Spatiotemporal patterns of leaf nutrients of wild apples in a wild fruit forest plot in the Ili Valley, China.

Malus sieversii, commonly known as wild apples, represents a Tertiary relict plant species and serves as the progenitor of globally cultivated apple varieties. Unfortunately, wild apple populations are facing significant degradation in localized areas due to a myriad of factors. To gain a comprehensive understanding of the nutrient status and spatiotemporal variations of M. sieversii, green leaves were collected in May and July, and the fallen leaves were collected in October. The concentrations of leaf nitrogen (N), phosphorus (P), and potassium (K) were measured, and the stoichiometric ratios as well as nutrient resorption efficiencies were calculated. The study also explored the relative contributions of soil, topographic, and biotic factors to the variation in nutrient traits. The results indicate that as the growing period progressed, the concentrations of N and P in the leaves significantly decreased (P < 0.05), and the concentration of K in October was significantly lower than in May and July. Throughout plant growth, leaf N-P and N-K exhibited hyperallometric relationships, while P-K showed an isometric relationship. Resorption efficiency followed the order of N < P < K (P < 0.05), with all three ratios being less than 1; this indicates that the order of nutrient limitation is K > P > N. The resorption efficiencies were mainly regulated by nutrient concentrations in fallen leaves. A robust spatial dependence was observed in leaf nutrient concentrations during all periods (70.1-97.9% for structural variation), highlighting that structural variation, rather than random factors, dominated the spatial variation. Nutrient resorption efficiencies (NRE, PRE, and KRE) displayed moderate structural variation (30.2-66.8%). The spatial patterns of nutrient traits varied across growth periods, indicating they are influenced by multifactorial elements (in which, soil property showed the highest influence). In conclusion, wild apples manifested differentiated spatiotemporal variability and influencing factors across various leaf nutrient traits. These results provide crucial insights into the spatiotemporal patterns and influencing factors of leaf nutrient traits of M. sieversii at the permanent plot scale for the first time. This work is of great significance for the ecosystem restoration and sustainable management of degrading wild fruit forests.

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.

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.

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.

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.

Gastro-oesophageal reflux disease increases the risk of intensive care unit admittance and mechanical ventilation use among patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study.

INTRODUCTION: Gastro-oesophageal reflux disease (GORD) is common among chronic obstructive pulmonary disease (COPD) patients and may have a deleterious effect on COPD prognosis. However, few studies have investigated whether GORD increases the risk of severe outcomes such as intensive care unit (ICU) admittance or mechanical ventilator use among COPD patients. METHODS: Propensity score matching by age, sex, comorbidities and COPD severity was used to match the 1,210 COPD patients with GORD sourced in this study to 2,420 COPD patients without GORD. The Kaplan-Meier method was used to explore the incidence of ICU admittance and machine ventilation with the log rank test being used to test for differences. Cox regression analysis was used to explore the risk of ICU admittance and mechanical ventilation use for patients with and without GORD. RESULTS: During the 12-month follow-up, GORD patients and non-GORD patients had 5.22 and 3.01 ICU admittances per 1000 person-months, and 4.34 and 2.41 mechanical ventilation uses per 1000 person-month, respectively. The log rank test revealed a difference in the incidence of ICU admittance and machine ventilation between the two cohorts. GORD was found to be an independent predicator of ICU admittance (adjusted hazard ratio (HRadj) 1.75, 95% confidence interval (CI) 1.28-2.38) and mechanical ventilation (HRadj 1.92, 95% CI 1.35-2.72). CONCLUSION: This is the first investigation to detect a significantly higher incidence rate and independently increased risk of admission to an ICU and mechanical ventilation use among COPD patients who subsequently developed GORD during the first year following their GORD diagnosis than COPD patients who did not develop GORD.

Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study.

AIMS: The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner. METHODS: We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively. RESULTS: The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person-years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22). CONCLUSIONS: MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis.

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).

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.

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.

Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.

Empirical data regarding the choice of antipsychotics for the management of psychosis in patients with Parkinson's disease are limited. This study aimed to evaluate the incidence and prescribing patterns of antipsychotics and to determine the predictors associated with the prescribing of typical antipsychotics in patients with Parkinson's disease. This was a retrospective cohort study analyzing data from the National Health Insurance Research Database in Taiwan between January 1, 2000, and December 31, 2006, in which patients with Parkinson's disease (ICD-9-CM codes 332) initially receiving any antiparkinsonian drug (n = 2095) were followed up to evaluate the subsequent use of antipsychotics. Kaplan-Meier statistics and multiple logistic regression were employed to evaluate the cumulative probability of antipsychotic use and determinants of prescribing of typical antipsychotics, respectively. The cumulative probability of initiation of an antipsychotic within 6 years was found to be 51%, and the proportion of patients who began taking an atypical antipsychotic increased from 11.1% in 2001 to 36.1% in 2005. Physician specialty was found to be the most influential predictor of the prescribing of typical antipsychotics: physicians with an internal medicine specialty were 10.62 times more likely (95% confidence interval, 4.64-24.32) to prescribe typical antipsychotics than were neurologists. The use of antipsychotics in Parkinson's disease is common, and the use of typical antipsychotics dominates antipsychotic treatment. Particular attention needs to be paid to improving practice, including efforts that encourage primary care providers to have the appropriate choice of antipsychotics in patients with Parkinson's disease.

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.

Risk of digoxin intoxication in heart failure patients exposed to digoxin-diuretic interactions: a population-based study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Increased frequency of electrolyte abnormalities and cardiac arrhythmias among patients exposed to digoxin-diuretic interactions has been well-documented in numerous descriptive studies. * Nonetheless, a clear causal relationship has not been established in these studies. WHAT THIS STUDY ADDS * The risks of digoxin intoxication associated with use of digoxin in combination with any diuretic use, types of diuretics, combinations of diuretics, and individual diuretics were quantified using a population-based nested case-control study design. * The combined therapy of digoxin with any diuretic is associated with a 3.08-fold increase in the risk of digoxin intoxication. * Regarding diuretic class, the risk carried by loop diuretics is greater than that of thiazides or potassium-sparing diuretics, and the risk varies with different combinations of diuretic classes and individual diuretics. AIMS To quantify the digoxin intoxication risk associated with exposure to digoxin-diuretic interactions, and evaluate whether the risk varies by diuretic type, individually or in combination. METHODS This was a population-based nested case-control study in which data from the National Health Insurance Research Database (NHIRD) in Taiwan were analysed. RESULTS The study cohort comprised 154 058 heart failure (HF) patients taking digoxin between 2001 and 2004, in whom digoxin intoxication requiring a hospitalization (ICD-9 code 972.1) occurred in 595 cases. A total of 28 243 matched controls were also selected for analysis. Cases were 3.08 times (adjusted OR 3.08, 95% CI 2.50, 3.79) more likely to have been prescribed diuretic medication in the previous month than controls. Regarding the class of diuretics, loop diuretics carried the greatest risk (adjusted OR 2.97, 95% CI 2.35, 3.75), followed by thiazides (OR 2.36, 95% CI 1.70, 3.29) and potassium-sparing diuretics (OR 1.72, 95% CI 0.83, 3.56). The risk was also observed to vary with different combinations of diuretics, and the loops/thiazides/potassium-sparing diuretics combination carried the greatest risk (adjusted OR 6.85, 95% CI 4.93, 9.53). Among the individual diuretics examined, hydrochlorothiazide carried the greatest risk (adjusted OR 4.63, 95% CI 2.50, 8.57). CONCLUSIONS This study provided empirical evidence that digoxin-diuretic interactions increased the risk of hospitalization for digoxin intoxication in HF patients. The risk was particularly high for concomitant use of digoxin with a combination of loop diuretics, thiazide and potassium-sparing diuretics. The combined use of digoxin and diuretics should be avoided if possible.

Risk of digoxin intoxication caused by clarithromycin-digoxin interactions in heart failure patients: a population-based study.

OBJECTIVE: To quantify the effect of exposures to digoxin­clarithromycin interactions on the risk of digoxin toxicity requiring hospitalizations in a population-based manner in a Taiwanese population. METHODS: This is a retrospective population-based nested case­control study. Data were retrieved from the National Health Insurance Research Database. Heart failure (HF) patients newly treated with digoxin between 1 January 2001 and 31 December 2004 were retrieved from the database as the study cohort. Case patients, admitted to the hospitals with the diagnosis of digoxin intoxication (ICD-9 code 972.1) were identified from the study cohort and compared with the matched controls for the receipt of clarithromycin. RESULTS: A total of 154,058 patients were identified as the study cohort; from these, 595 cases and 27,020 matched controls were selected for study. The prescription of clarithromycin at 7, 14, and 30 days prior to the index date was associated with a 4.36- (95% CI 1.28­14.79), 5.07- (95% CI 2.36­10.89), and 2.98-fold (95% CI 1.59­5.63) increase in hospitalization for digoxin intoxication, respectively. The results of the dose­response relationship also indicated that clarithromycin prescribed with a prescribed daily dose (PDD)/defined daily dose (DDD) ratio >2 led to a 55.41-fold (95% CI 9.31­329.9) increase of the risk, which is significantly greater than that prescribed with a 1­2 PDD/DDD ratio (adjusted OR 4.81; 95% CI 1.88­12.30) or with a <1 PDD/DDD ratio (adjusted OR 0.78; 95% CI 0.19­3.20). CONCLUSION: This study provides empirical evidence that digoxin­clarithromycin interactions do increase the risk of hospitalization for digoxin intoxication in HF patients and that this risk could reach as high as 55.4-fold. We strongly recommend that the combined use of digoxin with clarithromycin should be avoided and that digoxin concentrations should be monitored closely in situations where the combination can not be avoided.

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.

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.

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.