Adapting UK Biobank imaging for use in a routine memory clinic setting: The Oxford Brain Health Clinic.

The Oxford Brain Health Clinic (BHC) is a joint clinical-research service that provides memory clinic patients and clinicians access to high-quality assessments not routinely available, including brain MRI aligned with the UK Biobank imaging study (UKB). In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for memory clinic patients, 2) modified the imaging analysis pipeline to extract measures that are in line with radiology reports and 3) explored the alignment of measures from BHC patients to the largest brain MRI study in the world (ultimately 100,000 participants). Adaptations of the UKB acquisition protocol for BHC patients include dividing the scan into core and optional sequences (i.e., additional imaging modalities) to improve patients' tolerance for the MRI assessment. We adapted the UKB structural MRI analysis pipeline to take into account the characteristics of a memory clinic population (e.g., high amount of white matter hyperintensities and hippocampal atrophy). We then compared the imaging derived phenotypes (IDPs) extracted from the structural scans to visual ratings from radiology reports, non-imaging factors (age, cognition) and to reference distributions derived from UKB data. Of the first 108 BHC attendees (August 2020-November 2021), 92.5 % completed the clinical scans, 88.0 % consented to use of data for research, and 43.5 % completed the additional research sequences, demonstrating that the protocol is well tolerated. The high rates of consent to research makes this a valuable real-world quality research dataset routinely captured in a clinical service. Modified tissue-type segmentation with lesion masking greatly improved grey matter volume estimation. CSF-masking marginally improved hippocampal segmentation. The IDPs were in line with radiology reports and showed significant associations with age and cognitive performance, in line with the literature. Due to the age difference between memory clinic patients of the BHC (age range 65-101 years, average 78.3 years) and UKB participants (44-82 years, average 64 years), additional scans on elderly healthy controls are needed to improve reference distributions. Current and future work aims to integrate automated quantitative measures in the radiology reports and evaluate their clinical utility.

Inter- and intra-individual variation in brain structural-cognition relationships in aging.

The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ±4.9 years) and late-life (mean age = 67.7 ± 4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ± 4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive decline and maintenance across diverse cognitive functions are both positively and negatively associated with markers of cortical structure.

Can a virtual microbiology simulation be as effective as the traditional Wetlab for pharmacy student education?

BACKGROUND: Pharmacy practice education requires the development of proficiencies and an understanding of clinical microbiology. Learning in this area could be delivered using practical laboratory exercises, or potentially, simulation-based education. Simulation has previously successfully enhanced learning in health professional education. The current global climate due to COVID-19 has further highlighted the important role of technology-enhanced learning in delivering outcomes that meet the requisite learning objectives of a course. The aim of the present study was to compare the impact of a commercially available virtual microbiology simulation (VUMIE™) with a traditional wet laboratory (wetlab) on learner knowledge, skills and confidence in a second-year integrated pharmacotherapeutics course for Bachelor of Pharmacy students. METHODS: A randomised, crossover study was employed to determine whether the simulation intervention (VUMIE™) improves learning outcomes (knowledge, skills and confidence) of pharmacy students, when compared to a traditional wetlab intervention. Each student completed three 1-2 h length sessions, for both the wetlab and VUMIE™ interventions (6 sessions total). Data was collected using surveys deployed at baseline (pre-interventions), post-intervention 1 or 2 (VUMIE™ or wetlab) and endpoint (post-interventions 1 and 2). Statistical analysis was conducted using SPSS Statistics 25 and Instat™ software. RESULTS: Response rates were approximately 50% at initial survey and approximately 25% at endpoint survey. VUMIE™ produced higher post-intervention knowledge scores for the multiple-choice questions compared to the wetlab, however, the highest score was achieved at endpoint. Both interventions produced statistically significant differences for mean scores compared to baseline (pre-VUMIE™ and wetlab) across the domains of knowledge, skills and confidence. VUMIE™ produced higher post-intervention mean scores for knowledge, skills and confidence compared to post-intervention mean scores for the wetlab, however there was no statistical significance between the mean score for the two interventions, thus the VUMIE™ activity produced learning outcomes comparable to the wetlab activity. CONCLUSION: These findings suggest VUMIE™ provides similar effects on students' knowledge, skills, and confidence as a wetlab. The simulation's implementation was not cost-prohibitive, provided students with a physically and psychologically safe learning environment, and the benefit of being able to repeat activities, supporting deliberate practice.

Low-dose intravenous dexmedetomidine reduces shivering following cesarean delivery: a randomized controlled trial.

BACKGROUND: Intravenous dexmedetomidine 30 µg reduces shivering after cesarean delivery but can result in sedation and dry mouth. We hypothesized that prophylactic administration of 10 µg of IV dexmedetomidine would reduce the patient-reported severity of shivering after cesarean delivery, without an increased incidence of side effects. METHODS: After institutional review board approval and informed written consent, women undergoing scheduled cesarean delivery with spinal or combined spinal-epidural anesthesia were randomized to receive either intravenous normal saline or dexmedetomidine 10 µg immediately after delivery. The primary outcome was a patient-rated subjective shivering score using a 10-cm visual analog scale at 30 and 60 min after arrival in the Post-Anesthesia Care Unit. Secondary outcomes included subjective scores for pain, nausea, itching, dry mouth, and sedation, as well as 24-h medication administration and investigator-rated observations of shivering, vomiting, pruritus, and sedation. Repeated measures ANOVA with Tukey-Kramer multiple-comparison test was applied for primary outcomes. RESULTS: One hundred patients were enrolled, and 85 completed the study and were included in analysis. The mean ±â€¯SD shivering score in the dexmedetomidine group was significantly lower by repeated measures analysis than among controls across the first 60 min (P=0.0002), and individually at both 30 and 60 min (placebo 1.8 ±â€¯2.6 vs. dexmedetomidine 0.6 ±â€¯1.4 at 30 min; 1.2 ±â€¯2.1 vs. 0.3 ±â€¯0.6 at 60 min; both P <0.01). Patient-rated and observer-rated side effects did not significantly differ between groups. CONCLUSIONS: Prophylactic administration of intravenous dexmedetomidine 10 µg after delivery reduces shivering without notable side effects.

Neural markers of category-based selective working memory in aging.

Working memory (WM) is essential for normal cognitive function, but shows marked decline in aging. The importance of selective attention in guiding WM performance is increasingly recognized. Studies so far are inconclusive about the ability to use selective attention during WM in aging. To investigate the neural mechanisms supporting selective attention in WM in aging, we tested a large group of older adults using functional magnetic resonance imaging whilst they performed a category-based (faces/houses) selective-WM task. Older adults were able to use attention to encode targets and suppress distractors to reach high levels of task performance. A subsequent, surprise recognition-memory task showed strong consequences of selective attention. Attended items in the relevant category were recognized significantly better than items in the ignored category. Neural measures also showed reliable markers of selective attention during WM. Purported control regions including the dorsolateral and inferior prefrontal and anterior cingulate cortex were reliably recruited for attention to both categories. Activation levels in category-sensitive visual cortex showed reliable modulation according to attentional demands, and positively correlated with subsequent memory measures of attention and WM span. Psychophysiological interaction analyses showed that activity in category-sensitive areas were coupled with non-sensory cortex known to be involved in cognitive control and memory processing, including regions in the prefrontal cortex and hippocampus. In summary, we found that older adults were able to recruit a network of brain regions involved in top-down attention during selective WM, and individual differences in attentional control corresponded to the degree of attention-related modulation in the brain.

APOE genotype and cognition in healthy individuals at risk of Alzheimer's disease: A review.

APOE-ε4 is best known as a risk factor for Alzheimer's disease (AD). Consequently, there is considerable research interest in understanding whether APOE-ε4 influences cognition in healthy adults. Despite a substantial literature reporting effects of APOE genotype on cognition, findings are inconsistent. In particular, it is challenging to separate whether cognitive deficits in APOE-ε4 carriers reflect the influence of prodromal dementia pathology ("prodromal hypothesis"), or a direct contribution of APOE genotype to individual differences ("phenotype hypothesis"). Variable methodology across studies further complicates the issue. These challenges have limited what can be learnt about the processes underlying cognitive ageing and dementia by studying the influence of APOE genotype on cognition. In this review, we focus on the two compatible neurobiological mechanisms by which APOE genotype may influence cognition in healthy adults (prodromal and phenotype). We summarise the behavioural evidence for the influence of APOE on cognition in non-demented adults and explore key methodological challenges for disentangling the cognitive effects of different neurobiological mechanisms of APOE. Evidence suggests that at least some APOE-ε4 cognitive deficits are due to early AD pathology, whilst sensitive measures of cognition are beginning to reveal subtle cognitive differences between APOE genotypes in mid-adulthood, prior to the onset of the AD prodromal period. We conclude with recommendations for future research to investigate the cognitive consequences of neurobiological processes affected by APOE and maximise the translational potential of this research.

Improving the assessment of predator functional responses by considering alternate prey and predator interactions.

To improve understanding of the complex and variable patterns of predator foraging behavior in natural systems, it is critical to determine how density-dependent predation and predator hunting success are mediated by alternate prey or predator interference. Despite considerable theory and debate seeking to place predator-prey interactions in a more realistic context, few empirical studies have quantified the role of alternate prey or intraspecific interactions on predator-prey dynamics. We assessed functional responses of two similarly sized, sympatric carnivores, lynx (Lynx canadensis) and coyotes (Canis latrans), foraging on common primary (snowshoe hares; Lepus americanus) and alternate (red squirrels; Tamiasciurus hudsonicus) prey in a natural system. Lynx exhibited a hyperbolic prey-dependent response to changes in hare density, which is characteristic of predators relying primarily on a single prey species. In contrast, the lynx-squirrel response was found to be linear ratio dependent, or inversely dependent on hare density. The coyote-hare and coyote-squirrel interactions also were linear and influenced by predator density. We explain these novel results by apparent use of spatial and temporal refuges by prey, and the likelihood that predators commonly experience interference and lack of satiation when foraging. Our study provides empirical support from a natural predator-prey system that (1) predation rate may not be limited at high prey densities when prey are small or rarely captured; (2) interference competition may influence the predator functional response; and (3) predator interference has a variable role across different prey types. Ultimately, distinct functional responses of predators to different prey types illustrates the complexity associated with predator-prey interactions in natural systems and highlights the need to investigate predator behavior and predation rate in relation to the broader ecological community.

Prevalence of enterotoxin genes in Staphylococcus aureus colonising food handlers: does nasal carriage status matter?

This study investigated the association between the presence of staphylococcal enterotoxin (SE) genes and nasal carriage status, and determined temporal changes in the prevalence of these genes in Staphylococcus aureus strains isolated from healthy carriers between 2002 and 2011. Three large samples of food handlers recruited in 2002, 2003 and 2011 were nasally sampled on two occasions to determine S. aureus colonisation status. Those carrying the same spa type on both occasions were defined as persistent carriers. Genes for SEs SEA-SEU were amplified and associations between carriage status and presence of SE genes were investigated. Although 80 % of nasal isolates harboured at least one SE gene over the sampling period, persistent carriers were significantly more likely to harbour enterotoxigenic S. aureus than transiently colonised subjects [odds ratio (OR) 2.52-3.06]. Strains from persistent carriers more commonly harboured sea, seb and sem. The prevalence of classical SE genes and sej, sem, sen, seo, seq and ses was stable over time, but seh, sel, sep, ser, set and selu increased significantly. Increased toxigenicity of isolates from persistent carriers is consistent with the elevated antibody levels to classical SEs previously reported in persistent carriers, supporting the hypothesis that superantigen production in the nasal cavity may enhance colonisation.

Imagining a brighter future: the effect of positive imagery training on mood, prospective mental imagery and emotional bias in older adults.

Positive affect and optimism play an important role in healthy ageing and are associated with improved physical and cognitive health outcomes. This study investigated whether it is possible to boost positive affect and associated positive biases in this age group using cognitive training. The effect of computerised imagery-based cognitive bias modification on positive affect, vividness of positive prospective imagery and interpretation biases in older adults was measured. 77 older adults received 4 weeks (12 sessions) of imagery cognitive bias modification or a control condition. They were assessed at baseline, post-training and at a one-month follow-up. Both groups reported decreased negative affect and trait anxiety, and increased optimism across the three assessments. Imagery cognitive bias modification significantly increased the vividness of positive prospective imagery post-training, compared with the control training. Contrary to our hypothesis, there was no difference between the training groups in negative interpretation bias. This is a useful demonstration that it is possible to successfully engage older adults in computer-based cognitive training and to enhance the vividness of positive imagery about the future in this group. Future studies are needed to assess the longer-term consequences of such training and the impact on affect and wellbeing in more vulnerable groups.

Importance of early detection of vancomycin-resistant subpopulations in apparently susceptible meticillin-resistant Staphylococcus aureus clinical isolates.

This study aimed to investigate the presence of vancomycin-non-susceptible subpopulations in apparently susceptible meticillin-resistant Staphylococcus aureus (MRSA) and the ability of these isolates to develop into homogeneously resistant strains. Vancomycin MICs of 200 clinical MRSA isolates were determined using agar dilution (AD) and spiral gradient endpoint (SGE) technique. Isolates with an MIC≤2mg/L but displaying subpopulations with an MIC>2mg/L by SGE were re-tested by Etest and PAP-AUC and were incubated with 2mg/L vancomycin for 2 weeks. MIC testing was repeated weekly by AD, Etest and SGE to observe progression to non-susceptibility. A total of 17.5% and 16.0% of isolates were non-susceptible to vancomycin (MIC>2mg/L) by SGE and AD, respectively. Eight isolates (4%) displayed a resistant subpopulation; five met the definition of hVISA by PAP-AUC. The initial Etest MIC for these isolates was 2mg/L, but resistant subpopulations were observed in only three isolates on prolonged incubation. MICs of all eight isolates increased rapidly in the presence of vancomycin, reaching ≥3.0mg/L by Day 7 and ≥4mg/L after 14 days by all three methods. The prevalence of vancomycin-non-susceptible MRSA was high, and non-susceptibility developed rapidly in seemingly susceptible isolates with covert subpopulations. These were effectively detected by SGE. With increasing reports of vancomycin clinical failure, early detection of potentially non-susceptible isolates before or early in vancomycin therapy is essential to avoid further resistance development and poor clinical outcomes. SGE offers a novel and cost-effective technique for detection of potentially non-susceptible strains.

Sustainable reduction of nasal colonization and hand contamination with Staphylococcus aureus in food handlers, 2002-2011.

A longitudinal study of nasal colonization and hand contamination of food handlers with Staphylococcus aureus commenced in 2002 prior to the outbreak of severe acute respiratory syndrome. In the follow-up in 2003 when hygiene measures were strictly implemented, significant reductions in carriage were observed. To investigate if this change was sustained, nasal and hand carriage rates were compared between the earlier studies and a further sampling in 2011. The initial nasal carriage rate was 35% and hand contamination 41·2%, decreasing to 23·5% and 11·6%, respectively in 2003 (P < 0·001). In 2011, nasal carriage was similar to 2003 (22·9%), while hand contamination dropped further to 3·7% (P < 0·001). Spa-typing revealed 39 types in 2002 and 42 in 2011. This study reveals that the marked reduction in colonization had been sustained. This may be attributed to reduced opportunities for spread due to enhanced hygiene and reinforces its importance for control of disease.

Occupational exposure to raw meat: a newly-recognized risk factor for Staphylococcus aureus nasal colonization amongst food handlers.

Staphylococcus aureus contaminating raw meat may increase nasal colonization risk for occupationally-exposed food handlers. Food handlers from six catering establishments were nasally sampled for S. aureus and completed a questionnaire on carriage risk factors. Isolates were characterized for antibiotic susceptibility, spa type and, for methicillin-resistant strains, SCCmec type. Of 434 food handlers, 99 (22.8%) were colonized with S. aureus. Five isolates were methicillin-resistant belonging to SCCmec IV (2) and V (3). Resistance to tetracycline (20%), and erythromycin (16%) was high, but <10% to other antibiotics. Spa typing revealed 17% of isolates as t189, with 8% each t127 and t1081. Food handlers ever handling raw meat had a significantly higher colonization risk (OR=2.7; 95% CI: 1.7-4.5), increasing to 3.7 (95% CI: 2.0-6.8) for those always exposed. This is the first report of increased colonization risk in food handlers exposed to raw meat. This occupational hazard may increase infection risk, so improved compliance with workplace hygiene may be required.

Early auditory processing in area V5/MT+ of the congenitally blind brain.

Previous imaging studies of congenital blindness have studied individuals with heterogeneous causes of blindness, which may influence the nature and extent of cross-modal plasticity. Here, we scanned a homogeneous group of blind people with bilateral congenital anophthalmia, a condition in which both eyes fail to develop, and, as a result, the visual pathway is not stimulated by either light or retinal waves. This model of congenital blindness presents an opportunity to investigate the effects of very early visual deafferentation on the functional organization of the brain. In anophthalmic animals, the occipital cortex receives direct subcortical auditory input. We hypothesized that this pattern of subcortical reorganization ought to result in a topographic mapping of auditory frequency information in the occipital cortex of anophthalmic people. Using functional MRI, we examined auditory-evoked activity to pure tones of high, medium, and low frequencies. Activity in the superior temporal cortex was significantly reduced in anophthalmic compared with sighted participants. In the occipital cortex, a region corresponding to the cytoarchitectural area V5/MT+ was activated in the anophthalmic participants but not in sighted controls. Whereas previous studies in the blind indicate that this cortical area is activated to auditory motion, our data show it is also active for trains of pure tone stimuli and in some anophthalmic participants shows a topographic mapping (tonotopy). Therefore, this region appears to be performing early sensory processing, possibly served by direct subcortical input from the pulvinar to V5/MT+.

Colonization of butchers with livestock-associated methicillin-resistant Staphylococcus aureus.

Reports have documented colonization of swine in Europe, North America and more recently in China with livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA). Contamination of pig farmers, veterinarians and abattoir workers with these strains has been observed. However, although contamination levels of 10% of retail pork were reported from the Netherlands and Canada, there are limited data of contamination rates of workers handling raw meat. We investigated the rates of MRSA contamination of local butchers working in wet markets, where recently slaughtered pigs are cut up. Nasal swabs collected from 300 pork butchers at markets throughout Hong Kong were enriched in brain heart infusion broth with 5% salt and cultured on MRSASelect(®) . Isolates were confirmed as Staphylococcus aureus and susceptibility testing performed. The presence of mecA was confirmed, SCCmec and spa type determined and relatedness investigated by PFGE. Subjects completed a questionnaire on MRSA carriage risk factors. Seventeen samples (5.6%) yielded MRSA, 15 harbouring SCCmec IVb. Ten strains were t899 (CC9), previously reported from local pig carcasses. Five strains were healthcare associated: SCCmec type II, t701(CC6), colonizing two subjects at the same establishment, and single isolates of t008 (CC8), t002 (CC5) and t123 (CC45). The remaining isolates were t359 (CC97), previously reported from buffaloes, and t375 (CC5), reported from bovine milk. None of these butchers reported recent hospitalization or a healthcare worker in the family. Two had recently received antibiotics, one for a skin infection. Four reported wound infections within the last year. All were exposed to meat for >9 h per day. Carriage of MRSA was higher in butchers than in the general community. Although five strains were probably of healthcare origin, the high incidence of t899 (CC9) suggests that cross-contamination from pork occurs frequently. Washing of hands after touching raw pork is advised.

Presence of antiseptic resistance genes in porcine methicillin-resistant Staphylococcus aureus.

Numerous studies have documented the presence of methicillin-resistant Staphylococcus aureus (MRSA) in meat-producing animals, which has led to concern about its spread into the community. Disinfectants play an important role in reduction of contamination in both animal husbandry and food-preparation, helping control spread of organisms from foodstuffs, including raw meat. Plasmid-borne antiseptic resistance (AR) genes increasing tolerance to several disinfectants have been reported in S. aureus of human origin (qacA/B and smr) and from bovine, equine, and caprine staphylococcal isolates (qacG, qacH, and qacJ). This study investigated the presence of AR genes in porcine MRSA isolates. Plasmid DNA from 100 MRSA ST9 strains isolated from pig carcasses was amplified for the presence of AR genes. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) to benzalkonium chloride (BC) and chlorhexidine gluconate (CHX) were determined in AR gene-positive isolates. qacG was present in 45 strains, eight of which also harbored smr. No strains carried qacA/B, qacH or qacJ. Presence of smr increased MICs to both BC and CHX and MBCs of CHX, but qacG presence only resulted in elevated MBC for CHX. This is the first report of AR genes from a porcine source. AR gene positivity has previously been associated with methicillin resistance and AR gene presence in these strains may increase their ability to persist in the environment. Improved implementation of hygiene measures during transportation and pre- and post-slaughter should be considered to prevent spread in the community.

Characterization of methicillin-resistant Staphylococcus aureus isolates from pig carcasses in Hong Kong.

This study describes the isolation and characterization of methicillin-resistant Staphylococcus aureus (MRSA) from slaughtered pigs sampled from local markets in Hong Kong. The nares of 400 slaughtered pigs were cultured and MRSA isolates characterized for the presence of antibiotic-resistance determinants, toxins and SCCmec and spa types using PCR. Clonality was investigated using PFGE and MLST. The prevalence of MRSA colonization of slaughter pigs was 39.3%, the majority (92%) harbouring SCCmec type IVb. Of the 157 samples yielding MRSA, 13 had two distinct MRSA strains present. Spa type t899 was predominant, with only 5/170 isolates displaying closely related types (t4474, t1939, t2922 and t5390). PFGE with sma1 and MLST confirmed the strains as ST9. Most isolates were multidrug resistant. Tetracycline resistance (97%) was mainly attributable to tet(K) with only 3% of isolates additionally harbouring tet(M). Resistance to erythromycin (89%) and chloramphenicol (71%) was associated with the presence of erm(C), and fex(A), respectively. No strains carried cfr and there was no resistance to linezolid, although minimum inhibitory concentration (MICs) were close to the resistance break point. Resistance to clindamycin (99%), ciprofloxacin(78%), quinopristin-dalfopristin (44%) and cotrimoxazole (32%) was common, but remained low for fusidic acid (4%) and rifampicin (2%). All strains were negative for PVL, exfoliative, and enterotoxins. This survey confirmed the uniformity of MRSA isolates in pigs from several regions of China, in contrast to more diversified characteristics reported in European studies. Colonization rates were higher than previously reported. Isolates were resistant to a wide range of antibiotics, but resistance was not detected to linezolid, nitrofurantoin, vancomycin or tigecycline. Although the clinical importance of ST9 in humans is uncertain, continued surveillance, in particular of those occupationally-exposed, is recommended.

Safety and efficacy of protease-activated receptor-1 antagonists in patients with coronary artery disease: a meta-analysis of randomized clinical trials.

BACKGROUND: Thrombin receptor antagonists blocking protease-activated receptor-1 (PAR-1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. OBJECTIVES: We investigated the safety and efficacy of PAR-1 antagonists in patients with coronary artery disease (CAD). PATIENTS/METHODS: Randomized, placebo-controlled trials of the PAR-1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. RESULTS: A total of 41 647 patients from eight trials were included. PAR-1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39-1.57, P < 0.001), major (OR 1.46, 95% CI 1.28-1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40-2.00, P < 0.001) bleeding than placebo in the fixed-effects model. PAR-1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81-0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78-0.92, P < 0.001). Conversely, PAR-1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90-1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84-1.10, P = 0.59). CONCLUSIONS: PAR-1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.