ANÁLISIS DE LOS ESTUDIOS DE FARMACOLOGÍA CLÍNICA DE ONCOLOGÍA AUTORIZADOS POR LA AGENCIA REGULATORIA NACIONAL EN ARGENTINA ENTRE 2018 Y 2022 / Analysis of oncology clinical pharmacology studies authorized by the national regulatory agency of Argentina between 2018 and 2022

El paradigma tradicional de la investigación clínica farmacológica comprende la realización de estudios de fase 1, 2 y 3. Sin embargo, el reciente avance de lo que se ha dado en llamar "medicina de precisión" ha impulsado el surgimiento de innovaciones en el diseño de ensayos clínicos, en especial en el área de la oncología. Este artículo tiene como propósito describir y caracterizar los estudios de farmacología clínica de oncología autorizados por la Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) durante el período comprendido entre agosto de 2018 y julio de 2022; analizar el estado de situación de los diseños de los ensayos clínicos en oncología, las fases de investigación, los productos en investigación y el sitio de localización tumoral en relación con el avance de la medicina de precisión y los diseños innovadores.

The traditional paradigm of pharmacological clinical research involves carrying out phase 1, 2, and 3 studies. However, the recent advance of what has been called "precision medicine" has promoted the emergence of innovations in the design of clinical trials, especially in the area of oncology. The purpose of this article is to describe and characterize oncology clinical pharmacology studies authorized by the National Administration of Drugs, Food and Medical Devices (ANMAT) during the period from August 2018 to July 2022, and analyze the status of the clinical trial designs, research phases, investigational products and tumor site locations concerning the advancement of precision medicine and innovative designs

NCoA3 upregulation in breast cancer­associated adipocytes elicits an inflammatory profile.

Nuclear receptor coactivator 3 (NCoA3) is a transcriptional coactivator of NF­κB and other factors, which is expressed at relatively low levels in normal cells and is amplified or overexpressed in several types of cancer, including breast tumors. NCoA3 levels have been shown to be decreased during adipogenesis; however, its role in tumor­surrounding adipose tissue (AT) remains unknown. Therefore, the present study assessed the modulation of NCoA3 in breast cancer­associated adipocytes and evaluated its association with the expression of inflammatory markers. 3T3­L1 adipocytes were stimulated with conditioned medium from human breast cancer cell lines and the expression levels of NCoA3 were evaluated by reverse transcription­quantitative (q)PCR. NF­κB activation was measured by immunofluorescence, and tumor necrosis factor and monocyte chemoattractant protein 1 levels were analyzed by qPCR and dot blot assays. The results obtained from the in vitro model were supported using mammary AT (MAT) from female mice, MAT adjacent to tumors from patients with breast cancer and bioinformatics analysis. The results revealed that adipocytes expressing high levels of NCoA3 were mainly associated with a pro­inflammatory profile. In 3T3­L1 adipocytes, NCoA3 downregulation or NF­κB inhibition reversed the expression of inflammatory molecules. In addition, MAT from patients with a worse prognosis exhibited high levels of this coactivator. Notably, adipocyte NCoA3 levels could be modulated by inflammatory signals from tumors. The modulation of NCoA3 levels in synergy with NF­κB activity in MAT in a tumor context could be factors required to establish breast cancer­associated inflammation. As adipocytes are involved in the development and progression of breast cancer, this signaling network deserves to be further investigated to improve future tumor treatments.

Emergence and spread of a B.1.1.28-derived lineage with Q675H and Q677H Spike mutations in Uruguay

Uruguay was able to control the viral dissemination during the first nine months of the SARS-CoV-2 pandemic. Unfortunately, towards the end of 2020, the number of daily new cases exponentially increased. Herein we analyzed the country-wide genetic diversity of SARS-CoV-2 between November, 2020 and April, 2021. Our findings identified that the most prevalent viral variant during late 2020 was a B.1.1.28 sublineage carrying mutations Q675H+Q677H in the viral Spike, now designated as lineage P.6. This new lineage P.6 probably arose around November 2020, in Montevideo, Uruguays capital department and rapidly spread to other Uruguayan departments, with evidence of further local transmission clusters, also spread sporadically to the USA and Spain. The Q675H and Q677H mutations are in the proximity of the polybasic cleavage site at the S1/S2 boundary and also arose independently in many SARS-CoV-2 lineages circulating worldwide. Although the lineage P.6 was replaced by the Variant of Concern (VOC) P.1 as the predominant viral strain in Uruguay since April 2021, the monitoring of the concurrent emergence of Q675H+Q677H in VOCs should be of worldwide interest.

Implementation of a qPCR assay coupled with genomic surveillance for real-time monitoring of SARS-CoV-2 variants of concern.

We developed a genomic surveillance program for real-time monitoring of SARS-CoV-2 variants of concern in Uruguay. Here, we present the first results, including the proposed qPCR-VOC method, the general workflow and the report of the introduction and community transmission of the VOC P.1 in Uruguay in multiple independent events.

Recurrent dissemination of SARS-CoV-2 through the Uruguayan-Brazilian border

BackgroundUruguay is one of the few countries in the Americas that successfully contained the COVID-19 epidemic during the first half of 2020. Nevertheless, the intensive human mobility across the dry border with Brazil is a major challenge for public health authorities. We aimed to investigate the origin of SARS-CoV-2 strains detected in Uruguayan localities bordering Brazil as well as to measure the viral flux across this [~]1,100 km uninterrupted dry frontier. MethodsUsing complete SARS-CoV-2 genomes from the Uruguayan-Brazilian bordering region and phylogeographic analyses, we inferred the virus dissemination frequency between Brazil and Uruguay and characterized local outbreak dynamics during the first months (May-July) of the pandemic. FindingsPhylogenetic analyses revealed multiple introductions of SARS-CoV-2 Brazilian lineages B.1.1.28 and B.1.1.33 into Uruguayan localities at the bordering region. The most probable sources of viral strains introduced to Uruguay were the Southeast Brazilian region and the state of Rio Grande do Sul. Some of the viral strains introduced in Uruguayan border localities between early May and mid-July were able to locally spread and originated the first outbreaks detected outside the metropolitan region. The viral lineages responsible for Uruguayan suburban outbreaks were defined by a set of between four and 11 mutations (synonymous and non-synonymous) respect to the ancestral B.1.1.28 and B.1.1.33 viruses that arose in Brazil, supporting the notion of a rapid genetic differentiation between SARS-CoV-2 subpopulations spreading in South America. InterpretationAlthough Uruguayan borders have remained essentially closed to non-Uruguayan citizens, the inevitable flow of people across the dry border with Brazil allowed the repeated entry of the virus into Uruguay and the subsequent emergence of local outbreaks in Uruguayan border localities. Implementation of coordinated bi-national surveillance systems are crucial to achieve an efficient control of the SARS-CoV-2 spread across this kind of highly permeable borderland regions around the world. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSince the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of coronavirus disease 19 (COVID-19), was first detected in South America on February 26, 2020, it has rapidly spread through the region, causing nearly 350,000 deaths by December, 2020. In contrast to most American countries, Uruguay avoided an early exponential growth of SARS-CoV-2 cases and during the first six months of the pandemic it registered the lowest incidence of SARS-CoV-2 cases and deaths among South American countries. The intensive cross-border human mobility through the [~]1,100 km uninterrupted dry frontier between Uruguay and Brazil, might poses a major challenge for long-term control of the epidemic in Uruguay. Previous genomic studies conducted in Uruguay have analyzed sequences mostly sampled at the capital city, Montevideo, and detected prevalent SARS-CoV-2 lineages different from those described in Brazil, thus finding no evidence of frequent viral exchanges between these countries. Added value of this studyHere we present the first genomic study of SARS-CoV-2 strains detected in different Uruguayan and Brazilian localities along the bordering region. The samples analyzed include 30% (n = 59) of all laboratory confirmed SARS-CoV-2 cases from Uruguayan departments at the Brazilian border between March and July, 2020, as well as 68 SARS-CoV-2 sequences from individuals diagnosed in the southernmost Brazilian state of Rio Grande do Sul between March and August, 2020. We demonstrate that SARS-CoV-2 viral lineages that widely spread in the Southeastern Brazilian region (B.1.1.28 and B.1.1.33) were also responsible for most viral infections in Rio Grande do Sul and neighboring Uruguayan localities. We further uncover that major outbreaks detected in Uruguayan localities bordering Brazil in May and June, 2020, were originated from two independent introduction events of the Brazilian SARS-CoV-2 lineage B.1.1.33, unlike previous outbreaks in the Uruguayan metropolitan region that were seeded by European SARS-CoV-2 lineages. Implications of all the available evidenceOur findings confirm that although Uruguayan borders have remained essentially closed to non-Uruguayan citizens, dissemination of SARS-CoV-2 across the Uruguayan-Brazilian frontier was not fully suppressed and had the potential to ignite local transmission chains in Uruguay. These findings also highlight the relevance of implementing bi-national public health cooperation workforces combining epidemiologic and genomic data to monitor the viral spread throughout this kind of highly permeable dry frontiers around the world.

Doses of exposure to night shift work and nutritional status among nursing workers.

Introduction: Exposure to night work (NW) has been identified as a possible risk factor for body weight gain. Recent studies highlight the need to assess the intensity and frequency of exposure to night work (i.e., years of exposure and number of nights worked). Objectives: To investigate the relationships between the dose of exposure to night work (years working nights and number of nights worked) and nutritional status (excess weight, waist circumference), abdominal obesity, and body mass index in nursing professionals. Methods: Data were analyzed on night workers (n = 529) from a public hospital in Rio de Janeiro, Brazil. Descriptive analyses were conducted and crude and adjusted regression models were constructed to test the associations between exposures and outcomes. Analyses were performed using R, version 2.15. Results: Working at night for 10 years or more was associated with excess weight (odds ratio [OR] = 1.76; 95% confidence interval [95%CI] 1.14-2.72), with abdominal obesity (OR = 1.76; 95%CI 1.14-2.74), with increased body mass index (ß = 2.28; 95%CI 1.31-3.26), and with increased waist circumference (ß = 4.63; 95%CI 2.38-6.88), when compared with exposure to NW for less than 10 years, after adjusting for covariates. The current dose of night work only exhibited a borderline association between > 5 nights/fortnight and abdominal obesity (OR = 1.55; 95%CI 1.01-2.01). Conclusions: Detailing night work exposure can contribute data to support strategies for organizing working hours that consider the possibility of limiting the time exposed to night work.

Introdução: A exposição ao trabalho noturno (TN) vem sendo apontada como possível fator de risco para o aumento do peso corporal. Estudos recentes destacam a necessidade de avaliação da intensidade e da frequência da exposição ao TN (ou seja, anos de exposição e número de noites trabalhadas). Objetivos: Investigar a relação entre a dose de exposição ao TN (anos e número de noites trabalhadas) e o estado nutricional (excesso de peso, circunferência abdominal, obesidade abdominal e índice de massa corporal) em profissionais de enfermagem. Métodos: Foram analisados os dados referentes aos trabalhadores noturnos (n = 529) de um hospital público do Rio de Janeiro. Realizaram-se análises descritivas e modelos de regressão brutos e ajustados para testar as associações entre as exposições e os desfechos. As análises foram realizadas no programa R, versão 2.15. Resultados: Trabalhar à noite por 10 anos ou mais associou-se ao excesso de peso (odds ratio [OR] = 1,76; intervalo de confiança de 95% [IC95%] 1,14-2,72), à obesidade abdominal (OR = 1,76; IC95% 1,14-2,74), ao índice de massa corporal aumentado (ß = 2,28; IC95% 1,31-3,26) e à cintura abdominal aumentada (ß = 4,63; IC95% 2,38-6,88), comparado ao TN realizado há menos de 10 anos, após ajuste pelas covariáveis. No que se refere à dose atual de TN, foi observada apenas uma associação limítrofe entre mais de 5 noites/quinzena e a obesidade abdominal (OR = 1,55; IC95% 1,01-2,01). Conclusões: O detalhamento da exposição ao TN pode contribuir para subsidiar as estratégias de organização dos horários de trabalho que considerem a possibilidade de limitação do tempo de exposição ao TN.

An effective COVID-19 response in South America: the Uruguayan Conundrum

BackgroundSouth America has become the new epicenter of the COVID-19 pandemic with more than 1.1M reported cases and >50,000 deaths (June 2020). Conversely, Uruguay stands out as an outlier managing this health crisis with remarkable success. MethodsWe developed a molecular diagnostic test to detect SARS-CoV-2. This methodology was transferred to research institutes, public hospitals and academic laboratories all around the country, creating a "COVID-19 diagnostic lab network". Uruguay also implemented active epidemiological surveillance following the "Test, Trace and Isolate" (TETRIS) strategy coupled to real-time genomic epidemiology. ResultsThree months after the first cases were detected, the number of positive individuals reached 826 (23 deaths, 112 active cases and 691 recovered). The Uruguayan strategy was based in a close synergy established between the national health authorities and the scientific community. In turn, academia rapidly responded to develop national RT-qPCR tests. Consequently, Uruguay was able to perform [~]1,000 molecular tests per day in a matter of weeks. The "COVID-19 diagnostic lab network" performed more than 54% of the molecular tests in the country. This, together with real- time genomics, were instrumental to implement the TETRIS strategy, helping to contain domestic transmission of the main outbreaks registered so far. ConclusionsUruguay has successfully navigated the first trimester of the COVID-19 health crisis in South America. A rapid response by the scientific community to increase testing capacity, together with national health authorities seeking out the support from the academia were fundamental to successfully contain, until now, the COVID-19 outbreak in the country.

Multiple introductions, regional spread and local differentiation during the first week of COVID-19 epidemic in Montevideo, Uruguay

BackgroundAfter its emergence in China in December 2019, the new coronavirus disease (COVID-19) caused by SARS-CoV-2, has rapidly spread infecting more than 3 million people worldwide. South America is among the last regions hit by COVID-19 pandemic. In Uruguay, first cases were detected on March 13 th 2020 presumably imported by travelers returning from Europe. MethodsWe performed whole-genome sequencing of 10 SARS-CoV-2 from patients diagnosed during the first week (March 16th to 19th) of COVID-19 outbreak in Uruguay. Then, we applied genomic epidemiology using a global dataset to reconstruct the local spatio-temporal dynamics of SARS-CoV-2. ResultsOur phylogeographic analysis showed three independent introductions of SARS-CoV-2 from different continents. Also, we evidenced regional circulation of viral strains originally detected in Spain. Introduction of SARS-CoV-2 in Uruguay could date back as early as Feb 20th. Identification of specific mutations showed rapid local genetic differentiation. ConclusionsWe evidenced early independent introductions of SARS-CoV-2 that likely occurred before first cases were detected. Our analysis set the bases for future genomic epidemiology studies to understand the dynamics of SARS-CoV-2 in Uruguay and the Latin America and the Caribbean region.

Life-space mobility, perceived health, and depression symptoms in a sample of Mexican older adults.

Mobility in older adults is essential to preserving their physical independence and health. Changes in mobility are related to cognitive, physical, and emotional factors, among others. We explored symptoms of depression as a mediator variable between chronic diseases and comorbidities and the outcomes of perceived health and life-space mobility in a convenience sample of 135 older Mexican adults. A cross-sectional design was used. Simple and multiple linear regression models were adjusted to verify the assumptions of mediation using Baron and Kenny's model. Chronic diseases and comorbidities served as independent variables in two separate models, perceived health and life-space mobility served as dependent variables, and depressive symptoms as the mediator variable. Results showed that perceived health and life-space mobility are affected by chronic diseases and comorbidities. However, when symptoms of depression enter the equation, the ß coefficients decreased suggesting partial mediation. It is important to assess and treat depression symptoms in older adults rather than assuming that, at their age, depression is normal.

Diagnóstico radiográfico de coroas protéticas / Radiographic diagnosis of prosthetics crowns

O objetivo do presente estudo foi o de avaliar a presença e a ausência de falhas por meio de imagens radiográficas em coroas protéticas unitárias, em relação ao contorno proximal, contato proximal, excesso e falta de material, adaptação marginal e quanto ao término do preparo com a crista óssea alveolar. Participaram da pesquisa 292 pacientes inscritos para tratamento na Faculdade de Odontologia de Pernambuco - FOP/ UPE, onde, após avaliação clínica das coroas presentes, foi solicitada uma tomada radiográfica para melhor visualização. As imagens radiográficas foram analisadas através de um negatoscópio com lupa de três vezes de aumento. Todas as coroas analisadas apresentaram algum tipo de falha, identificando-se em uma mesma coroa mais de um defeito. Observou-se associação significante (p=0,034) entre a variável excesso de material em elementos anteriores, comparativamente aos elementos posteriores assim como associação (p=0,022) do término do preparo das coroas dos elementos posteriores em relação à proximidade da crista óssea alveolar. Concluiu-se, portanto, que a reabilitação protética deve não apenas restabelecer o princípio funcional e estético, mas principalmente o biológico, proporcionando uma harmonia com os tecidos periodontais e uma maior longevidade do trabalho restaurador. Este estudo, porém, observou uma forte presença de falhas na confecção de coroas protéticas.

The purpose of this study was to evaluate the presence and absence of failures by radiographic images of single prosthetic crowns, related to proximal contour, proximal contact, excess and lack of material, marginal fit and relation of the end of the preparation with the alveolar bone crest. Study participants included 292 patients enrolled for treatment at the Faculdade de Odontologia de Pernambuco - FOP/UPE, where after a clinical evaluation of the crowns, was conducted a radiographic procedure for optimal viewing. The radiographic images were analyzed using a negatoscope with a loupe with three times of increase. It was observed that all prosthetic crowns analyzed failed, identifying in a single crown more than one failure. It was observed significant association (p=0.034) between the variable excess of material in the anterior crowns, compared to posterior crowns, as well as association (p=0.022) between the cervical margin of the posterior crowns in relation to the proximity to the alveolar bone crest. It was concluded, therefore, that the prosthetics rehabilitation should not only restore the principle of aesthetic and functional, but mainly the biological, providing harmony between the prosthetic procedures and periodontal tissues and greater longevity of the restorative treatment, however this study observed a strong presence of failures in the confection of prosthetic crowns.