Comparison of Two Highly Discriminatory Typing Methods to Analyze Aspergillus fumigatus Azole Resistance

Aspergillus fumigatus molecular typing has become increasingly more important for detecting outbreaks as well as for local and global epidemiological investigations and surveillance. Over the years, many different molecular methods have been described for genotyping this species. Some outstanding approaches are based on microsatellite markers (STRAf assay, which is the current gold standard), or based on sequencing data (TRESP typing improved in this work with a new marker and was renamed TRESPERG). Both methodologies were used to type a collection of 212 A. fumigatus isolates that included 70 azole resistant strains with diverse resistance mechanisms from different geographic locations. Our results showed that both methods are totally reliable for epidemiological investigations showing similar stratification of the A. fumigatus population. STRAf assay offered higher discriminatory power (D = 0.9993) than the TRESPERG typing method (D = 0.9972), but the latter does not require specific equipment or skilled personnel, allowing for a prompt integration into any clinical microbiology laboratory. Among azole resistant isolates, two groups were differentiated considering their resistance mechanisms: cyp51A single point mutations (G54, M220, or G448), and promoter tandem repeat integrations with or without cyp51A modifications (TR34/L98H, TR46/Y121F/A289T, or TR53). The genotypic differences were assessed to explore the population structure as well as the genetic relationship between strains and their azole resistance profile. Genetic cluster analyses suggested that our A. fumigatus population was formed by 6–7 clusters, depending on the methodology. Also, the azole susceptible and resistance population showed different structure and organization. The combination of both methodologies resolved the population structure in a similar way to what has been described in whole-genome sequencing works

Light-induced strain and its correlation with the optical absorption at charged domain walls in polycrystalline ferroelectrics

Photostrictive materials have a growing interest because of their great potential as light-driven actuators, among other optomechanical applications. In this context, the optical control of macroscopic strain in ferroelectrics has recently attracted remarkable attention as an effective alternative to the conventional electric control of strain. Here, a clear correlation between optical absorption and light-induced strain in polycrystalline BaTiO3 is shown. Specifically, the grain size and the sample thickness dependence of optical absorption when the material is irradiated with energy photons lower than the band gap evidence that light absorption at charged domain walls is the core of the observed photo-response in ferroelectrics. The photoinduced electronic reconstruction phenomenon is proposed as the primary physical mechanism for light absorption at charged domain walls. Results open a new pathway to designing ferroelectric-based devices with new functionalities like thickness gradient-based photo-controlled nanoactuators.Postprint (published version

Aspergillus fumigatus and aspergillosis: From basics to clinics

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them.AA, RGR, and DSP were supported by NIH AI 109025. MH was supported by NIH UL1TR001442. AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (CEECIND/03628/2017 and PTDC/MED GEN/28778/2017). Additional support was provided by FCT (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023), the European Union's Horizon 2020 Research and Innovation programme under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003. DJA was supported by CF Trust Strategic Research Centre TrIFIC (SRC015), Wellcome Trust Collaborative Award 219551/Z/19/Z and the NIHR Centre for Antimicrobial Optimisation.S

Aportaciones a los estudios económico-administrativos. Reflexiones teóricas y evidencias empíricas

La economía y la administración están inmersas en el universo de las ciencias sociales, áreas del conocimiento que comprenden dominios diferentes, pero también convergen y se intersectan en un objeto de estudio: las organizacienones y sus agregados (industrias o sectores). Desde una perspectiva social, los estudios económico-administrativos informan sobre cómo hacer eficientes a las organizaciones y competitivos a los sectores con la finalidad de impactar positivamente en la justicia social (por ejemplo: mediante productos de mejor calidad a mejores precios). El auge de este tipo de estudios está extendido a fenómenos clave en el mundo de hoy, tales como: la ventaja competitiva, la innovación, la administración de la cadena de suministros y la administración verde, entre otros.El objetivo de este libro es difundir las aportaciones hechas a los estudios económico-administrativos, ya sea como reflexiones teóricas o a modo de evidencia empírica, pues la conjunción de varias ciencias ayuda a comprender fenómenos complejos mejor que una disciplina en forma aislada. Más que la homogeneidad de teorías o hegemonía de unas sobre otras, la investigación interdisciplinaria construye un acercamiento a la diversidad de puntos de vista: se buscan factores, métodos o lenguajes comunes alrededor de un objeto de estudio (Fernández, 2009; Martínez, 1997), llegándose a conformar una comunidad científica con antecedentes disciplinarios diferentes, pero con cierta unidad, relaciones y acciones recíprocas (Kuhn, 1995). Así, en este texto el objeto de estudio es el funcionamiento e interacción de las organizaciones, como integrantes de los sectores económicos, en los mercados locales y globales. La comunidad científica está conformada por investigadores y egresados del Doctorado en Ciencias Económico-Administrativas, el cual nace en 2006 en la Universidad Autónoma del Estado de México, a cargo de la Dependencia de Educación Superior (DES) Económico-Administrativa

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Comparison of Two Highly Discriminatory Typing Methods to Analyze Aspergillus fumigatus Azole Resistance

Aspergillus fumigatus molecular typing has become increasingly more important for detecting outbreaks as well as for local and global epidemiological investigations and surveillance. Over the years, many different molecular methods have been described for genotyping this species. Some outstanding approaches are based on microsatellite markers (STRAf assay, which is the current gold standard), or based on sequencing data (TRESP typing improved in this work with a new marker and was renamed TRESPERG). Both methodologies were used to type a collection of 212 A. fumigatus isolates that included 70 azole resistant strains with diverse resistance mechanisms from different geographic locations. Our results showed that both methods are totally reliable for epidemiological investigations showing similar stratification of the A. fumigatus population. STRAf assay offered higher discriminatory power (D = 0.9993) than the TRESPERG typing method (D = 0.9972), but the latter does not require specific equipment or skilled personnel, allowing for a prompt integration into any clinical microbiology laboratory. Among azole resistant isolates, two groups were differentiated considering their resistance mechanisms: cyp51A single point mutations (G54, M220, or G448), and promoter tandem repeat integrations with or without cyp51A modifications (TR34/L98H, TR46/Y121F/A289T, or TR53). The genotypic differences were assessed to explore the population structure as well as the genetic relationship between strains and their azole resistance profile. Genetic cluster analyses suggested that our A. fumigatus population was formed by 6-7 clusters, depending on the methodology. Also, the azole susceptible and resistance population showed different structure and organization. The combination of both methodologies resolved the population structure in a similar way to what has been described in whole-genome sequencing works.This work has been supported by Fondo de Investigación Sanitaria (FIS PI15_00019), and Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/CIII/0004/0003), co-financed by European Development Regional Fund ERDF “A way to achieve Europe,” Operative program Intelligent Growth 2014–2020. PE (CPI15/00115) and JG (CPII15/00006) are recipients of a Miguel Servet contract supported by Fondo de Investigación Sanitaria.S

Genome-Wide Comparative Analysis of Aspergillus fumigatus Strains: The Reference Genome as a Matter of Concern

Aspergillus fumigatus is a ubiquitous saprophytic mold and a major pathogen in immunocompromised patients. The effectiveness of triazole compounds, the A. fumigatus first line treatment, is being threatened by a rapid and global emergence of azole resistance. Whole genome sequencing (WGS) has emerged as an invaluable tool for the analysis of genetic differences between A. fumigatus strains, their genetic background, and antifungal resistance development. Although WGS analyses can provide a valuable amount of novel information, there are some limitations that should be considered. These analyses, based on genome-wide comparative data and single nucleotide variant (SNV) calling, are dependent on the quality of sequencing, assembling, the variant calling criteria, as well as on the suitable selection of the reference genome, which must be genetically close to the genomes included in the analysis. In this study, 28 A. fumigatus genomes sequenced in-house and 73 available in public data bases have been analyzed. All genomes were distributed in four clusters and showed a variable number of SNVs depending on the genome used as reference (Af293 or A1163). Each reference genome belonged to a different cluster. The results highlighted the importance of choosing the most suitable A. fumigatus reference genome to avoid misleading conclusions