A dynamical measure of the black hole mass in a quasar 11 billion years ago.

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH)1-3. These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase4-6. A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8-12 billion years ago (redshifts 1-3)7. Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-µas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 108 solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 1011 solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems.

Increased risk of haematological malignancy in adults over age 60 with thrombocytopenia compared with matched controls: Time for an upfront bone marrow evaluation?

International societies have conflicting recommendations on whether bone marrow aspirate/biopsy (BMB) is needed during workup for isolated thrombocytopenia. Our objective was to determine if thrombocytopenia in patients aged ≥60 years is associated with an increased incidence of haematological malignancy. We performed a retrospective population-based cohort study in patients aged ≥60 years between January 1, 2009 to December 31, 2019. Exposed patients had specialist consultation for thrombocytopenia, with platelet count <100 × 109/L, but normal haemoglobin and white blood cell count. Unexposed patients were those who never had specialist consultation for thrombocytopenia and whose platelets were ≥100 × 109/L. The primary outcome was the diagnosis of haematological malignancy using a competing risk of death model. During 4.0 years (IQR 2.2-6.7) of follow-up, 378/4930 exposed (19.1/1000PY, 95% CI 17.1-21.0), and 204/17556 unexposed patients (2.5/1000PY, 95% CI 2.2-2.8) were diagnosed with haematological malignancy (HR 15.5 (95% CI 11.3-21.4, p < 0.0001) in year 1, and 5.3 (95% CI 4.4-6.6, p < 0.0001) in years 2+). This finding persisted in analyses stratified by sex, age, severity, or duration of thrombocytopenia, and treatment with corticosteroids within 2 weeks of consultation. This study found a strong association between isolated thrombocytopenia and haematological malignancy in patients ≥60 years, supporting consideration of diagnostic testing including BMB during outpatient specialist consultation.

Technical and economic performance favours fully automated climate control broiler housing.

1. This study compared two broiler housing models with different technologies (conventional versus fully automated climate control) to verify their performance and carcass characteristics at slaughter, as well as the economics of production.2. A database regarding 20 443 flocks of heavy broilers produced in an integrated operation during the years 2020 and 2021, in eight Brazilian regions was used in the analysis. The dependent variables included feed conversion, average live weight gain, total and partial carcass condemnation and the total mortality. For economic analysis, the production cost of each technology including feed, labour, energy, heating and depreciation was calculated.3. The technology used in the broiler houses had a significant effect on the technical indicators which were positive for fully automated climate control in most geographical regions. One important exception was the effect on total and partial carcass condemnations, with better results seen for conventional housing. The total cost per ton of broiler meat delivered, deducting condemnation losses, was lower in the automated climate controlled housing compared to conventional housing.4. In conclusion, there was a reduction in broiler chicken production costs for birds raised in fully automated climate controlled housing, indicating better economic results for this model in Brazil.

Impact of Extracellular DNA on Architectural Parameters of Leptospira biflexa Biofilm.

Extracellular DNA (eDNA) is a major component of bacterial biofilms. In this study, we performed a three-dimensional analysis of Leptospira biofilm using advanced imaging by confocal laser scanning microscopy (CLSM) and multi-parameter analysis by COMSTAT 2 software, with quantification of Leptospira and eDNA fluorescence. To investigate the role of eDNA in Leptospira biofilm, we treated Leptospira biflexa biofilms with DNase I enzyme (DNase), which digested eDNA, and compared DNase treated biofilms and controls. There was a significant reduction of the biomass of biofilms treated with DNase, by spectrophotometry and COMSTAT analysis. The multiparameter analysis evidenced for DNase-treated biofilms a significant decrease in the surface area and the average thickness; opposing to a significant augmentation of the surface/biovolume ratio and the roughness coefficient (Ra*), when compared to controls. We analyzed the parameters of DNase-treated biofilms by Pearson's correlation coefficient and found significant positive correlations between biomass and average thickness; biomass and surface area; surface area and average thickness. On the other hand, there were significant negative correlations between Ra* and biomass; Ra* and average thickness; Ra* and surface area. These findings suggest that eDNA digestion results in biofilm instability and alteration of the three-dimensional architecture, justifying the negative correlation between Ra* and the above-mentioned parameters. In conclusion, our study showed that eDNA digestion produced a massive structural loss, instability, and dramatic changes in the three-dimensional architecture of Leptospira biflexa biofilm. These findings contribute to a better understanding of the role of eDNA and highlight the importance of eDNA as a key component in Leptospira biofilms.

Intra-articular leflunomide-loaded poly(ε-caprolactone) implants to treat synovitis in rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune pathology that manifests as chronic inflammatory arthropathy and synovitis. Treatment of rheumatoid arthritis is based on the administration of different types of drugs, including leflunomide, an antirheumatic drug. However, the long-term systemic use of leflunomide may be associated with adverse effects. Local therapy could be an efficient strategy to treat synovitis triggered by rheumatoid arthritis without inducing adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) implants (leflunomide PCL implants) were evaluated as local drug delivery systems capable of attenuating inflammation and angiogenesis, which represent events of synovitis. Leflunomide PCL implants were designed by hot molding technique; and they were characterized by FTIR and DSC. These analytical techniques demonstrated the chemical integrity and dispersion of drug into the polymeric chains. Then, a spectrophometric method was developed and validated to quantify the leflunomide incorporated into the PCL implants and released from them. Linearity was obtained by ordinary least squares regression method to estimate the linear regression equation. Residues were evaluated considering normality, independence and homoscedasticity. Precision was lower than 5 %, and accuracy ranged from 98 to 104.5 %. Quantitation limit was 2.0 µg mL-1. PCL implants provided controlled and sustained release of leflunomide for 30 consecutive days after inserting these systems in the subcutaneous tissue of mice. The main mechanisms of drug delivery were solubilization and diffusion from polymer. Then, a non-biocompatible sponge was inserted into the subcutaneous tissue of mice to function as a frame to develop the inflammatory and angiogenic processes. Leflunomide PCL implants were inserted in direct contact with the sponge. At 4, 7 and 10 days after-sponge implantation, the key components of inflammatory angiogenesis were measured to verify the regression of these events induced by drug. Leflunomide controlled released from polymeric implants downregulated the neutrophil and monocyte/macrophage infiltration due to the reduced expression of myeloperoxidase (MPO) and N-acetyl-ß-d-glucosaminidase (NAG), respectively. As the influx of these pro-inflammatory cells was modulated by leflunomide, the production of nitric oxide (NO), a pro-inflammatory substance, reached low concentrations in the sponge. As a consequence of the modulation of inflammation at the pathological site, the angiogenic process was downregulated, since the hemoglobin levels in the sponge were drastically reduced. The accumulation of leflunomide in the pathological site did not induce nephrotoxicity or hepatototoxicity, as confirmed by histological analyses. Finally, intra-articular leflunomide PCL implants represent a potential therapeutic alternative to treat locally the synovitis triggered by rheumatoid arthritis without inducing systemic adverse effects.

ESCRT: nipping the wound in the bud?

Rapid repair of plasma membrane wounds is critical for cellular survival. Exocytic patches, membrane tension reduction and endocytosis were previously proposed to mediate resealing. A recent study implicating the ESCRT complex adds to the growing evidence that repair involves removal of damaged plasma membrane, and not simply patching the wound.

Resemblance in physical activity levels: The Portuguese sibling study on growth, fitness, lifestyle, and health.

OBJECTIVES: To investigate the relationships of biological, behavioral, familial, and environmental characteristics with siblings´ physical activity (PA) levels as well as the intrapair resemblance in PA. METHODS: The sample comprises 834 (390 females) biological siblings [brother-brother (BB), sister-sister (SS), brother-sister (BS)] aged 9 to 20 years. Total PA index (TPAI) was estimated by questionnaire. Information on potential behavioral, familial, and environmental correlates was obtained by self-report; body mass index (BMI), biological maturation, and physical fitness were measured. Multilevel models were used to analyze siblings´ clustered data, and sibling resemblance was estimated with the intraclass correlation (ρ). RESULTS: On average, younger sibs, those more physically fit, and those with more parental support had greater TPAI. Further, BB pairs had higher TPAI levels than SS or BS pairs, but also had greater within-pair variance. When adjusted for all covariates, SS pairs demonstrated greater resemblance in TPAI (ρ = 0.53, 95%CI = 0.38-0.68) than BS (ρ = 0.26, 95%CI = 0.14-0.43) or BB pairs (ρ = 0.18, 95%CI = 0.06-0.44). CONCLUSIONS: Age, physical fitness, and parental support were the best predictors of TPAI levels. A moderate level of resemblance in TPAI was observed in SS pairs, while lower resemblance was found for BS and BB pairs. These findings may be due to differences in the roles of shared genetic factors, familial, and environmental characteristics across different sibling types.

Modeling children's development in gross motor coordination reveals key modifiable determinants. An allometric approach.

Children change their body size, shape, and gross motor coordination (GMC) as they grow. Further, GMC is expected to link to changes in children's body size, physical activity (PA), and physical fitness (PF). The objective was to model GMC changes in children followed longitudinally and to investigate associations between these changes and PA and PF levels. A total of 245 children (122 girls) were observed at 6 years of age and followed annually until 9 years. A sequence of allometric models was fitted, that is, 1. body mass, stature, and PA; 2. addition of four PF tests; 3. addition of four more PF tests. In Model 1, changes in GMC are nonlinear, and body mass (-0.60 ± 0.07, P < .001) and stature (2.91 ± 0.35, P < .001) parameter estimates were significant suggesting children with a more linear body size/shape showed higher GMC performances. Girls tend to outperform boys across time, and PA was not associated with GMC changes. Model 2 fitted the data better, and the PF tests (handgrip, standing long jump, 50-yard dash, and shuttle run) were significantly linked to GMC change. In Model 3, adding the remaining PF tests did not change the order of any factors importance. The greatest GMC changes were achieved by children whose body size/shape has an ectomorphic dominance across the years. Considering that leaner and physically fitter children tended to be more coordinated, physical education should also focus on PF development in components related to muscular strength, speed, agility, and aerobic capacity, along with nutritional education to reduce fat mass.

Above the fray: Surface remodeling by secreted lysosomal enzymes leads to endocytosis-mediated plasma membrane repair.

The study of plasma membrane repair is coming of age. Mirroring human adolescence, the field shows at the same time signs of maturity and significant uncertainty, confusion and skepticism. Here we discuss concepts that emerged from experimental data over the years, some of which are solidly established while others are still subject to different interpretations. The firmly established concepts include the critical requirement for Ca(2+) in wound repair, and the role of rapid exocytosis of intracellular vesicles. Lysosomes are being increasingly recognized as the major vesicles involved in injury-induced exocytosis in many cell types, as a growing number of laboratories detect markers for these organelles on the cell surface and lysosomal hydrolases in the supernatant of wounded cells. The more recent observation of massive endocytosis following Ca(2+)-triggered exocytosis initially came as a surprise, but this finding is also being increasingly reported by different groups, shifting the discussion to the mechanisms by which endocytosis promotes repair, and whether it operates or not in parallel with the shedding of membrane blebs. We discuss how the abundant intracellular vesicles that undergo homotypic fusion close to wound sites, previously interpreted as exocytic membrane patches, actually acquire extracellular tracers demonstrating their endocytic origin. We also suggest that an initial, temporary patch that prevents cytosol loss until the bilayer is restored might result not from vesicular fusion, but from rapid Ca(2+)-dependent crosslinking and aggregation of cytosolic proteins. Finally, we propose that cell surface remodeling, orchestrated by the extracellular release of lysosomal hydrolases and perhaps also cytosolic molecules, may represent a key aspect of the plasma membrane repair mechanism that has received little attention so far.

Correlates of children's compliance with moderate-to-vigorous physical activity recommendations: a multilevel analysis.

This study aimed to investigate the association between individual and school characteristics associated with the number of school days children comply with moderate-to-vigorous physical activity (MVPA) recommendations. Sample comprises 612 Portuguese children, aged 9-11 years, from 23 schools. Time spent in MVPA was measured by accelerometry, while individual-level correlates were obtained by anthropometry and questionnaires. School-level variables were collected by questionnaire, and accelerometer wear time and season were also considered. Maximum likelihood estimates of model parameters were obtained via a multilevel analysis with children as level-1, and school as level-2. Children who spent more time in sedentary activities and girls were less likely to comply with MVPA/daily. More mature children and those who use active transportation to school were more likely to attain the PA recommendation. Furthermore, greater accelerometer wear time and spring season increased the chance to achieve the recommended MVPA. In terms of school-level correlates, a greater number of available facilities was negatively associated with children MVPA compliance. Given the set of variables, our results showed that individual characteristics seem to be more relevant for children's compliance rates with PA/day than school context variables, which should be taken into account in the implementation of school policies and practices.

Great tit response to decreasing industrial heavy metal emissions.

This study evaluated the effects of environmental pollution on decreasing great tit (Parus major) breeding parameters in an industrial area in the west coast of Portugal. Several great tit breeding parameters were monitored in the industrial area, as well as in a rural area not affected by industrial emissions. Low levels of air pollution in both industrial and rural areas were confirmed by assessing trace element concentrations in pine needles. Concentrations of Cd and Hg in pine needles from the industrial area (Cd = 0.05 ppm; Hg = 0.005 ppm) were significantly lower than those found in needles collected from the reference area (Cd = 0.07 ppm; Hg = 0.007 ppm). Additionally, the breeding success of great tits increased in the industrial area in comparison to the reference area (0.93 ± 0.08 and 0.62 ± 0.22, respectively). The changes on great tit breeding parameters were probably related with changes in the breeding density of other competitive species, together with a decreasing frass-fall biomass. Further long-term ecological studies in industrial areas are necessary to understand the changing breeding performance and strategies used by great tits in response to pollution shifts in the environment.

Body mass index, cardiorespiratory fitness and cardiometabolic risk factors in youth from Portugal and Mozambique.

OBJECTIVES: The objectives of this study are to examine differences in cardiometabolic risk indicators, as well as their prevalences, in Portuguese and Mozambican youth, and to investigate the associations between weight status and cardiorespiratory fitness levels with cardiometabolic risk. METHODS: The sample comprises 721 adolescents (323 Mozambican and 398 Portuguese), aged 10-15 years. Anthropometry (height, sitting height, weight and waist circumference), blood pressure, serum-fasting triglycerides, high-density lipoprotein cholesterol and glucose, and cardiorespiratory fitness were measured. Maturity offset was estimated and a cardiometabolic risk score adjusted for sex, age and biological maturity was computed. Adolescents were classified as normal weight and overweight/obese as well as fit or unfit (cardiorespiratory fitness). RESULTS: Portuguese youth have better cardiometabolic and cardiorespiratory fitness profiles. About 32% and 30% of Portuguese boys and girls, respectively, are overweight/obese; in Mozambicans, these prevalences are 7.5% for boys and 21% for girls; in addition, 81.6% of Portuguese boys and 77.7% of Portuguese girls were classified as cardiorespiratory fit, against 54% and 44.4% of Mozambican boys and girls, respectively. No statistically significant differences (P>0.05) were found between Mozambicans and Portuguese for the cluster of three or more cardiometabolic risk indicators. A positive relationship (P<0.001) was found between weight status and cardiometabolic risk in adolescents from both countries; however, a negative association (P<0.001) between cardiorespiratory fitness and cardiometabolic risk was only found among Portuguese youth. CONCLUSIONS: Portuguese and Mozambican youth differ in their cardiometabolic risk profiles, body weight and cardiorespiratory fitness, favoring Portuguese. Overweight/obesity and low cardiorespiratory fitness levels are related to a worse cardiometabolic risk profile, being relevant to design public health intervention strategies to reduce excess weight and increase cardiorespiratory fitness.

The risk of falls on initiation of antihypertensive drugs in the elderly.

SUMMARY: Antihypertensive drugs are associated with an immediate increased falls risk in elderly patients which was significant during the first 14 days after receiving a thiazide diuretic, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blocker, or beta-adrenergic blocker. Fall prevention strategies during this period may prevent fall-related injuries. INTRODUCTION: The purpose of this study is to evaluate if initiation of the common antihypertensive drugs is associated with the occurrence of falls. METHODS: This population-based self-controlled case series study used healthcare administrative databases to identify new users of antihypertensive drugs in the elderly aged 66 and older living in Ontario, Canada who suffered a fall from April 1, 2000 to March 31, 2009. The risk period was the first 45 days following antihypertensive therapy initiation, further subdivided into 0-14 and 15-44 days with control periods before and after treatment in a 450-day observation period. We calculated the relative incidence (incidence rate ratio, IRR), defined as the rate of falls in the risk period compared to falls rate in the control periods. RESULTS: Of the 543,572 new users of antihypertensive drugs among community-dwelling elderly, 8,893 experienced an injurious fall that required hospital care during the observation period. New users had a 69 % increased risk of having an injurious fall during the first 45 days following antihypertensive treatment (IRR = 1.69; 95 % CI, 1.57-1.81). This finding was consistent for thiazide diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, and beta-adrenergic blockers but not angiotensin II receptor antagonists. There was also an increased falls risk during the first 14 days of antihypertensive drug initiation (IRR = 1.94; 95 % CI, 1.75-2.16), which was consistent for all antihypertensive drug classes. CONCLUSIONS: This study suggests that initiation of antihypertensive drugs is a risk factor for falls in the elderly. Fall prevention strategies during this period may reduce injuries.

Increased circulating platelet microparticles as a potential biomarker in asthma.

BACKGROUND: Endothelial (EMPs) and platelet microparticles (PMPs) have been studied as biomarkers in several inflammatory diseases and as central players in intercellular communication. METHODS: In this cross-sectional study, we aimed to assess microparticle levels in asthma. Circulating microparticles and inflammatory and angiogenic markers were assessed by clinical and laboratorial evaluation, flow cytometry, and immunoassays, in a group of 20 asthmatic and 15 nonasthmatic subjects. RESULTS: Circulating levels of PMPs (either CD31+/42b+ or CD31+/42b+/AnV+) were significantly increased in asthmatics (P = 0.021) even after adjustment for confounders. Apoptotic EMPs (CD31+/42b--/AnV+) were significantly increased before (P = 0.005) but not after adjustments (P = 0.117). CONCLUSIONS: We propose that PMPs may be putative asthma biomarkers, playing a role in asthma pathophysiology.

Progression through diabetes therapies among new elderly users of metformin: a population-based study.

AIMS: To examine temporal changes in progression to second-line therapies among older patients with diabetes newly treated with metformin. METHODS: We conducted a population-based study among residents of Ontario, Canada aged 66 years and older with diabetes newly treated with metformin monotherapy in 1997, 2000, 2003 or 2006. Each annual cohort was followed until progression to a second oral hypoglycaemic agent, insulin or until 31 December 2010. Time to progression to a second oral hypoglycaemic agent or insulin was compared across the cohorts. RESULTS: In the four annual cohorts, we identified a total of 46 104 people newly treated with metformin monotherapy. The median time to progression to any second diabetes therapy lengthened significantly over time, from 5.0 years in 1997 to 6.1 years in 2003 (P < 0.0001). Similarly, the time to progression to insulin lengthened over the study period (P = 0.03). Furthermore, the choice of second-line therapy changed over time. While 80.7% of new metformin users in 1997 progressed to glyburide therapy as second-line treatment, the corresponding figure by 2006 was only 45.1% as newer treatment options emerged. CONCLUSIONS: Although recent guidelines recommend aggressive intensification of oral therapy for patients with Type 2 diabetes, older Ontarians with diabetes who started metformin in 2006 remained on monotherapy for longer than those who started in 1997. Furthermore, although there is no consensus regarding a preferred second-line therapy, the introduction of new alternatives has led to greater variation in the selection of second-line therapies in this population.

Trends in selection and timing of first-line pharmacotherapy in older patients with type 2 diabetes diagnosed between 1994 and 2006.

AIMS: To characterize temporal trends in the selection and timing of first-line pharmacotherapy among older patients with Type 2 diabetes. DESIGN AND METHODS: We studied five population-based cohorts every 3 years, from 1994 to 2006. In each of those years, we identified all subjects aged 66 years or older newly diagnosed with diabetes and determined the initial glucose-lowering drug and the time between diagnosis and drug initiation. We calculated the proportion of patients prescribed each agent and estimated time from diagnosis to initiation using Kaplan-Meier survival analysis. RESULTS: We identified a total of 64 368 eligible people who initiated drug therapy during the study period. From 1994 to 2006, first-line metformin use increased from 20.1 to 79.0%. Glyburide (glibenclamide) decreased from 71.1% of all first-line therapies in 1994 to 9.8% in 2006, while first-line use of insulin or combination therapy have changed little at approximately 5% each. No other medication exceeded 2% of first-line therapies. The median time from diagnosis to initiation of pharmacotherapy increased dramatically during the study period, from 1.8 years in 1994 to 4.6 years in 2006. CONCLUSIONS: Metformin has become the most commonly used initial medication for the treatment of diabetes. Although guidelines have evolved to recommend more aggressive initiation and intensification of pharmacotherapy, our results suggest that the time from diagnosis to initiation has increased substantially.

An integrated biological effects assessment of the discharge water into the Sunndalsfjord from an aluminium smelter.

An integrated biological effects study using field transplanted mussels was applied to determine the potential biological effects of an effluent discharge from an aluminium smelter into a Norwegian fjord. Chemical body burden and biological effects were measured in mussels positioned downstream (1, 2, 5, 10 and 20 km) from the aluminium smelters discharge for a period of 6 weeks. A suite of biomarkers, from whole organism to subcellular responses were measured. Chemical concentrations in mussel tissues were low; however, a change in the PAC (polyaromatic compound) profile from high to low pyrogenic influence provided evidence of exposure to the smelter's effluent. Overall, the biological responses observed where greater in the mussels positioned closest to the smelter (1-5 km). Lowest chemical accumulation and biomarker responses were observed in mussels positioned 10 km from the smelter and were considered as the reference field population. Mussels located furthest from the smelter (20 km) exhibited significant biomarker responses and suggested a different contaminant source within the fjord. The integrated biological response index (IBR) was applied and reflected the expected level of exposure to the smelters discharge, with highest IBR calculated in mussels positioned closest to the discharge (1-5 km). Principal component analysis (PCA) also differentiated among mussel groups, with the most impacted located closest to the smelter. Not one chemical factor could explain the biological responses observed in mussels, but the presence of PAH16, PAH41 and metals Mn, Ni and Cr were the main contributors measured to the higher stress seen in the mussels from the 1 and 5 km groups.

Adverse cardiovascular events during treatment with glyburide (glibenclamide) or gliclazide in a high-risk population.

AIMS: Sulphonylureas promote insulin release by inhibiting pancreatic potassium channels. Older sulphonylureas such as glyburide (glibenclamide), but not newer ones such as gliclazide, antagonize similar channels in myocardium, interfering with the protective effects of ischaemic preconditioning. Whether this imparts a higher risk of adverse cardiac events is unknown. METHODS: We conducted a population-based cohort study of patients aged 66 years and older who were hospitalized for acute myocardial infarction or who underwent percutaneous coronary intervention between 1 April 2007 and 31 March 2010 while receiving either glyburide or gliclazide. We used a high-dimensional propensity score matching process to ensure similarity of glyburide- and gliclazide-treated patients. The primary outcome was a composite of death or hospitalization for myocardial infarction or heart failure. RESULTS: During the 2-year study period, we matched 1690 patients treated with glyburide to 984 patients treated with gliclazide at the time of hospitalization for acute myocardial infarction or percutaneous coronary intervention. We found no difference in the risk of the composite outcome among patients receiving glyburide (adjusted hazard ratio 1.01; 95% CI 0.86-1.18). We found similar results in secondary analyses of each outcome individually, and in two supplementary analyses (haemorrhage and pneumonia) in which we anticipated no difference between the two patient groups. CONCLUSIONS: Among older patients hospitalized for acute myocardial infarction or percutaneous coronary intervention, treatment with glyburide is not associated with an increased risk of future adverse cardiovascular events relative to gliclazide, suggesting that the effect of glyburide on ischaemic preconditioning is of little clinical relevance.