Gobernanza para la supervisión ética de la investigación sobre COVID-19 en América Latina: un estudio exploratorio / Governance for ethical oversight of COVID-19 research in Latin America: an exploratory study

Presentación de "Estudio Exploratorio de los Marcos de Gobernanza para la Revisión y Supervisión Ética de la Investigación de COVID-19 en América Latina", trabajo descriptivo para identificar si los países de América Latina adoptaron políticas para acelerar la evaluación ética de las investigaciones, a la vez de que aseguraban los estándares éticos para su realización, durante la pandemia.

Satisfacción laboral de los médicos que trabajan en los servicios de emergencias en la República Argentina durante la pandemia por COVID-19 / Emergency department physicians’ job satisfaction in the Argentine Republic during the COVID-19 pandemic

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Governance frameworks for COVID-19 research ethics review and oversight in Latin America: an exploratory study.

BACKGROUND: Research has been an essential part of the COVID-19 pandemic response, including in Latin American (LA) countries. However, implementing research in emergency settings poses the challenge of producing valuable knowledge rapidly while upholding research ethical standards. Research ethics committees (RECs) therefore must conduct timely and rigorous ethics reviews and oversight of COVID-19 research. In the LA region, there is limited knowledge on how countries have responded to this need. To address this gap, the objective of our project is to explore if LA countries developed policies to streamline ethics review and oversight of research in response to the pandemic while ensuring its adherence to ethical standards, and to analyze to what extent these governance frameworks are in accordance with international guidance. METHODS: We conducted a descriptive and exploratory study assessing the COVID-19 research ethics governance frameworks of 19 LA countries, considering 4 dimensions based on international COVID-19 ethics guidance documents: (i) ethics review organizational model adopted, (ii) measures to coordinate between RECs and other research stakeholders, (iii) operational guidance for RECs, and (iv) key ethical issues for review and oversight of COVID-19 research. RESULTS: 10 out of 19 LA countries have some policy to streamline ethics review of COVID-19 research. Of these countries only 6 issued comprehensive documents following international guidance that contemplate strategies with recommendations for concrete actions for a timely and rigorous review. CONCLUSION: LA countries adopted partial strategies and operational guidance that may demonstrate a lack of a comprehensive view of research ethics for the review and oversight of COVID-19 research. Continuing efforts should be directed to strengthen LA countries' research capacity to respond timely and ethically to future health emergencies. Past lessons and the ones from this pandemic should be the basis to develop international standards and operational guidelines for ethics review and oversight of any research for public health emergencies.

Utilización de prácticas clínicas para promover la cesación tabáquica en personas que viven con VIH en Argentina / Use of smoking cessation clinical practices among persons living with HIV in Argentina

INTRODUCCIÓN: El consumo de tabaco en las personas que viven con VIH (PVV) en Argentina está entre un 40 y un 60%. El consumo de tabaco se relaciona con la aparición de cáncer en la población general y con una disminución de la respuesta al tratamiento antirretroviral en las PVV. Los médicos que atienden a las PVV pueden tener un papel fundamental en ayudar a sus pacientes a dejar de fumar. Este estudio examinó los factores relacionados con la utilización de las prácticas clínicas de cesación tabáquica en una muestra de médicos infectólogos que atienden a PVV en Argentina. MÉTODOS: Se administró una encuesta en línea a miembros de la Sociedad Argentina de Infectología, quienes referían atender a PVV. Se realizaron análisis descriptivos y modelos lineales generalizados. RESULTADOS: Participaron 138 profesionales (20,4% de los convocados). La implementación de métodos para la cesación tabáquica por los infectólogos fue significativamente mayor en aquellos profesionales que habían recibido educación al respecto (RPa: 1,22; IC 95%: 1,10-1,35), y disminuía significativamente en quienes no habían recibido entrenamiento formal (RPa: 0,64; IC 95%: 0,44-0,94). DISCUSIÓN: Hay necesidad de incorporar el entrenamiento en cesación tabáquica en la capacitación profesional de médicos que atienden a PVV para aumentar sus destrezas en estas prácticas clínicas y disminuir el consumo de tabaco en esta población

Unraveling the Influence of Common von Willebrand factor variants on von Willebrand Disease Phenotype: An Exploratory Study on the Molecular and Clinical Profile of von Willebrand Disease in Spain Cohort.

The clinical diagnosis of von Willebrand disease (VWD), particularly type 1, can be complex because several genetic and environmental factors affect von Willebrand factor (VWF) plasma levels. An estimated 60% of the phenotypic variation is attributable to hereditary factors, with the ABO blood group locus being the most influential. However, recent studies provide strong evidence that nonsynonymous single nucleotide variants (SNVs) contribute to VWF and factor VIII phenotypic variability in healthy individuals. This study aims to investigate the role of common VWF SNVs on VWD phenotype by analyzing data from 219 unrelated patients included in the "Molecular and Clinical Profile of von Willebrand Disease in Spain project." To that end, generalized linear mixed-effects regression models were fitted, and additive and epistatic analyses, and haplotype studies were performed, considering five VWD-related measures (bleeding score, VWF:Ag, VWF:RCo, factor VIII:C, and VWF:CB). According to these analyses, homozygotes: for p.Thr789Ala(C) would be expected to show 39% higher VWF:Ag levels; p.Thr1381Ala(C), 27% lower VWF:Ag levels; and p.Gln852Arg(C), 52% lower VWF:RCo levels. Homozygotes for both p.Thr789Ala(C) and p.Gln852Arg(T) were predicted to show 185% higher VWF:CB activity, and carriers of two copies of the p.Thr1381Ala(T)/p.Gln852Arg(T) haplotype would present a 100% increase in VWF:RCo activity. These results indicate a substantial effect of common VWF variation on VWD phenotype. Although additional studies are needed to determine the true magnitude of the effects of SNVs on VWF, these findings provide new evidence regarding the contribution of common variants to VWD, which should be taken into account to enhance the accuracy of the diagnosis and classification of this condition. ClinicalTrials.gov identifier: NCT02869074.

Exposure to tobacco in video games and smoking among gamers in Argentina.

BACKGROUND: Our objective was to assess whether exposure to tobacco in video games is associated with smoking among adolescent gamers from Argentina. METHODS: Cross-sectional data were analysed from students in public and private middle schools in Argentina. Tobacco content in video games was estimated using previously validated methods and adolescents' tobacco exposure was assessed by multiplying tobacco content in the top three video games they play by the hours played per day. The primary outcome was current smoking. Multilevel logistic regression models adjusted for clustering within schools, regressing current smoking on tobacco exposure in video games (ie, none, low, high) after controlling for age, sex, parental education, parenting style, parental rules about the use of video games, rebelliousness, sensation seeking and 'technophilia'. RESULTS: Of the 3114 students who participated, 92% of boys (1685/1802) and 56% of girls (737/1312) played video games and were included in the analytical sample. The prevalence of smoking was 13.8% among boys and 22.0% among girls; 74.5% of boys played video games more than 1 hour per day compared with 47.7% of girls. High exposure to tobacco content in video games compared with no exposure was independently associated with current smoking among girls (OR 1.78; 95% CI 1.02 to 3.09) but not among boys (OR 0.98; 95% CI 0.64 to 1.51). CONCLUSIONS: Greater exposure to tobacco content in video games was associated with higher likelihood of smoking among Argentine girls who play video games, suggesting the need for policies that limit these exposures.

Unraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNA.

Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to the identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7437G>A) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of three mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that four of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease. clinicaltrials.gov identifier:02869074.

Role of multimeric analysis of von Willebrand factor (VWF) in von Willebrand disease (VWD) diagnosis: Lessons from the PCM-EVW-ES Spanish project.

The multimeric analysis (MA) of plasma von Willebrand factor (VWF) evaluates structural integrity and helps in the diagnosis of von Willebrand disease (VWD). This assay is a matter of controversy, being considered by some investigators cumbersome and only slightly informative. The centralised study 'Molecular and Clinical Profile of von Willebrand Disease in Spain (PCM-EVW-ES)' has been carried out by including the phenotypic assessment and the genetic analysis by next generation sequencing (NGS) of the VWF gene (VWF). The aim of the present study was to evaluate the role of MA to the diagnosis of these patients and their potential discrepancies. Two hundred and seventy out of 480 patients centrally diagnosed with VWD had normal multimers, 168 had abnormal multimers and 42 a total absence of multimers. VWF MA was of great significance in the diagnosis of 83 patients (17.3%), it was also of help in the diagnosis achieved in 365 additional patients (76%) and was not informative in 32 cases (6.7%). With regard to discrepancies, 110 out of 480 (23%) patients centrally diagnosed with VWD presented some kind of discordance between VWF:RCo/VWF:Ag and/or VWF:CB/VWF:Ag ratios, multimeric study and/or genetic results. The VWF MA was key in the presence of novel mutations as well as in cases with phenotypic discrepancies. A comparison between the contribution of MA and VWF:CB showed a clearly higher contribution of the former in the diagnostic process. These data seem to reinforce the relevance of the VWF MA in VWD diagnosis, despite all its limitations.

Efecto de la terapia hormonal en bienestar de personas transgénero / Effect of hormone therapy on the well-being of transgender people

Frecuentemente las personas trans demandan terapia hormonal cruzada (THC) como estrategia de afirmación de género y, consecuentemente, como forma de mejorar su bienestar. El objetivo fue evaluar el efecto de la terapia hormonal cruzada (THC) sobre la calidad de vida en salud (CVS) y el funcionamiento psicológico en hombres y mujeres trans. Asimismo, se exploró la influencia de las modificaciones corporales y del estigma por identidad de género sobre estas variables. El componente transversal incluyó 102 personas trans sin THC, 91 personas trans bajo THC y 140 personas cisgénero. El componente longitudinal evaluó 64 personas trans al inicio y a los 6 meses de THC. Los participantes realizaron controles clínicos, exámenes de laboratorio y completaron una batería psico-social. Se encontró que las personas trans sin THC tienen un menor bienestar psicológico y CVS, en el componente de salud mental, que las personas trans bajo THC y las personas cisgénero. Sin embargo, este malestar se reduce a 6 meses de iniciada la THC. Además, se encontró que el estigma por identidad de género predice la salud mental de las personas trans, pero que el mismo se reduce cuando las personas acceden a la THC. Este estudio multicéntrico brinda evidencia acerca de la relevancia de facilitar el acceso a la THC en personas trans, conforme a la Ley de Identidad de Género

Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients.

Molecular diagnosis of patients with von Willebrand disease is pending in most populations due to the complexity and high cost of conventional molecular analyses. The need for molecular and clinical characterization of von Willebrand disease in Spain prompted the creation of a multicenter project (PCM-EVW-ES) that resulted in the largest prospective cohort study of patients with all types of von Willebrand disease. Molecular analysis of relevant regions of the VWF, including intronic and promoter regions, was achieved in the 556 individuals recruited via the development of a simple, innovative, relatively low-cost protocol based on microfluidic technology and next-generation sequencing. A total of 704 variants (237 different) were identified along VWF, 155 of which had not been previously recorded in the international mutation database. The potential pathogenic effect of these variants was assessed by in silico analysis. Furthermore, four short tandem repeats were analyzed in order to evaluate the ancestral origin of recurrent mutations. The outcome of genetic analysis allowed for the reclassification of 110 patients, identification of 37 asymptomatic carriers (important for genetic counseling) and re-inclusion of 43 patients previously excluded by phenotyping results. In total, 480 patients were definitively diagnosed. Candidate mutations were identified in all patients except 13 type 1 von Willebrand disease, yielding a high genotype-phenotype correlation. Our data reinforce the capital importance and usefulness of genetics in von Willebrand disease diagnostics. The progressive implementation of molecular study as the first-line test for routine diagnosis of this condition will lead to increasingly more personalized and effective care for this patient population.

Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm.

The diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/genotypic association was estimated in 96.5% of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis.

Infecciones Intrahospitalarias: Agentes, Manejo Actual y Prevención / Nosocomial Infections: Agents, Current Management and Prevention

Las infecciones intrahospitalarias se desarrollan en relación directa a la estancia hospitalaria. Considerando que la frecuencia de estas situaciones va entre en un 5 a 10% de pacientes hospitalizados es necesario conocer los agentes involucrados, las actuales medidas preventivas y los tratamientos hoy vigentes para el control de estas infecciones. De los agentes, quienes tienen mayor relevancia epidemiológica para estas infecciones son las bacterias, otros patógenos como virus y hongos son menos frecuentes pero igual de importantes en lo que a su atención se refiere. La prevención parte exclusivamente por el equipo médico considerando siempre que todas estas medidas giran en torno a las medidas practicadas sobre el paciente y al ambiente que rodea al mismo. El tratamiento de las diferentes infecciones se basa en el empleo de antibióticos a los cuales sea susceptible la bacteria identificada como causante de la infección.

Nosocomial infections develop in direct relation to hospital stay. Considering the frequeney of these situations goes from 5 to 10% of hospitalized patients is necessary to know the involved agents, the currently preventive measures and treatment to control these infections. Agents, who have greater epidemiological significance to these infections are bacteria, other pathogens such as viruses and fungus are less common but just as important as your care is concerned.The prevention is by the medical team exclusively considering that all these measures goes around the actions performed on the patient and the environment that surrounds it. The treatment of different infections is based on the use of antibiotics to which is susceptible the identified bacteria as the cause of infection.

Identification of deletion carriers in hemophilia B: quantitative real-time polymerase chain reaction or multiple ligation probe amplification.

Gross deletions in the F9 gene are easily detected by routinely sequencing hemophilia B-affected men. Nevertheless, a carrier diagnosis proves difficult as the presence of a normal allele does not recognize the partial or complete loss of the F9 gene and may be challenging if no DNA sample from affected men is available. This work aimed to identify hemophilia carriers in 2 families in which gross deletions of the F9 gene could be expected. The indirect genetic study was not conclusive, and sequencing did not show genetic defects in family 1. A real-time polymerase chain reaction (RT-PCR) assay using SYBR Green revealed the deletion of a copy of exon 8 in 3 women, whereas the multiple ligation-dependent probe amplification (MLPA) assay showed the deletion of a copy of exons 7 and 8 in these 3 women. These studies enabled us not only to rule out a pregnant woman as a carrier but also to confirm a complete deletion of the gene in the patient from family 2 and the heterozygous state of his mother. The advantages that the MLPA method offers are the identification of a multiple exon deletion in the same assay and commonly used technology. The RT-PCR technology used involves standardizing and analyzing each exon independently.

Novel missense mutation c.2685G>C (p.Q895H) in VWF gene associated with very low levels of VWF mRNA.

Homozygous patients for null alleles in VWF gene show a severe von Willebrand phenotype, whereas compound heterozygous patients only show the phenotype of the expressed allele. Five members of the same family were studied. The two patients showed borderline VWF levels, a mild factor VIII (FVIII) deficiency and a decrease of the binding of VWF to exogenous FVIII. The genetic analyses of the VWF gene confirmed that the patients were compound heterozygous for c.2561G>A (R854Q) and c.2685G>C (p.Q895H) mutations. The latter, is located in the 3' extreme of exon 20, and it has not been previously described. Studies of the cDNA from platelet mRNA were performed to investigate the expression of p.H895 allele. The loss of heterozygosity at the cDNA level suggests a lack of expression of the p.H895 allele. The overall studies can explain the type 2N phenotype of the two patients, since the allele carrying the new missense mutation p.Q895H has shown a low expression of VWF gene.

Severe and moderate hemophilia A: identification of 38 new genetic alterations.

Hemophilia A is an X-linked recessive disorder caused by a lack or decrease of factor VIII activity. Its socio-economic impact is high given its high bleeding expression and treatment cost. Our aim was to establish the mutation of each patient to improve family management. A total of 116 unrelated families with severe and moderate hemophilia A were involved. Non-carriers of intron 22 and intron 1 rearrangements were included in F8 gene screening. Intron 1 and 22 inversion frequencies were 3% and 52.5% respectively. Putative mutations were identified in all the families; 38 were new. The cumulative inhibitor incidence was 22%. Approximately half the families carry non-recurrent mutations, which were unique in around one third. Harmful effects for mutations predicting null alleles are expected. Missense mutation consequences are not easily predictable, despite the help of some bio-informatics tools.

Von Willebrand's disease: a novel mutation, P1824H and the incidence of R1205H defect among families with dominant quantitative von Willebrand factor deficiency.

To date, few mutations associated with a dominant quantitative deficiency of von Willebrand factor (VWF) and a high penetrance have been reported. This phenotype was confirmed in seven unrelated families of several patients diagnosed with von Willebrand's disease out of 70 who requested genetic studies of the VWF gene. The mutations linked to this type were identified: R1205H in five families; T1156M in one family; and the new P1824H alteration in one other family. The R1205H mutation linked to the different haplotypes might well be frequent among this variant. The P1824H in the A3 domain is associated with very low VWF levels and with a moderate-to-severe bleeding tendency, unlike the other mutations reported in this domain.

Essential role of limiting telomeres in the pathogenesis of Werner syndrome.

Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening.