A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome.

BACKGROUND: Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive. METHODS: A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques. RESULTS: The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics. CONCLUSIONS: These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.

Influence of host-guest interactions on analytical performance of direct analysis in real-time mass spectrometry.

To systematically study the influence of host-guest interactions on the analytical performance of direct analysis in real time mass spectrometry (DART-MS), the interactions between cyclodextrins (CDs) and different Sudan dyes were investigated. The results showed that the host-guest interaction between CDs and Sudan dyes did not affect qualitative analysis of the target compounds, but led to a lower signal intensity for Sudan dyes, thus affecting quantitative analysis of the target compounds. The stronger the host-guest interaction, the weaker the signal intensity of target compound on DART-MS. The results also show that both in solution and in solid-phase microextraction (SPME), the addition of organic solvents can weaken the host-guest interaction between CDs and Sudan dyes, thus improving the signal intensity in DART-MS. In SPME, adding organic solvents has a certain practical value and can improve the efficiency of Sudan dye analysis. This study suggests that appropriate sample pretreatment is needed to weaken noncovalent interactions prior to DART-MS analysis to obtain more accurate quantitative results. The data provide some insight into the effects of other noncovalent interactions on the efficiency of DART-MS as an analytical tool, as well as the potential to study intermolecular interactions with DART-MS.

Longitudinal change in lung function and subsequent risks of cardiovascular events: evidence from four prospective cohort studies.

BACKGROUND: Lung function is constantly changing over the life course. Although the relation of cross-sectional lung function measure and adverse outcomes has been reported, data on longitudinal change and subsequent cardiovascular (CV) events risks are scarce. Therefore, this study is to determine the association of longitudinal change in lung function and subsequent cardiovascular risks. METHODS: This study analyzed the data from four prospective cohorts. Subjects with at least two lung function tests were included. We calculated the rate of forced respiratory volume in 1 s (FEV1) and forced vital capacity (FVC) decline for each subject and categorized them into quartiles. The primary outcome was CV events, defined as a composite of coronary heart disease (CHD), chronic heart failure (CHF), stroke, and any CV death. Cox proportional hazards regression and restricted cubic spline models were applied. RESULTS: The final sample comprised 12,899 participants (mean age 48.58 years; 43.61% male). Following an average of 14.79 (10.69) years, 3950 CV events occurred. Compared with the highest FEV1 quartile (Q4), the multivariable HRs for the lowest (Q1), 2nd (Q2), and 3rd quartiles (Q3) were 1.33 (95%CI 1.19, 1.49), 1.30 (1.16, 1.46), and 1.07 (0.95, 1.21), respectively. Likewise, compared with the reference quartile (Q4), the group that experienced a faster decline in FVC had higher HRs for CV events (1.06 [95%CI 0.94-1.20] for Q3, 1.15 [1.02-1.30] for Q2, and 1.28 [1.14-1.44] for Q1). The association remained robust across a series of sensitivity analyses and nearly all subgroups but was more evident in subjects < 60 years. CONCLUSIONS: We observed a monotonic increase in risks of CV events with a faster decline in FEV1 and FVC. These findings emphasize the value of periodic evaluation of lung function and open new opportunities for disease prevention.

Dispersive Magnetic Solid-Phase Extraction Coupled to Direct Analysis in Real Time Mass Spectrometry for High-Throughput Analysis of Trace Environmental Contaminants.

Coupling dispersive magnetic solid-phase extraction (DMSPE) to direct analysis in real time mass spectrometry (DART-MS) with a newly developed metal iron probe enables high-throughput, sensitive detection of herbicides such as triazine in environmental waters. Magnetic graphene oxide was used as a dispersive sorbent because it increased adsorption capacity in the DMSPE process. The planar structure and excellent thermal conductivity of graphene oxide facilitated the desorption and ionization of target analytes in DART-MS analysis. The iron probe, which is designed to fit into the moving trail of the DART interface, served as the sorbent collector as well as the support for the magnetic graphene oxide after DMSPE, and was put directly into the DART system. The ratio of magnetic core to graphene oxide in the nanoparticles and other key parameters in DMSPE and DART-MS procedures were systematically investigated and optimized. In addition, the presence of water on the sorbent proves to have a significant effect on DART-MS analysis. No organic solvents are used in this method, and the reusable iron probe is of low cost. Under the optimal conditions, limits of detection were found in the range of 1.6-152.1 ng/L for the triazines. Recovery and reproducibility were found to be in the ranges of 87.5-115.0% and 1.9-10.2%, respectively, for the six herbicides studied. The analytical performance of the DMSPE-DART-MS method indicated that applications for trace analysis of other compounds in liquid samples are also possible.

Direct Analysis in Real Time Mass Spectrometry for Characterization of Large Saccharides.

Polysaccharide characterization posts the most difficult challenge to available analytical technologies compared to other types of biomolecules. Plant polysaccharides are reported to have numerous medicinal values, but their effect can be different based on the types of plants, and even regions of productions and conditions of cultivation. However, the molecular basis of the differences of these polysaccharides is largely unknown. In this study, direct analysis in real time mass spectrometry (DART-MS) was used to generate polysaccharide fingerprints. Large saccharides can break down into characteristic small fragments in the DART source via pyrolysis, and the products are then detected by high resolution MS. Temperature was shown to be a crucial parameter for the decomposition of large polysaccharide. The general behavior of carbohydrates in DART-MS was also studied through the investigation of a number of mono- and oligosaccharide standards. The chemical formula and putative ionic forms of the fragments were proposed based on accurate mass with less than 10 ppm mass errors. Multivariate data analysis shows the clear differentiation of different plant species. Intensities of marker ions compared among samples also showed obvious differences. The combination of DART-MS analysis and mechanochemical extraction method used in this work demonstrates a simple, fast, and high throughput analytical protocol for the efficient evaluation of molecular features in plant polysaccharides.

High-Throughput Analysis for Artemisinins with Deep Eutectic Solvents Mechanochemical Extraction and Direct Analysis in Real Time Mass Spectrometry.

A fast, simple, efficient, and high-throughput analytical protocol using deep eutectic solvents (DES) for mechanochemical extraction (MCE) combined with direct analysis in real time mass spectrometry (DART-MS) was developed to quantify heat-labile bioactive compounds artemisinin (AN), arteannuin B, and artemisinic acid from Aretemisia annua. MCE is performed at room temperature, and target analytes are released into DESs within seconds; this method demonstrated multiple advantages over traditional extraction methods and organic solvents. DART-MS was then used for the structure confirmation and quantification for the three artemisinin major components extracted from plants of five locations. Liquid chromatography (LC) measurements were performed as well for results verification and comparison, and the amounts obtained were consistent between the two techniques. DART-MS showed advantages in simplicity, low limit of detection (5-15 ng mL-1), and superior speed (10-20 s), but with slightly higher relative standard deviation (0.7-10.8%). The entire protocol can be accomplished in a few minutes from raw materials to quantitative results. This study aims to establish a methodology combining high-efficiency sample pretreatment and rapid chemical analysis from complex matrixes, where the time-consuming separation procedure can be eliminated. Additionally, the use of toxic organic solvents needed in the process of chemical extraction and analysis is largely avoided. In general, this investigation provides a robust analytical procedure that can be widely used in many areas of research and industrial activities.

Application of magnetic graphitic carbon nitride nanocomposites for the solid-phase extraction of phthalate esters in water samples.

Magnetic graphitic carbon nitride nanocomposites were successfully prepared in situ and used to develop a highly sensitive magnetic solid-phase extraction method for the preconcentration of phthalate esters such as di-n-butyl phthalate, butyl phthalate, dihexyl phthalate, and di-(2-ethyl hexyl) phthalate from water. The adsorption and desorption of the phthalate esters on magnetic graphitic carbon nitride nanocomposites were investigated and the parameters affecting the partition of the phthalate esters, such as adsorption, desorption, recovery, were assessed. Under the optimized conditions, the proposed method showed excellent sensitivity with limits of detection (S/N = 3) in the range of 0.05-0.1 µg/L and precision in the range of 1.1-2.6% (n = 5). This method was successfully applied to the analysis of real water samples, and good spiked recoveries over the range of 79.4-99.4% were obtained. This research provides a possibility to apply this nanocomposite for adsorption, preconcentration, or even removal of various carbon-based ring or hydrophobic pollutants.

Facile synthesis of poly(ionic liquid)-bonded magnetic nanospheres as a high-performance sorbent for the pretreatment and determination of phenolic compounds in water samples.

Poly(ionic liquid)-bonded magnetic nanospheres were easily synthesized and applied to the pretreatment and determination of phenolic compounds in water samples, which have detrimental effects on water quality and the health of living beings. The high affinity of poly(ionic liquid)s toward the target compounds as well as the magnetic behavior of Fe3 O4 were combined in this material to provide an efficient and simple magnetic solid-phase extraction approach. The adsorption behavior of the poly(ionic liquid)-bonded magnetic nanospheres was examined to optimize the synthesis. Different parameters affecting the magnetic solid-phase extraction of phenolic compounds were assessed in terms of adsorption and recovery. Under the optimal conditions, the proposed method showed excellent detection sensitivity with limits of detection in the range of 0.3-0.8 ng/mL and precision in the range of 1.2-3.3%. This method was also applied successfully to the analysis of real water samples; good spiked recoveries over the range of 82.5-99.2% were obtained.

Polyhydroxy glucose functionalized silica for the dehydration of bio-ethanol distillate.

Although most of the water in a bio-ethanol fermentation broth can be removed by distillation, a small amount of water remains in the bio-ethanol distillate as the water-ethanol azeotrope. To improve the use of ethanol as a fuel, glucose-modified silica, as an adsorbent, was prepared using a facile method and applied to the dehydration of bio-ethanol distillate. The factors affecting the adsorption capacity of the adsorbent, such as the particle size, initial concentration of water in the samples, adsorption temperature and adsorbent dose, were examined by measuring the adsorption kinetics and equilibrium. The Langmuir, Freundlich and Temkin isotherms were used to evaluate the adsorption efficiency. Of these, the Freundlich and Temkin isotherms showed a good correlation with the experimental data. The Langmuir isotherm showed some deviation from the experimental results, and indicated that adsorption in this case was not a simple monolayer adsorption. The property of the adsorbent was attributed to functionalized silica with many hydroxyl groups on its surface. An examination of the separation factors of water/ethanol revealed the modified silica to have preferential selectivity for water. Compared to activated carbon and silica, glucose-modified silica exhibited higher adsorption capacity for water under the same adsorption conditions. In addition, the glucose-modified silica adsorbent exhibited a relatively constant adsorption capacity for five adsorption/desorption cycles.

Strategies for using magnetic beads in enhanced deep eutectic solvent-mechanochemical extraction of natural products from orange peels.

To address the challenges of low recovery, prolonged extraction times, and environmental pollution caused by toxic solvents in traditional extraction methods, magnetic bead-enhanced deep eutectic solvent mechanochemical extraction was developed for extracting natural products from orange peels. The extraction efficiencies of deep eutectic solvents were experimentally evaluated, and theoretical methods were used to guide solvent selection. Choline chloride-ethylene glycol demonstrated the highest efficiency under the optimal extraction conditions: a molar ratio of 1:2, no water content, a solid-liquid ratio of 0.08 g/mL, and an extraction time of 60 s. The synergy between the deep eutectic solvent and magnetic bead-enhanced the mechanochemical extraction efficiencies. The study also examined the effects of different magnetic bead types and orange peel powder particle sizes on extraction efficiency, finding that a 0.11 mm particle size combined with CIP@SiO2 yielded the best results. Overall, this study holds promise as an environmentally friendly and efficient extraction method.

Eco-friendly regeneration of lignin with acidic deep eutectic solvent for adsorption of pollutant dyes for water cleanup.

In this study, a simple and eco-friendly method was used to treat alkaline lignin with an acidic deep eutectic solvent (DES) to obtain regenerated lignin for the efficient adsorption of pollutant dyes from aqueous environment. Based on the yield and adsorption capacity of the sorbent for these dyes, conditions such as the type and concentration of DES component, solid-to-liquid ratio, reaction time, and temperature were optimized. By characterizing and comparing alkali lignin with regenerated lignin, a series of reactions were demonstrated to occur during the DES treatment process. The performance and mechanism of methylene blue and rhodamine B adsorption on regenerated lignin were studied systematically, and the maximum adsorbed amounts were 348.29 and 551.05 mg/g at 323 K, respectively. This study provides a new strategy for the green preparation of functionalized lignin and its use in the water pollutant treatment.

Application of anion-exchange imidazolium silica for the multiphase dispersive extraction of phenolic acids.

This paper reports the application of a multiphase dispersive extraction method to the extraction, separation, and determination of the phenolic acids from Salicornia herbacea L. using silica-confined ionic liquids as sorbents. A suitable sorbent for phenolic acid extraction and separation was first identified based on the adsorption behavior of the phenolic acids on different silica-confined ionic liquids. The sample was then mixed with the optimized sorbent and solvent to achieve multiphase dispersive extraction. The sample/sorbent ratio was optimized using theoretical calculations from the adsorption isotherm and experiments. After transferring the supernatant to an empty cartridge, an SPE process was used to separate the three phenolic acids from the other interference. Through systematic optimization, the optimal conditions produced high recovery rates of protocatechuic acid (91.20%), caffeic acid (94.03%), and ferulic acid (91.33%). Overall, the proposed method is expected to have wide applicability.

Adsorption of alcohol from water by poly(ionic liquid)s.

Bioethanol is used widely as a solvent and is considered a potential liquid fuel. Ethanol can be produced from biomass by fermentation, which results in low concentrations of alcohol in water. Conventional distillation is normally used to separate ethanol from water, but it required high energy consumption. Therefore, alternative approaches to this separation are being pursued. This study examined the potential use of poly(ionic liquid)s (PILs) for the extraction and separation of alcohols from the aqueous phase. Hydrophobic PILs were developed and evaluated by the adsorption of ethanol from ethanol/water solutions. All the necessary parameters, such as cations and anions of the ionic liquid, morphology of the polymer and processing conditions, were evaluated.

Multi-phase extraction of glycoraphanin from broccoli using aminium ionic liquid-based silica.

INTRODUCTION: Glucosinolates, a class of phytochemicals found in broccoli, have attracted recent interest due to the potential health benefits associated with their dietary intake. Glucoraphanin, the most common glucosinolate in broccoli can be converted to a known cancer chemopreventive agent. Multi-phase extraction in solid-phase extraction cartridges was developed to simultaneously extract and separate this compound. OBJECTIVE: Multi-phase extraction with functionalised ionic liquid-based silica as a sorbent was used to simultaneously extract and separate glucoraphanin from broccoli. METHODOLOGY: The sorbent and broccoli sample were packed into a single cartridge, and a fixed volume of water was then used to extract and remove the target compound from the sample to the sorbent over 15 repetitions. The sorbent was then washed with n-hexane to remove any interference and the target compound was eluted with water-1% acetic acid (vol.). RESULTS: Under the optimised condition, 0.038 mg/g of glucoraphanin was obtained by multi-phase extraction with 0.2 g of sorbent. CONCLUSION: The adsorption isotherm allowed investigation of the interactions between the sorbent and target compound and provided evidence for the accuracy of this method. The low deviation error, small amount of solvents required, highly selective separation and stability of the method justify further research.

[Synthesis of porous organic framework materials based on deep eutectic solvents and their application in solid-phase extraction].

This paper reviews the application of deep eutectic solvents (DESs) in the synthesis of metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) as well as their prospects in the field of solid-phase extraction (SPE). Porous organic frameworks (POFs) have unique properties such as a large specific surface area, high porosity, and easy modification. Thus, these materials are widely applied in the fields of catalysis, adsorption, drug delivery, gas storage, and separation. POFs include MOFs, COFs, conjugated microporous polymers (CMPs), porous aromatic frameworks (PAFs), and covalent triazine frameworks (CTFs). MOFs are constructed from metal ions/clusters and organic ligands through coordination bonds and can be extended in two or three dimensions by repeated coordination with potential voids. COFs are formed from two monomers containing light elements (such as carbon, hydrogen, oxygen, nitrogen, boron, and other elements) via coordination bonds and have large two- or three-dimensional structures. However, conventional POF synthesis methods generally suffer from disadvantages such as long synthesis times, high temperature and pressure requirements, and the use of toxic and hazardous reaction solvents. DES consists of a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD) bound by hydrogen-bonding interactions. It is a promising green solvent for material synthesis owing to its low vapor pressure, high stability, and ease of preparation. DES can be used to prepare MOFs and COFs and, in specific cases, acts as a structure-directing agent, which has an important impact on the structure and properties of the resulting frameworks. Using appropriate DES formulations, researchers can modulate the crystal structures, pore sizes, and surface properties of MOFs and COFs, resulting in materials with excellent characteristics. SPE is an analytical technique in which a sample solution is added to an SPE column; the sample solution is forced through the stationary phase, and the target compounds are collected for analysis by elution with an organic solvent. Therefore, suitable stationary-phase materials are critical for SPE. Owing to their large specific surface areas and abundant active sites, MOFs and COFs exhibit outstanding adsorption capacity and selectivity in SPE and can effectively enrich target analytes from complex samples. DES-based MOFs and COFs have shown potential use in a wide range of applications, such as in environmental analysis, food testing, and biological sample analysis. Although DES-based MOFs and COFs for SPE are still in the early stages of development, their properties such as efficient enrichment and high selectivity offer good prospects for practical applications. Future research should continue to explore DES-based synthesis methods in depth to prepare other MOFs and COFs with the desired properties and investigate their potential applications in various fields. These efforts are expected to apply these novel materials in commercialized solid-phase extraction methods, bringing new development opportunities in the field of analytical chemistry.

Plant polysaccharide itself as hydrogen bond donor in a deep eutectic system-based mechanochemical extraction method.

A deep eutectic system (DESys) is formed when a hydrogen bond acceptor (HBA) is processed with polysaccharide (hydrogen bond donor, HBD) containing plant substance in water to dissolve, extract, and recover the polysaccharide directly, instead of using a traditional deep eutectic solvent (DES). The extraction efficiency is enhanced by the direct formation of the DESys, in a mechanochemical extraction (MCE) system. Key factors affecting the extraction efficiency were systematically studied and optimized. The effects of the DESys on the structure and physicochemical properties of polysaccharides were studied by several analytical techniques. The findings demonstrated that the direct DESys formation extraction efficiency was superior than that of traditional extraction methods while retaining physicochemical properties of polysaccharides. Moreover, the composition of polysaccharides extracted with this method is different from that obtained by conventional methods. The recovery and purification process of polysaccharides is simplified by eliminating the need for an additional HBD.

Ionic liquid as hydrogen bond acceptor in the extraction of nutritional natural products.

In-depth studies of the extraction mechanism using deep eutectic solvents (DES), especially extraction through the formation of a deep eutectic system (DESys), revealed commonalities between the DES- and ionic liquids (IL)-based extraction systems. New applications of ILs and DES for extraction of nutritional natural products were presented. In this study, the extraction behavior of choline chloride (ChCl) and 1-(2-hydroxyethyl)-3-methylimidazolium chloride ([HMIm][Cl]) in DES and IL, respectively, in mechanochemical extraction of target compounds from Moringa oleifera leaves was systematically studied. The results suggested that both extraction methods were based on the formation of a DESys, either a normal DESys or an IL DESys. Considering the DESys-based one-step extraction improves the extraction efficiency and reduces the preparation time, the same idea can be used in IL for performance improvement. By formation of a new IL deep eutectic system based on hydrogen bond interaction in extraction, similar improvement was obtained.

Preparation of carbon-rich material from Dendrobium officinale polysaccharide in deep eutectic system.

A carbon-rich material (DESysChar) was prepared from polysaccharide within a deep eutectic system (DESys) containing oxalic acid, and systematically characterized using various analytical techniques. The investigation of reaction mechanism revealed concurrent dehydration and etherification processes. This study commenced with the extraction of plant polysaccharide using the DESys-based mechanochemical extraction method from Dendrobium officinale. Subsequently, the DESys method was used to carbonize the extracted Dendrobium officinale polysaccharide and produce DESysChar. DESysChar was then used for the adsorption and determination of pollutants in water. This study represents a significant advancement in eco-friendly material synthesis, enabling the low-temperature (120 °C) carbonization of plant-derived polysaccharides, thereby reducing energy consumption and environmental impact. The effective adsorption of methylene blue by DESysChar underscores its potential in environmental remediation. This study presents a more responsible and efficient approach to polysaccharide extraction and carbonization, addressing environmental concerns. Embracing the 4S workflow (involving Sustainable raw materials converted into Sustainable degradable products, by using Sustainable technology throughout the process to create a Sustainable environment) promotes sustainability in material development, laying the foundation for future eco-friendly practices in various industries. In summary, this study propels sustainable polysaccharide development for widespread use.

Systolic Blood Pressure and Cardiovascular Risk in Normotensive Adults.

OBJECTIVE: To examine the association of systolic blood pressure (SBP) and cardiovascular risk in normotensive adults. PATIENTS AND METHODS: This study analyzed data from 7 prospective cohorts between September 29, 1948, and December 31, 2018. Complete information on history of hypertension and baseline blood pressure measurements were required for inclusion. We excluded individuals younger than 18 years old, those with a history of hypertension, and patients with baseline SBP measurements of less than 90 mm Hg or 140 mm Hg or higher. Cox proportional hazards regression and restricted cubic spline models were used to evaluate the hazards of cardiovascular outcomes. RESULTS: A total of 31,033 participants were included. The mean ± SD age was 45.3±14.8 years, 16,693 of the participants (53.8%) were female, and the mean ± SD SBP was 115.8±11.7. Over a median follow-up of 23.5 years, 7005 cardiovascular events occurred. Compared with those who had SBP levels of 90 to 99 mm Hg, participants with SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg experienced 23% (hazard ratio [HR], 1.23; 95% CI, 1.07 to 1.42), 53% (HR, 1.53; 95% CI, 1.33 to 1.76), 87% (HR, 1.87; 95% CI, 1.62 to 2.16), and 117% (HR, 2.17; 95% CI, 1.87 to 2.52) increased risks of cardiovascular events, respectively. Compared with follow-up SBP of 90 to 99 mm Hg, the HRs for cardiovascular events were 1.25 (95% CI, 1.02 to 1.54), 1.93 (95% CI, 1.58 to 2.34), 2.55 (95% CI, 2.09 to 3.10), and 3.39 (95% CI, 2.78 to 4.14), respectively, for follow-up SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg. CONCLUSION: In adults without hypertension, there is a stepwise increase in risk of cardiovascular events, with increasing SBP starting at levels as low as 90 mm Hg.

Administration of macrolide antibiotics increases cardiovascular risk.

Background: The increased risk of cardiovascular events in patients prescribed macrolides has been subject to debate for decades. Methods: Medline, EMBASE databases and ClinicalTrials.gov were searched from inception until August 31, 2022 for studies investigating the link between macrolides and cardiovascular risk. A meta-analysis was performed using a random-effects model. Results: A total of 80 studies involving 39,374,874 patients were included. No association was found between macrolides and all-cause death. However, compared with the non-macrolide group, macrolides were associated with a significantly increased risk of ventricular arrhythmia or sudden cardiac death (VA or SCD) (azithromycin, relative ratio [RR]: 1.53; 95% confidence interval [CI]: 1.19 to 1.97; clarithromycin, RR: 1.52; 95% CI: 1.07 to 2.16). Besides, administration of macrolides was associated with a higher risk of cardiovascular disease (CVD) death (azithromycin, RR: 1.63; 95% CI: 1.17 to 2.27) and a slightly increased risk of myocardial infarction (MI) (azithromycin, RR: 1.08; 95% CI: 1.02 to 1.15). Interestingly, no association was observed between roxithromycin and adverse cardiac outcomes. Increased risk of VA or SCD was observed for recent or current use of macrolides, MI for former use, and CVD death for current use. Conclusion: Administration of macrolide antibiotics and timing of macrolide use are associated with increased risk for SCD or VTA and cardiovascular death, but not all-cause death.