. Substitutions of the terminal chlorides with ethanethiolate, methanethiolate, thiophenolate, p-thiocresolate and azide occurred smoothly, while the replacement of the chlorides with carbene ligands required the reduction of the precursor into [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]2- first. The reduced cluster core could also be supported by thiophenolates as terminal ligands, but not thiolates or azides. It is remarkable that the thiophenolate ligated reduced cluster can be synthesized from the precursor [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]1-via different synthetic routes, either reduction followed by substitution or substitution followed by reduction, either in situ or stepwise. This work indicates that terminal ligands contribute significantly to determine the chemical and physical properties of the clusters, even though they might affect the cluster core to a limited extent from a structural point of view, which raises the possibility of delicate control in regulating the physical/chemical properties of M-Fe-S clusters with a heteroleptic core incorporating 2p atom(s).

Comparison of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel High- vs Low-Affinity Sulfonylureas and Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With Metformin.

Importance: Sulfonylureas are frequently used as add-on to metformin in type 2 diabetes (T2D), and individual sulfonylurea agents carry different risks of cardiovascular disease. Sulfonylureas' different affinities to cardiac mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels have been speculated to account for the intraclass difference in cardiovascular risk from in vitro and ex vivo studies; however, this hypothesis has not been assessed in a general population with diabetes receiving sulfonylureas added to metformin. Objective: To compare the risk of myocardial infarction (MI), ischemic stroke, or cardiovascular death in patients with T2D treated with mitoKATP channel high-affinity sulfonylureas and low-affinity sulfonylureas as add-on to metformin. Design, Setting, and Participants: This is a new-user, active-comparator, and propensity score-matched cohort study with analysis of the Taiwanese Diabetes Mellitus Health Database from 2006, to 2017. Data analysis was performed from August 2020 to July 2021. Exposures: Cardiac mitoKATP channel high-affinity (glyburide and glipizide) and low-affinity (gliclazide and glimepiride) sulfonylureas combined with metformin. Main Outcomes and Measures: Primary outcome was major adverse cardiovascular events (MACEs), a composite of cardiovascular death or hospitalization for either MI or ischemic stroke. Secondary outcomes included individual MACE components, heart failure, arrhythmia, all-cause mortality, and severe hypoglycemia. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs). Results: Each sulfonylurea group comprised 53 714 patients (mean [SD] age, 54.7 [12.1] years; 31 962 men [59.5%]). MitoKATP channel high-affinity sulfonylureas vs low-affinity sulfonylureas when combined with metformin were associated with an increased risk of MACE (aHR, 1.18; 95% CI, 1.03-1.34), MI (aHR, 1.34; 95% CI, 1.04-1.73), all-cause mortality (aHR, 1.27; 95% CI, 1.03-1.57), and severe hypoglycemia (aHR, 1.82; 95% CI, 1.58-2.10), but not with increased risks of ischemic stroke, cardiovascular death, arrhythmia, and heart failure. The duration analyses revealed the highest MACE risk during 1 to 90 days after initiation of mitoKATP channel high-affinity sulfonylureas (aHR, 6.06; 95% CI, 4.86-7.55). Conclusions and Relevance: Use of mitoKATP channel high-affinity sulfonylureas vs low-affinity sulfonylureas was associated with an increased MACE risk in patients with T2D concomitantly receiving metformin, suggesting that high-affinity blockage of the mitoKATP channels could account for sulfonylurea-associated MACEs.

Associations of Naturally Occurring Antibodies to Presenilin-1 with Brain Amyloid-ß Load and Cognitive Impairment in Alzheimer's Disease.

BACKGROUND: Imbalance between the production and clearance of amyloid-ß (Aß) promotes the development of Alzheimer's disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aß production. The profiles of autoantibodies are dysregulated in AD patients. OBJECTIVE: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD. METHODS: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma. RESULTS: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aß load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%. CONCLUSION: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD.

Association Between Specificity of Sulfonylureas to Cardiac Mitochondrial KATP Channels and the Risk of Major Adverse Cardiovascular Events in Type 2 Diabetes.

OBJECTIVE: Previous studies have revealed an intraclass difference in major adverse cardiovascular events (MACE) among sulfonylureas. In vitro and ex vivo studies reported several sulfonylureas to exhibit high-affinity blockage of cardiac mitochondrial ATP-sensitive potassium (mitoKATP) channels and could interfere with ischemic preconditioning, the most important mechanism of self-cardiac protection. However, no studies have examined whether these varying binding affinities of sulfonylureas could account for their intraclass difference in MACE. We compared mitoKATP channel high-affinity versus low-affinity sulfonylureas regarding the MACE risk in real-world settings. RESEARCH DESIGN AND METHODS: Using the Taiwan nationwide health care claims database, patients with type 2 diabetes initiating sulfonylurea monotherapy between 2007 and 2016 were included in the cohort study. A total of 33,727 new mitoKATP channel high-affinity (glyburide and glipizide) and low-affinity (gliclazide and glimepiride) sulfonylurea users, respectively, were identified after 1:1 propensity score matching. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs) and 95% CI. RESULTS: MitoKATP channel high-affinity sulfonylureas were associated with a significantly increased risk of three-point MACE (aHR 1.21 [95% CI 1.03-1.44]), ischemic stroke (aHR 1.23 [95% CI 1.02-1.50]), and cardiovascular death (aHR 2.61 [95% CI 1.31-5.20]), but not with that of myocardial infarction (aHR 1.04 [95% CI 0.75-1.46]). The duration-response analyses revealed the highest MACE risk to be within 90 days of therapy (aHR 4.67 [95% CI 3.61-6.06]). CONCLUSIONS: Cardiac mitoKATP channel high-affinity sulfonylureas were associated with an increased MACE risk compared with low-affinity sulfonylureas in a nationwide population with diabetes.

Status and prospects of the application of root exudates in the restoration of polluted or desertated soil.

Ecological and environmental problems including heavy metal pollution have received increasing concerns. Given the shortage of physical and chemical remediation methods in high cost and secondary pollution, using plants and microorganisms for joint remediation of environment has become one of the most important strategies. Root exudates are an important medium for information and nutrient exchange between plants and soil. The roles of plant root exudates in remediation of polluted and degradated soil have been widely studied. In this review, we described the composition, secretion mechanism and functions of root exudates and summarized the functions of root exudate in heavy metal absorption, allelopathy, interaction between roots and rhizosphere microorga-nisms, and changes in soil physical and chemical properties. The progress, challenges and prospect of applying root exdudates and rhizosphere microorganisms in the remediation of ecology and environment have also been discussed. This review could provide theoretical support for the application of plant-microorganism based environmental remediation.

Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting ß2-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting ß2-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study.

BACKGROUND: Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting ß2-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects. RESEARCH QUESTION: Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD? STUDY DESIGN AND METHODS: We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vs three commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively. RESULTS: Patients with COPD initiating IND/GLY and VI/UMEC showed an 11% (incidence rate ratio [IRR], 0.89; 95% CI, 0.80-0.98) and 20% (IRR, 0.80; 95% CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vs FF/BDP, were associated with a 27% (hazard ratio [HR], 0.73; 95% CI, 0.59-0.90) to 42% (HR, 0.58; 95% CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs. INTERPRETATION: Both LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.

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.

Risk of severe hypoglycemic events from amiodarone-sulfonylureas interactions: A population-based nested case-control study.

PURPOSE: To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. METHODS: We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). RESULTS: We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). CONCLUSIONS: Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.

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.

Risk of adverse cardiovascular events with use of inhaled long-acting bronchodilators in management of chronic obstructive pulmonary disease.

Inhaled long-acting bronchodilators, including long-acting ß2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the mainstay therapy in the treatment of chronic obstructive pulmonary disease (COPD), a disease that poses a heavy burden on morbidity and mortality worldwide. Use of LABAs and LAMAs in patients with COPD, however, has been concerned about an increased risk of adverse cardiovascular events, despite inconsistent findings reported from randomized controlled trials (RCTs) and observational studies. In this review, we detailed the relevant evidence generated from RCTs and observational studies with respect to the risk of cardiovascular disease with use of LABAs and LAMAs in management of COPD, and analyzed the contradictory findings in the literature, as well as recommended future research directions to clear the air regarding the cardiovascular safety of inhaled long-acting bronchodilators.

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 Antipsychotic Agents and Risk of Acute Respiratory Failure in Patients With Chronic Obstructive Pulmonary Disease.

Importance: Acute respiratory failure (ARF) is a life-threatening event that has been linked in case reports to antipsychotic use, but this association lacks population-based evidence. Particular attention should be focused on patients with chronic obstructive pulmonary disease (COPD) regarding this drug safety concern because these patients are prone to ARF and are commonly treated with antipsychotics. Objective: To determine whether the use of antipsychotics is associated with an increased risk of ARF in patients with COPD. Design, Setting, and Participants: A population-based case-crossover study analyzing the Taiwan National Health Insurance Research Database was conducted of all patients with COPD, who were newly diagnosed with ARF in hospital or emergency care settings necessitating intubation or mechanical ventilation from January 1, 2000, to December 31, 2011. Patients with prior ARF, lung cancer, and cardiogenic, traumatic, or septic ARF were excluded to analyze idiopathic ARF. The pilot study was conducted from November 1 to December 31, 2013, and full data analysis was performed from October 15, 2015, to November 8, 2016. Exposures: The use of antipsychotics was self-compared during days 1 to 14 (the risk period according to previous case reports) and days 75 to 88 (control period) preceding the ARF event or index date. The antipsychotic class, route of administration, and dose were also examined. Main Outcomes and Measures: Risk of ARF. Results: There were 5032 patients with ARF (mean [SD] age, 74.4 [9.9] years; 3533 males [70.2%]) among the 61 620 patients with COPD. Five hundred ninety patients with ARF (11.7%) filled at least 1 antipsychotic prescription during the case period compared with 443 (8.8%) during the control period, corresponding to a 1.66-fold (95% CI, 1.34-2.05; P < .001) adjusted increased risk of ARF regardless of antipsychotic class and administration route. A dose-dependent risk of ARF associated with antipsychotics was identified (test for trend, adjusted odds ratio, 1.35; 95% CI, 1.19-1.52; P < .001), which increased from a 1.52-fold risk for a low daily dose (95% CI, 1.20-1.92; P < .001) to a 3.74-fold risk for a high dose (95% CI, 1.68-8.36; P = .001). The increased risk persisted under a case-time-control analysis (adjusted odds ratio, 1.62; 95% CI, 1.16-2.27; P = .005) and nested case-control study (adjusted odds ratio, 2.16; 95% CI, 1.91-2.15; P < .001). Conclusions and Relevance: Antipsychotic use is associated with an acute and dose-dependent increased risk of ARF in patients with COPD. Clinicians should exercise caution when prescribing antipsychotics to patients with COPD and avoid high doses if possible.

Therapeutic potential of naringin: an overview.

CONTEXT: Naringin is a natural flavanone glycoside that is found in the Chinese herbal medicines and citrus fruits. Studies have demonstrated that naringin possesses numerous biological and pharmacological properties, but few reviews of these studies have been performed. OBJECTIVE: The present review gathers the fragmented information available in the literature describing the extraction of naringin, its pharmacology and its controlled release formulations. Current research progress and the therapeutic potential of naringin are also discussed. METHODS: A literature survey for relevant information regarding the biological and pharmacological properties of naringin was conducted using Pubmed, Sciencedirect, MEDLINE, Springerlink and Google Scholar electronic databases from the year 2007-2015. RESULTS: Naringin modulates signalling pathways and interacts with signalling molecules and thus has a wide range of pharmacological activities, including anti-inflammatory, anti-cancer activities, as well as effects on bone regeneration, metabolic syndrome, oxidative stress, genetic damage and central nervous system (CNS) diseases. Information was gathered that showed the extraction of naringin can be improved using several modifications. There has been some progress in the development of controlled release formulations of naringin. CONCLUSION: Naringin is a promising candidate for further in vivo studies and clinical use. More detailed studies regarding its mechanism of action are required.

Use of antipsychotics and risk of venous thromboembolism in postmenopausal women. A population-based nested case-control study.

Despite continued uncertainty of venous thromboembolism (VTE) caused from antipsychotic agents, this safety issue has not been examined in postmenopausal women, a population with high usages of antipsychotics and at high risk for VTE. We assessed whether antipsychotic use was associated with an increased VTE risk in women after menopause. We conducted a nested case-control study of all Taiwanese women aged ≥ 50 years (n = 316,132) using a nationwide healthcare claims database between 2000 and 2011. All newly diagnosed VTE patients treated with an anticoagulant or thrombectomy surgery were identified as cases (n = 2,520) and individually matched to select controls (n = 24,223) by cohort entry date, age, cancer diagnosis and major surgery procedure. The odds ratios (ORs) and 95 % confidence interval (CI) of VTE associated with antipsychotics were estimated by multivariate conditional logistic regressions. Current use of antipsychotics was associated with a 1.90-fold (95 % CI = 1.64-2.19) increased VTE risk compared with nonuse in postmenopausal women. The VTE risk existed in a dose-dependent fashion (test for trend, p<0.001), with a more than quadrupled risk for high-dose antipsychotics (adjusted OR = 4.60; 95 % CI = 2.88-7.33). Current parenteral administration of antipsychotics also led to a 3.46-fold increased risk (95 % CI = 2.39-5.00). Conversely, there was no increased VTE risk when antipsychotics were discontinued for > 30 days. In conclusion, current use of antipsychotics is significantly associated with a dose-dependent increased risk of VTE in postmenopausal women, especially for those currently taking high-dose or receiving parenteral antipsychotics.

Antidepressant use and risk of recurrent stroke: a population-based nested case-control study.

OBJECTIVE: Antidepressants may carry an increased risk for incident stroke, but there is little safety evidence regarding poststroke antidepressant use. This study aimed to examine whether antidepressants are associated with an increased risk of stroke recurrence. METHOD: A population-based nested case-control study was conducted analyzing the Taiwan universal health care claims database from January 1, 2000, to December 31, 2008. We followed up 19,825 patients who survived a first admission for stroke at the age of ≥ 18 years, among which 3,536 hospitalized cases with stroke recurrence (ICD-9-CM codes 430.xx-437.xx) were identified and individually matched to 6,679 randomly-selected controls. Multivariate conditional logistic regression models were used to characterize the risk associated with antidepressant use. RESULTS: The study cohort had a mean age of 66 years and was followed up for a median of 2.9 person-years. Use of any tricyclic antidepressants (TCAs) was associated with a 1.41-fold (95% CI, 1.19-1.67) increased risk of stroke recurrence, whereas any use of selective serotonin reuptake inhibitors (SSRIs) or other antidepressants showed no association. Stopping TCAs for 1-30 days was associated with a 1.87-fold (95% CI, 1.22-2.86) increased risk of stroke recurrence, and the risk was attenuated for a longer discontinuation. The stroke risk associated with TCA use was not present in a dose-dependent or duration-dependent manner. CONCLUSIONS: Use of TCAs, but not SSRIs or other antidepressants, was associated with an increased risk of stroke recurrence. The risk is particularly elevated with abrupt cessation of TCA therapy. Health care professionals should be vigilant to that risk during TCA therapy in poststroke patients.

Antimicrobial effects of a bioactive glass combined with fluoride or triclosan on Streptococcus mutans biofilm.

OBJECTIVE: The objective of this study was to investigate the antibacterial effects on a cariogenic biofilm of a bioactive glass (BAG) combined with either sodium fluoride (NaF) or triclosan (TCS). DESIGN: According to minimal bactericidal concentrations, 37.5mg/ml of BAG, 4.69 mg/ml of NaF, and 15.53 µg/ml of TCS solutions were prepared. When used alone, the three antimicrobial solutions were increased to double-dosage strength (2 MBC). The study contained the following experimental groups: group 1, BAG (2 MBC); group 2, NaF (2 MBC); group 3, TCS (2 MBC); group 4, BAG+NaF; group 5, BAG+TCS; group 6, control (saline). Streptococcus mutans biofilm was cultured with 0.1% sucrose anaerobically on 66 sterilized coverslips (1 × 1 cm(2)) for 24h uninterrupted. After 10 min of exposure to the experimental groups, the microbial kinetics, morphology, and viability of the S. mutans biofilms were assessed by evaluation of colony-forming units (CFUs), scanning electron microscopy (SEM), and confocal laser scanning microscopy (CLSM). RESULTS: BAG (2 MBC) used alone showed significantly stronger antibacterial effects than the other two antimicrobials used alone. The combination groups also displayed the same or greater biofilm inactivation effects as BAG (2 MBC) in the plate count test. SEM showed smaller stacks (towers) and fewer surrounding bacteria in groups BAG (2 MBC), BAG+NaF, and BAG+TCS. Confocal microscopy also determined higher live/dead ratios in groups NaF (2 MBC), TCS (2 MBC), and control than in groups BAG (2 MBC), BAG+NaF, and BAG+TCS. CONCLUSIONS: The combinations of BAG with either NaF or TCS enhanced the inactivation effects of BAG (2 MBC) on S. mutans biofilm, and these findings should be further investigated clinically for the control of dental biofilms.