Improved diagnostics and surveillance identify novel reassortant swine influenza A viruses in Chile

Influenza A Virus (IAV) circulates endemically in nature, representing a constant concern to public health and animal production systems worldwide. The emergence of the 2009 H1N1 influenza A pandemic (A(H1N1)pdm09) highlighted the need of conducting systematic surveillance studies, and evidenced the significant gap of knowledge of the swine IAVs (SwIAV) circulating in pigs worldwide at the time of the outbreak. This also highlighted the role of swine as important reservoirs for the generation of endemic strains with zoonotic and pandemic potential. Despite this, comprehensive information of SwIAV circulating in Latin America is still lacking. While Chile has strong ecological barriers and high stringency controls regarding livestock trading, IAV is endemic and has been consistently detected in pigs. This has caused great concerns for the swine industry, because of the on-going clinical and production losses. Nevertheless, few surveillance efforts have been conducted in Chile and there is limited information regarding the genetic diversity and origin of swIAVs. Determining the viral subtypes and genotypes circulating in swine is key for the development of appropriate vaccine approaches and control measures for the swine industry, and it is crucial for identifying novel strains with pandemic potential. We developed improved diagnostic tools to detect endemic viruses and characterized the diversity and origin of SwAIV and its prevalence in Chilean swine production farms. From December 2013 to June 2015, we sampled 27 farms representative of intensive swine production systems located between the Valparaiso and Araucania administrative regions. Animals were mainly found to be susceptible to IAV infection at 50 to 110 days of age. Serological analysis of 718 serum samples obtained from 3 different farms showed 91-59% prevalence to SwIAV, with 18-67% positivity to A(H1N1)pdm09-like strains and 29-58% positivity to a novel SwH1N2 virus. We also obtained a total of 1016 nasal swabs (NS, 85%) and 176 oral fluids (OF, 15%) that were tested by Real-time RT-PCR (qPCR) and virus isolation. Of these, 295 samples (25%) were positive to swIAV (23% of NS and 38% of OF). A large number of farms (21 out of 27, 78%) were positive in at least one visit, and most farms showed temporal co-circulation of at least 2 viruses or mixed infections. We subtyped selected positive samples and sequenced 51 complete viral genomes using the Illumina platform. Nineteen additional hemagglutinins (HA) genes were sequenced by Sanger. We performed Bayesian Evolutionary Analyses to reconstruct the phylogenies of the viral segments. This identified the circulation of 2 predominant swIAV genotypes in Chile, the A(H1N1)pdm09-like (35%) strain and a novel SwH1N2 virus (45%). This H1N2 virus is unique to Chile since it is genetically distinct from the H1 virus clusters seen in North America and is not related to any previously reported IAV. The genome of this swH1N1 virus contains genes from 3 different human contemporary viruses. Its H1 and N2 genes are derived from human H1N1 and H3N2 viruses from the mid 90’s, respectively, suggesting that both of these human viruses were likely introduced into the Chilean swine population during that time. All the internal genes are from the A(H1N1)pdm09 strain, indicating that multiple and recent reassortment events gave rise to this novel reassortant virus. Of interest, we identified additional reassortant viruses that also contain the internal genes derived from the A(H1N1)pdm09 strain. These included an H1N1 containing the novel SwH1 and NA gene derived from the A(H1N1)pdm09-like strain, an H1N2 virus containing an H1 derived from the A(H1N1)pdm09 strain and the novel SwN2, a SwH3N2 virus and a human-like H3N2 virus, among others. Additionally, our analyses also revealed at least 3 independent human-to-swine introductions of the A(H1N1)pdm09 strain within the last 4 years in Chile. Overall this indicates that close human-swine interactions greatly contribute to the genetic diversity and emergence of IAVs in Chilean swine. This is the first comprehensive molecular epidemiological study of swIAV in Chile demonstrating the co-circulation of multiple viral strains in intensive swine production systems. Our data emphasizes the value of conducting long-term SwIAV surveillance in Latin America, a poorly studied region of the world. Acknowledgements: CEIRS program: HHSN266200700010C, HHSN272201400008C from NIH-NIAID, FONDEF IDeA Grant ID14I10201 and Proyecto Anillo de Investigación en Ciencia y Tecnología - PIA ACT1408, both from CONICYT Chile

Cross-protection of commercial vaccines against Chilean swine influenza A virus using the guinea pig model as a surrogate

Influenza A virus poses a significant threat to public health and the swine industry. Vaccination is the primary measure for controlling the disease, but the effectiveness of vaccines can vary depending on the antigenic match between vaccine strains and circulating strains. In Chile, H1N1pdm09 and other lineages H1N2 and H3N2 have been detected in pigs, which are genetically distinct from the strains included in commercial vaccines. This study aimed to evaluate the cross-protection by commercial vaccines against strains circulating in Chile using the guinea pig model. For this study, four circulating strains [A/swine/Chile/H1A-7/2014(H1N2), A/swine/Chile/H1B-2/2014(H1N2), A/swine/Chile/H1P-12/2015(H1N1), and A/swine/Chile/H3-2/2015(H3N2)] were selected. Guinea pigs were divided into vaccinated and control groups. The vaccinated animals received either a multivalent antigenically heterologous or monovalent homologous vaccine, while the control animals remained unvaccinated. Following vaccination, all animals were intranasally challenged, and nasal wash samples were collected at different time points post-infection. The results showed that the homologous monovalent vaccine-induced hemagglutinin-specific antibodies against the Chilean pandemic H1N1pdm09 strain. However, the commercial heterologous multivalent vaccine failed to induce hemagglutinin-specific antibody titers against the H1N2 and H3N2 challenge strains. Furthermore, the homologous monovalent vaccine significantly reduced the duration of viral shedding and viral titers specifically against the Chilean pandemic H1N1pdm09 strain and heterologous multivalent vaccine only partial. These findings highlight the importance of regularly updating vaccine strains to match the circulating field strains for effective control of swine influenza. Further research is needed to develop vaccines that confer broader protection against diverse strains of swine influenza A virus

"Cardiovascular Health Investigation and Collaboration to Assess the Markers and Outcomes of Chagas disease" (CHICAMOCHA): Concepto, métodos y características de una cohorte de donantes de sangre en Bucaramanga, Colombia

Introduction: Geographical and socio-demographic conditions expose Colombian population to the threat of vector-borne diseases (such as Chagas’ [CHAD]) and cardiovascular disease of atherosclerotic origin (CVD). Objective: To assemble a cohort study of young adults, to promote understanding of CHAD and CVD in Bucaramanga, Colombia. Methodology: A study of blood donors with serological screening for T.cruzi was designed. A database of consecutive donors with positive results (T[+]) was built. This group was compared with a random sample of T[-] individuals (1:4 ratio, within strata of bank and month of donation). Participants classified by serology and electrocardiography status underwent clinical interviews (additional cardiovascular tests to T[+] and a random sample to T[-] were performed. In the following years, T[+] individuals participated in randomized trials whereas those whereas those T[-] participated in repeated measurements to test CVD risk factors. Results: From 6,228 donors in the database (18 to 50 years old) registered in the database (1997-2203), 2,130 blood donors (mean age 36.4 (SD 8.4) years, 64% males, 73.4% living in low socioeconomic strata, 486 T[+]) agreed to participate. Our contact protocol, and follow-up procedure with participants allowed us to obtain repeatedly measurements of at least 80% of the participants.  Conclusions: CHICAMOCHA represents a social asset that builds local research capacity. Continued efforts are required to enhance its potential for research training, scholarly work and health care guidance. [Villar JC, Herrera VM, Cháves-Neira AM, Martínez-Contreras LX, Villar-Centeno LA, Ardila E, Marcell-Vásquez S, Vásquez SM. “Cardiovascular Health Investigation and Collaboration to Assess the Markers and Outcomes of Chagas disease” (CHICAMOCHA): Concept, methods and characteristics of a cohort of blood donors in Bucaramanga, Colombia. MedUNAB 2015; 18 (1): 14-26]Introducción: Colombia está expuesta simultáneamente a las enfermedades transmitidas por vectores como la Enfermedad de Chagas (ECHA), así como a la carga creciente de la enfermedad cardiovascular de origen aterosclerótico (ECV). Objetivo: Estudiar a través del ensamblaje de un estudio de cohorte de adultos jóvenes de Bucaramanga, el desarrollo de la ECHA y la ECV. Metodología: Se diseñó un estudio a partir de donantes de sangre con tamización serológica para T. cruzi. Se construyó una base de datos de donantes consecutivos con estatus positivo (T[+]) apareada (en relación 1:4, estratificada por banco y mes de donación) con donantes T[-]. Los participantes fueron clasificados por estado serológico y electrocardiograma y evaluados clínicamente (realizando pruebas adicionales de función cardiovascular a los T[+] y a una muestra aleatoria de T[-]). En los siguientes años se iniciaron ensayos clínicos en los participantes T[+] y mediciones repetidas en los T[-] para estudios de riesgo de ECV. Resultados: De 6,228 donantes (18 a 50 años de edad) registrados en la base (1997-2003), 2,130 donantes de sangre (edad media 36.4 [DE 8.4] años, 64.0% hombres, 73.4% residentes en los estratos 1-3, 486 T[+]) consintieron participar. El protocolo de contacto, seguimiento y recuperación de participantes ha logrado que se obtengan mediciones repetidas en al menos el 80% de los participantes. Conclusiones: CHICAMOCHA constituye un activo de valor social que aumenta las capacidades locales de investigación. Se requieren esfuerzos continuados para ensanchar sus posibilidades de formación de investigadores, g e n e r a c i ó n d e p r o d u c t o s d e c o n o c i m i e n t o y recomendaciones para el sistema de salud.[Villar JC, Herrera VM, Cháves-Neira AM, Martínez-Contreras LX, Villar-Centeno LA, Ardila E, Marcell-Vásquez S, Vásquez SM. “Cardiovascular Health Investigation and Collaboration to Assess the Markers and Outcomes of Chagas disease” (CHICAMOCHA): Concepto, métodos y características de una cohorte de donantes de sangre en Bucaramanga, Colombia. MedUNAB 2015; 18 (1): 14-26]&nbsp

“Pesquisa de sáudes cardiovascular e colaborcao para evaliar os marcadores e os resultados da foeca da Chagas”: coceito, metordos e características de grupo de doadores de sagre em Bucaramanga, Colombia

Colombia está expuesta simultáneamente a las enfermedades transmitidas por vectores como la Enfermedad de Chagas (ECHA), asÍ como a la carga creciente de la enfermedad cardiovascular de origen aterosclerótico (ECV). Objetivo: Estudiar a través del ensamblaje de un estudio de cohorte de adultos jóvenes de Bucaramanga, el desarrollo de la ECHA y la ECV. MetodologÍa: Se diseñó un estudio a partir de donantes de sangre con tamización serológica para T. cruzi. Se construyó una base de datos de donantes consecutivos con estatus positivo (T[+]) apareada (en relación 1:4, estratificada por banco y mes de donación) con donantes T[-]. Los participantes fueron clasificados por estado serológico y electrocardiograma y evaluados clÍnicamente (realizando pruebas adicionales de función cardiovascular a los T[+] y a una muestra aleatoria de T[-]). En los siguientes años se iniciaron ensayos clÍnicos en los participantes T[+] y mediciones repetidas en los T[-] para estudios de riesgo de ECV. Resultados: De 6,228 donantes (18 a 50 años de edad) registrados en la base (1997-2003), 2,130 donantes de sangre (edad media 36.4 [DE 8.4] años, 64.0% hombres, 73.4% residentes en los estratos 1-3, 486 T[+]) consintieron participar. El protocolo de contacto, seguimiento y recuperación de participantes ha logrado que se obtengan mediciones repetidas en al menos el 80% de los participantes. Conclusiones: CHICAMOCHA constituye un activo de valor social que aumenta las capacidades locales de investigación. Se requieren esfuerzos continuados para ensanchar sus posibilidades de formación de investigadores, g e n e r a c i ó n d e p r o d u c t o s d e c o n o c i m i e n t o y recomendaciones para el sistema de salud.[Villar JC, Herrera VM, Cháves-Neira AM, MartÍnez-Contreras LX, Villar-Centeno LA, Ardila E, Marcell-Vásquez S, Vásquez SM. "Cardiovascular Health Investigation and Collaboration to Assess the Markers and Outcomes of Chagas disease " (CHICAMOCHA): Concepto, métodos y caracterÍsticas de una cohorte de donantes de sangre en Bucaramanga, Colombia. MedUNAB 2015; 18 (1): 14-26]Geographical and socio-demographic conditions expose Colombian population to the threat of vector-borne diseases (such as Chagas’ [CHAD]) and cardiovascular disease of atherosclerotic origin (CVD). Objective: To assemble a cohort study of young adults, to promote understanding of CHAD and CVD in Bucaramanga, Colombia. Methodology: A study of blood donors with serological screening for T.cruzi was designed. A database of consecutive donors with positive results (T[+]) was built. This group was compared with a random sample of T[-] individuals (1:4 ratio, within strata of bank and month of donation). Participants classified by serology and electrocardiography status underwent clinical interviews (additional cardiovascular tests to T[+] and a random sample to T[-] were performed. In the following years, T[+] individuals participated in randomized trials whereas those whereas those T[-] participated in repeated measurements to test CVD risk factors. Results: From 6,228 donors in the database (18 to 50 years old) registered in the database (1997-2203), 2,130 blood donors (mean age 36.4 (SD 8.4) years, 64% males, 73.4% living in low socioeconomic strata, 486 T[+]) agreed to participate. Our contact protocol, and follow-up procedure with participants allowed us to obtain repeatedly measurements of at least 80% of the participants. Conclusions: CHICAMOCHA represents a social asset that builds local research capacity. Continued efforts are required to enhance its potential for research training, scholarly work and health care guidance. [Villar JC, Herrera VM, Cháves-Neira AM, MartÍnez-Contreras LX, Villar-Centeno LA, Ardila E, Marcell-Vásquez S, Vásquez SM. "Cardiovascular Health Investigation and Collaboration to Assess the Markers and Outcomes of Chagas disease " (CHICAMOCHA): Concept, methods and characteristics of a cohort of blood donors in Bucaramanga, Colombia. MedUNAB 2015; 18 (1): 14-26

In vivo production of fluorine-18 in a chicken egg tumor model of breast cancer for proton therapy range verification

Range verification of clinical protontherapy systems via positron-emission tomography (PET) is not a mature technology, suffering from two major issues: insufficient signal from low-energy protons in the Bragg peak area and biological washout of PET emitters. The use of contrast agents including O-18, Zn-68 or Cu-63, isotopes with a high cross section for low-energy protons in nuclear reactions producing PET emitters, has been proposed to enhance the PET signal in the last millimeters of the proton path. However, it remains a challenge to achieve sufficient concentrations of these isotopes in the target volume. Here we investigate the possibilities of O-18-enriched water (18-W), a potential contrast agent that could be incorporated in large proportions in live tissues by replacing regular water. We hypothesize that 18-W could also mitigate the problem of biological washout, as PET (F-18) isotopes created inside live cells would remain trapped in the form of fluoride anions (F-), allowing its signal to be detected even hours after irradiation. To test our hypothesis, we designed an experiment with two main goals: first, prove that 18-W can incorporate enough O-18 into a living organism to produce a detectable signal from F-18 after proton irradiation, and second, determine the amount of activity that remains trapped inside the cells. The experiment was performed on a chicken embryo chorioallantoic membrane tumor model of head and neck cancer. Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeV protons (range in water: 0.74 mm), equivalent to clinical protons at the end of particle range. The activity produced after irradiation was detected and quantified in a small-animal PET-CT scanner, and further studied by placing ex-vivo tumours in a gamma radiation detector. In the acquired images, specific activity of F-18 (originating from 18-W) could be detected in the tumour area of the alive chicken embryo up to 9 h after irradiation, which confirms that low-energy protons can indeed produce a detectable PET signal if a suitable contrast agent is employed. Moreover, dynamic PET studies in two of the eggs evidenced a minimal effect of biological washout, with 68% retained specific F-18 activity at 8 h after irradiation. Furthermore, ex-vivo analysis of 4 irradiated tumours showed that up to 3% of oxygen atoms in the targets were replaced by O-18 from infused 18-W, and evidenced an entrapment of 59% for specific activity of F-18 after washing, supporting our hypothesis that F- ions remain trapped within the cells. An infusion of 18-W can incorporate O-18 in animal tissues by replacing regular water inside cells, producing a PET signal when irradiated with low-energy protons that could be used for range verification in protontherapy. F-18 produced inside cells remains entrapped and suffers from minimal biological washout, allowing for a sharper localization with longer PET acquisitions. Further studies must evaluate the feasibility of this technique in dosimetric conditions closer to clinical practice, in order to define potential protocols for its use in patients

Memoria del Derecho y disciplinas jurídicas. Estudios

This work collects the presentations made at the III International Seminar Memory of Law and Legal Disciplines (XIX-XX centuries) held on May 25 and 26, 2022 at the Santa María de la Rábida Campus of the International University of Andalusia, in Palos de la Frontera, Huelva. The following pages discuss the lives of legal scholars as well as the emergence of legal disciplines and legal education in Spain in the period spanning from the Moyano Law of Public Instruction (1857) to the University Reform Law (1983).PublishedEsta es una obra colectiva que recoge las contribuciones realizadas en el III Seminario Internacional Memoria del derecho y disciplinas jurídicas (siglos XIX-XX) celebrado los días 25 y 26 de mayo de 2022 en la Sede de Santa María de la Rábida de la Universidad Internacional de Andalucía, en Palos de la Frontera, Huelva. En estas páginas se da cuenta de la memoria del jurista, así como de la formación de las disciplinas y enseñanzas jurídicas, durante el largo período que va de la Ley Moyano de Instrucción Pública (1857) hasta Ley de Reforma Universitaria (1983)

Summary of Pb isotopic compositions in epitermal precios metal deposits, Orcopampa área of Southern Peru, Berenguela area of Western Bolivia, and the Maricunga belt in north-central Chile

The Mesozoic and Cenozoic Central Andes are divided into three Pb isotopic provinces, based upon the Pb isotopic compositions of ore minerals (MacFarlane et al., 1990). Macfarlane et al., 0990), furthermore, argue that the Pb isotopic compositions of the ore minerals reílect those of the igneous rocks associated with the deposits. Province I lies along the coast of Perú, Chile, and westernmost Bolivia. Mcsozoic and early Cenozoic volcapic and plutonic ares built upon a rifted and thinned continental margin dominate this province. Three subprovinces are distinguished based upon slight differences in Pb isotopic compositions. Province la includes northern and central Chile south of 19°S; province lb includes central Perú north of 13°S; whereas province le includes central and southern Perú between the two other subprovinces. Province II lies in the high Andes of central Perú and, perhaps, in northern Chile and Argentina, where miogeoclinal sedimentary rocks crop out and the crust underwent a lower magnitude of extension in the early Mesozoic. This region generally represents a back-arc position relative to the Mesozoic and early Cenozoic magmatic ares, and extensive magmatism related to the Andean cycle has only occurred since the Oligocene. Paleozoic ares are the dominant basement in this province. Province III lies in the Cordillera Oriental and Altiplano of Perú and Bolivia where Paleozoic, Mesozoic, and Cenozoic sedimentary rocks are multiply dcformed by thrust faults. Magma ti-e episodes of Triassic to Jurassic and Oligocene to Miocene age are documented. Proterozoic rocks of the Brazilian shicld are underthrust beneath the Cordillera Oriental, with the youngest shortcning episode beginning in the Oligocene. Province III is subdivided into two subprovinces: ma lies in southeastern Perú where both episodes of magmatism occurred, whereas IIIb lies in Bolivia where magmatism is primarily of Oligocene and Miocene age. Pb isotopic compositions for Province I are slightly less radiogenic than those from province II, whereas province III isotopic compositions are much more varied with consistently higher 207Pb/ 204pb and 208pb/204pb at a given 206pb/ 204pb_Province I Pb isotopic compositions (206pb/ 204pb =18.21-18.82; 207Pb/2<YíPb = 15.55-15.69; 2º8Pb/2º4Pb = 38.11-38.95) overlap with and extend below the average crustal growth curve of Staccy and Kramers (1975) on the uranogenic diagram (207pb/204pb versus 206pb/204Pb). Province lT Pb isotopic compositions (206pb/2<Yípb = 18.76-18.90; 207pb/204pb 15.62-15.73; 208pb/204pb 38.63-39.16) and Province III Pb isotopic compositions (206pb/204Pb 17.97-25.18; 207pb/204pb 15.51-16.00; 208pb/20/4pb 37.71-40.07) lie above the average crustal growth curve on the same diagram. The Pb isotopic compositions from these last two provinces require contribution from a high mu (238U/204pb) Proterozoic or Archean source. On the thorogcnic Pb isotopic variation diagram (208Pb/ 204Pb versus 206pb/204pb), isotopic compositions for province I, 11, and IIIa scatter along the average crustal growth curve of Stacey and Kramers (1975-) indicating that a time averaged Th/U ratio - 4 (the average cristal value) characterizes the Central Andes. Pb isotopic compositions for province IIIb are the most radiogenic and also the most heterogeneous. The variable radiogenic Pb isotopic compositions of province III suggcst heterogeneous upper cristal sources, whereas the isotopic compositions of province I probably reflect a mafic cristal lithospheric source, probably modified by subduction processcs. Province II isotopic compositions conceivably represent a mix betwecn the two model reservoirs

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality