Abstract
Objectives
Azole resistance among Aspergillus fumigatus isolates is a growing concern worldwide. Induction of mutations during azole therapy, environment-acquired mutations caused by azole ...fungicides and intrinsic resistance of cryptic Fumigati species all contribute to the burden of resistance. However, there is a lack of data in Canada on this emerging threat.
Methods
To gain insights into the magnitude and mechanisms of resistance, a 14 year collection of Aspergillus section Fumigati comprising 999 isolates from 807 patients at a Montreal hospital was screened for azole resistance, and resistance mechanisms were investigated with the combined use of genome sequencing, 3D modelling and phenotypic efflux pump assays.
Results
Overall azole resistance was low (4/807 patients; 0.5%). A single azole-resistant A. fumigatus sensu stricto strain, isolated from a patient with pulmonary aspergillosis, displayed efflux-pump-mediated resistance. Three patients were colonized or infected with azole-resistant cryptic Fumigati species (one Aspergillus thermomutatus, one Aspergillus lentulus and one Aspergillus turcosus). Evidence is presented that azole resistance is efflux-pump-mediated in the A. turcosus isolate, but not in the A. lentulus and A. thermomutatus isolates.
Conclusions
Azole resistance is rare in our geographic area and currently driven by cryptic Fumigati species. Continued surveillance of emergence of resistance is warranted.
Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known ...about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs.
Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6-80 years; 340 males) and 782 control subjects (age range, 6-80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression.
All CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia.
The findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs.
Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have ...typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen's d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.
Here, we present the draft genome sequence of Aspergillus thermomutatus (formerly known as Neosartorya pseudofischeri; strain HMR-AF-39/LSPQ-01276), a cryptic species of Aspergillus section Fumigati. ...This species is intrinsically resistant to antifungal azoles and is recognized as an agent of invasive aspergillosis among immunocompromised hosts.
Off-pump coronary artery bypass surgery (OPCAB) has been revived and has gained popularity, although the exact subsets of patients who might benefit most from this technique are unknown. The aim of ...this retrospective study was to compare the results of coronary artery bypass grafting surgery (CABG) in octogenarians using cardiopulmonary bypass (CPB) or OPCAB techniques.
Over a 5-year period (1995-1999), 125 patients older than 80 years of age were operated for isolated myocardial revascularization (63 using CPB and 62 with OPCAB). There was no statistically significant difference in preoperative comorbidities between groups or in mean left ventricular ejection fraction (54.5+/-15.3% in the CPB group and 50.9+/-13.5% in the OPCAB group, respectively). The mean number of distal anastomosis per patient was 2.9 in CPB group and 2.6 in OPCAB group (P=ns). The majority of patients in both groups had unstable angina and were operated on an urgent basis. The operative mortality was 15.9% in the CPB group and 4.8% in the OPCAB group (P=0.04). There were 4 postoperative strokes (6.3%) in the CPB group and none (0%) in the OPCAB group (P=0.04). The percentage of patients transfused was 92.1% in the CPB group and 72.6% in the OPCAB group (P<0.01). Postoperative myocardial infarction occurred in 11.3% in the CPB group and 14.5% in the OPCAB group (P=NS). For all the parameters entered in the multivariate analysis with logistic regression model, the type of surgery (CPB or OPCAB) was an independent predictor of operative mortality and stroke (P=0.0375). The odds ratio (OR) indicates that operative mortality and stroke occur 4 times (OR=4.171) more often in CPB patients than in OPCAB patients. Follow-up showed no significant difference between the 2 groups in terms of cardiac events and mortality.
This retrospective study suggests a benefit of OPCAB in terms of operative mortality and stroke for octogenarian patients when compared with CPB in our institution.
We present the draft genome sequences of two clinical strains of Aspergillus turcosus, one azole-susceptible (strain HMR-AF-23/LSPQ-01275) and the other azole-resistant (strain ...HMR-AF-1038/LSPQ-01280), isolated from bronchoalveolar lavage fluid of two adult patients. These two strains are the first reported clinical isolates of A. turcosus.
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