Evolución de la virulencia de SARS-CoV-2 en Chile / Evolution of the virulence of SARS CoV-2 in Chile

INTRODUCCIÓN: La evolución de la virulencia ha despertado el interés de la biología evolutiva por décadas. Se trata de co-evolución entre agentes patógenos y sus hospederos. Se han planteado diferentes hipótesis para la evolución de la virulencia, entre ellas la evolución con un compromiso virulencia-transmisión. OBJETIVO: Estudiar la evolución de la letalidad y la transmisión del SARS CoV-2 en Chile, con la hipótesis que ha existido un compromiso con disminución de la letalidad y aumento de la transmisión de esta durante la epidemia. RESULTADOS: La letalidad diaria en Chile disminuyó claramente. Aunque no se encontró correlación entre la letalidad diaria y el número reproductivo efectivo, el número reproductivo efectivo máximo asociado a cada variante viral, presentó un aumento claro desde la aparición de la variante γ en adelante (δ y O) en Chile. CONCLUSIÓN: Este estudio muestra una evolución de la virulencia con un compromiso virulenciatransmisión. Esto puede ser explicado en gran parte por la evolución viral, pero el cambio en letalidad también puede ser afectado por las intervenciones no farmacológicas y farmacológicas realizadas por la población humana.

BACKGROUND: The evolution of virulence has aroused the interest of evolutionary biology for decades. It is about co-evolution between pathogens and their hosts. Different hypotheses have been put forward for the evolution of virulence, including evolution with a virulence-transmission trade-off. AIM: To study the evolution of the fatality rate and transmission of SARS CoV-2 in Chile, with the hypothesis that there has been a trade-off to a decrease in lethality and an increase in its transmission during the epidemic. RESULTS: The daily fatality rate in Chile clearly decreased. Although no correlation was found between daily fatality rate and effective reproductive number, the maximum effective reproductive number associated with each viral variant showed a clear increase from the appearance of the γ variant onwards (δ and O) in Chile. CONCLUSION: This study shows an evolution of virulence with a virulence-transmission trade-off. This can be largely explained by viral evolution, but the change in lethality can also be affected by non-pharmacological and pharmacological interventions carried out by the human population.

[Review of the concept of herd immunity, in the context of COVID-19 epidemic and the development of vaccines]. / Revisión del concepto de inmunidad poblacional, a propósito de la epidemia COVID-19 y del desarrollo de vacunas.

The concept of herd immunity is briefly reviewed, showing that some popularized ideas do not correspond to the original concept. The relationship with the basic and effective reproductive numbers is established. It is pointed out that the threshold for the herd effect does not indicate the number of individuals that will be infected in an epidemic. The relationship with the effective vaccination threshold and its relationship with the effectiveness of the vaccine are established. The reducing effect of the herd immunity threshold produced by the heterogeneity of transmission and mixing in the population and the existence of isolated subpopulations are analyzed, which could be important and could explain the low levels of post-epidemic seroprevalence in some places helping to mitigate new outbreaks.

Revisión del concepto de inmunidad poblacional, a propósito de la epidemia COVID-19 y del desarrollo de vacunas / Review of the concept of herd immunity, in the context of COVID-19 epidemic and the development of vaccines

Resumen Se revisa brevemente el concepto de inmunidad de grupo, poblacional o efecto "rebaño", mostrando que algunas ideas popularizadas no corresponden al concepto original. Se establece la relación con los números reproductivo básico y efectivo, enfatizándose que el umbral para el efecto rebaño no indica el número de individuos que se contagiarán en una epidemia. Se establece la relación con el umbral de vacunación efectiva y su relación con la efectividad de la vacuna. Se analiza el efecto reductor del umbral de inmunidad de rebaño producido por la heterogeneidad de transmisión y mezcla en la población y la existencia de subpoblaciones aisladas lo que podría llegar a ser importante y que podría explicar los bajos niveles de seroprevalencia post-epidemia de algunos lugares, ayudando a mitigar nuevos brotes.

Abstract The concept of herd immunity is briefly reviewed, showing that some popularized ideas do not correspond to the original concept. The relationship with the basic and effective reproductive numbers is established. It is pointed out that the threshold for the herd effect does not indicate the number of individuals that will be infected in an epidemic. The relationship with the effective vaccination threshold and its relationship with the effectiveness of the vaccine are established. The reducing effect of the herd immunity threshold produced by the heterogeneity of transmission and mixing in the population and the existence of isolated subpopulations are analyzed, which could be important and could explain the low levels of post-epidemic seroprevalence in some places helping to mitigate new outbreaks.

[Bayesian inference in clinical reasoning]. / Bases científicas del razonamiento clínico: inferencia Bayesiana.

A conceptual analysis of diagnostic reasoning in clinical practice is carried out. Using Bayesian inference as an alternative to frequentist inference usually used in science, clinical reasoning uses the scientific method step by step. The concepts of scientific method, probability, statistics and Bayesian inference are reviewed, highlighting their fundamental differences with the frequentist approach. This paper shows how the diagnostic approach proceeds in a Bayesian sense, ending with a basic example of application.

Bases científicas del razonamiento clínico: inferencia Bayesiana / Bayesian inference in clinical reasoning

A conceptual analysis of diagnostic reasoning in clinical practice is carried out. Using Bayesian inference as an alternative to frequentist inference usually used in science, clinical reasoning uses the scientific method step by step. The concepts of scientific method, probability, statistics and Bayesian inference are reviewed, highlighting their fundamental differences with the frequentist approach. This paper shows how the diagnostic approach proceeds in a Bayesian sense, ending with a basic example of application.

Análisis comparado de la dinámica epidemiológica de la Influenza A (H1N1) en Chile / Comparative analysis of A(H1N1) influenza epidemiological dynamics in Chile

In order to increase awareness of the pandemic and to streamline control measures before any new outbreak of influenza we analyze the behavior of the cases of Chile and from 9 countries with more cases in 2009. Reproductive numbers, doubling times and estimations of susceptible and infected at the end of the epidemic were estimated. Epidemic curves to the situation in Chile under different initial conditions were adjusted and simulations for different reproductive numbers and notification scenarios were performed. The reproductive numbers varied between 1.37 and 1.82, with doubling times of between 5 and 8 days at 30 days of the epidemic. According to this, the proportions of infected by the end of the epidemic vary between 58 percent and 78.5 percent. The transmission coefficient ranged from 2 to 132 new cases per day x 10(6) susceptible individuals. The adjustments showed that the onset of the epidemic probably had more cases than reported. All estimates suggest that there must have been a large number of susceptible and therefore can not be explained as small outbreaks in 2009. A large number of susceptible individuals may still exist who are at risk from a possible new outbreak.

[Short-term predictability of influenza AH1N1 cases based on deterministic models]. / Predictibilidad a corto plazo del número de casos de la influenza pandémica AH1N1 basada en modelos determinísticos.

Influenza AH1N1 severely affected the population of Chile. It has high transmissibility, which may stress the health system capacity. An adequate prediction of number of cases and frequency of complications is needed. Chilean and OMS dialy reports of cases from April to Jun 2009 were analyzed in this study. We developed a simple methodology for short-term forecast of case number, based on deterministic models. Predicted and observed values were compared with regression analyses and Bland-Altman diagrams. We found that the intrinsic rate of increase of the number of cases in the world and in Chile, after an initial high instability, decreases to stable valúes, allowing a relatively accurate forecasting the next day and for a serial period. The estimators obtained are over-estimators, which allow an adequate safety factor for the estimations. The method is easy to implement in software for routine use and can be useful in monitoring this epidemic and others in the future.

Percolación de la epidemia de influenza AH1N1 en el mundo: utilidad de los modelos predictivos basados en conectividad espacial / Percolation of infuenza AH1N1 epidemic in the world: usefulness of the spatial-connectivity models

Background: The 2009 AH1N1 epidemics expanded rapidly around the world by the current connectivity conditions. The spread of epidemics can be described by the phenomenon of percolation, that allows the estimation of the threshold conditions that produce connectivity between different regions and that has been used to describe physical and ecological phenomena. Aim: To analyze the spread of AH1N1 epidemic based on information from the WHO. Material and Methods: The world was considered as composed of a set of countries and regular cells. The moment when the percolation occurred was analyzed and logistic regressions were adjusted to the change in the proportion of infected units versus time, comparing predicted and observed rates. Results: Percolation occurred in America on day 15, in Eurasia on day 32 and in the world on day 74. The models showed adequate predictive capacity. The predictions for the percolation of the epidemic in the world varied between days 66 and 75. The prediction based on countries was better than that based on cells. Conclusions: These results show that percolation theory fts well to the spread of epidemics. Predictions based only on data on-off (infected non infected) and in the progression of the proportion of infected cells are a good way of predicting the spread of an epidemic and when this crosses a region geographically.

Predictibilidad a corto plazo del número de casos de la influenza pandémica AH1N1 basada en modelos determinísticos / Short-term predictability of influenza AH1N1 cases based on deterministic models

Influenza AH1N1 severely affected the population of Chile. It has high transmissibility, which may stress the health system capacity. An adequate prediction of number of cases and frequency of complications is needed. Chilean and OMS dialy reports of cases from April to Jun 2009 were analyzed in this study. We developed a simple methodology for short-term forecast of case number, based on deterministic models. Predicted and observed values were compared with regression analyses and Bland-Altman diagrams. We found that the intrinsic rate of increase of the number of cases in the world and in Chile, after an initial high instability, decreases to stable valúes, allowing a relatively accurate forecasting the next day and for a serial period. The estimators obtained are over-estimators, which allow an adequate safety factor for the estimations. The method is easy to implement in software for routine use and can be useful in monitoring this epidemic and others in the future.

La influenza AH1N1 se encuentra asolando gravemente a la población de Chile. Tiene transmisibilidad alta, lo que puede afectar la capacidad del sistema de salud por lo que se necesita una adecuada predicción de los posibles casos y complicaciones. Estudiamos los reportes diarios de casos totales emitidos por la OMS y los reportes actualizados de la situación en Chile desde abril a junio de 2009. En este estudio desarrollamos una metodología simple para la predicción a corto plazo de los casos, basada en modelos determinísticos y comparamos los valores predichos con los observados con análisis de regresión y diagramas de Bland-Altman. Encontramos que la tasa intrínseca de crecimiento del número de casos en el mundo y en Chile, después de una inestabilidad y valores iniciales altos, decrece estabilizándose y permitiendo una predicción relativamente buena al día siguiente y a un período serial. Los estimadores que se obtienen son sobre-estimadores, lo que permite un coeficiente de seguridad adecuada para las estimaciones. El método es de implementación rápida en programas computacionales de uso habitual y puede ser de utilidad en el seguimiento de esta epidemia y de otras futuras.

Comparison of the oxygen diffusing capacity of the picui ground dove (Columbina picui) with other doves of Chile / Comparación de la capacidad de difusión de oxígeno de la tórtola picus (Columbina picui) con otras tórtolas de Chile

We studied the respiratory surface density and the thickness of the air-blood barrier in the Picui Ground Dove (Columbina picui), and compared it with Eared Dove (Zenaida auriculata) and Blacked-winged Ground Dove (Metropelia melanoptera), two larger species. As expected, Columbina picui BMR and VO2max showed higher values than those of the larger species according to the expected for their body size. The respiratory surface density and the thickness of the blood-air barrier were not different among the different species of doves. However C. picui showed an anatomical diffusion factor lower than M. melanoptera and Z. auriculata. Picui Ground Dove had low values of oxygen diffusion capacity, such as cursorial birds. A differential oxygen partial pressure of 7.5 Kpa, an usual value at sea level, it can hardly meet their maximal energy requirements and it means that Picui Ground Dove, would have serious limitations to live at high altitudes, which is consistent with the observation that this species inhabits lowlands and at the foot hills of the Andes.

Se estudió la densidad de superficie respiratoria y el espesor de la barrera sangre-aire en la Tortolita cuyana (Columbina picui), y se comparó con la Tórtola cordillerana (Metropelia melanoptera) y la Tórtola (Zenaida auriculata), dos especies más grandes. Como era de esperar, en C. picui el metabolismo basal y el metabolismo máximo fueron más altos que los de especies más grandes, pero de acuerdo a lo esperado para el tamaño corporal. La densidad de la superficie respiratoria y el espesor de la barrera sangre-aire no fueron diferentes entre las diferentes especies de tórtolas. Sin embargo C. picui mostró un factor de difusión anatómica inferior a M. melanoptera y Z. auriculata. C. picui tuvo valores bajos de capacidad de difusión de oxígeno, como las aves cursoriales. A una diferencia de presión parcial de oxígeno de 7,5 Kpa, un valor habitual a nivel del mar, apenas podría satisfacer sus necesidades de energía máxima y esto significa que tendría serias limitaciones para vivir a gran altura, lo cual es coherente con la observación de que esta especie habita en las tierras bajas y en la zona precordillerana de los Andes.

[Comparative analysis of A(H1N1) influenza epidemiological dynamics in Chile]. / Análisis comparado de la dinámica epidemiológica de la Influenza A (H1N1) en Chile.

In order to increase awareness of the pandemic and to streamline control measures before any new outbreak of influenza we analyze the behavior of the cases of Chile and from 9 countries with more cases in 2009. Reproductive numbers, doubling times and estimations of susceptible and infected at the end of the epidemic were estimated. Epidemic curves to the situation in Chile under different initial conditions were adjusted and simulations for different reproductive numbers and notification scenarios were performed. The reproductive numbers varied between 1.37 and 1.82, with doubling times of between 5 and 8 days at 30 days of the epidemic. According to this, the proportions of infected by the end of the epidemic vary between 58% and 78.5%. The transmission coefficient ranged from 2 to 132 new cases per day x 10(6) susceptible individuals. The adjustments showed that the onset of the epidemic probably had more cases than reported. All estimates suggest that there must have been a large number of susceptible and therefore can not be explained as small outbreaks in 2009. A large number of susceptible individuals may still exist who are at risk from a possible new outbreak.

Valor de la secuencia de difusión en el estudio de cáncer de próstata en pacientes con antígeno prostático específico elevado / Value of diffusion-weighted sequences in the study of prostate cancer in patients with increased prostate specific antigen levels

En el carcinoma prostático la arquitectura glandular es reemplazada por células cancerosas, produciendo barreras al movimiento del agua, que pueden ser estudiadas con resonancia magnética potenciada en difusión. Para evaluar el aporte de estas secuencias en el estudio de la próstata, realizamos estudio descriptivo e inferencia!, utilizando difusión en 26 pacientes con tacto rectal anormal y antígeno prostático elevado. Se analizó sensibilidad, especificidad y curvas ROC basadas en coeficiente aparente de difusión (CAD). Se realizó biopsia prostática en 14 pacientes; 7 resultaron positivos. Con CAD <1000 um2/s, se encontraron altas sensibilidades con bajas especificidades y valores predictivos moderados. Incorporando T2 mejoraron: certeza diagnóstica, especificidad y valores predictivos. Al comparar los valores CAD en zonas con y sin cáncer, obtuvimos diferencias para CAD promedio y mínimo. Las curvas ROC mostraron áreas elevadas y significativas, sugiriéndose valores de corte de 1059 um2/s y 969 um2/s entre "normales" y con cáncer; LR(+) para valores de corte: 6,97 y 5,23 respectivamente. Nuestros resultados permiten proponer que se obtiene mayor ganancia diagnóstica en la interpretación conjunta de imágenes T2 y secuencias de difusión y que CAD permite diferenciar entre tejido normal y cáncer, por lo que se debiera incorporar en el estudio prostático.

In prostatic carcinoma, the glandular architecture is replaced by cancer cells producing barriers to water motion, anomaly that can be studied through diffusion-enhanced MRI technique. To assess the contribution of these sequences in the prostate cancer exploration, we conducted a descriptive and inferential study using diffusion-enhanced MRI technique in 26 patients with abnormal digital rectal examination (DRE) and increased prostate specific antigen (PSA) values. We analyzed sensitivity, specificity and ROC curves based on apparent diffusion coefficient (ADC). Seven out of 14 biopsies were positive in patients undergoing prostate biopsy. When applying ADC <1000 _m2/se, high sensitivity with low specificity levels, as well as moderate predictive values were obtained. By incorporating T2-weighted images, improved diagnostic accuracy, specificity and predictive values were achieved. When comparing ADC values in tissues with and without cancer, average and minimum ADC appeared to exhibit different values. ROC curves depicted increased and significant values, suggesting cutoff values of 1059 um2/s and 969/um2/s for healthy and malignant tissues, respectively; LR (+) for cut-off value: 6.97 and 5.23, respectively. Our results enable us to propose that improved diagnostic outcomes are attained through combined interpretation of T2-weighted images and diffusion-weighted sequences and that the ADC permits discrimination between normal and malignant tissues. Therefore, we strongly support that these criteria should be taken into account when performing prostate explorations.

Hallazgos de imagen en tomografia computada de voluntarios fumadores de larga data / Findings on computed tomography imaging of long-standing volunteer smokers

The finding of pulmonary nodules in computed tomography is extremely common, with a reported prevalence ranging between 8 percent and 51 percent in volunteers, usually around 25 percent. Of these, about 2 percent to 13 percent are malignant nodules. Age, medical records of extra thoracic cancer existing 5 years before nodule detection, spiculated edges, big size, upper location and a recorded history of tobacco consumption are major risk factors for malignancy. Among these, smoking is one of the most common, with a known increased risk of malignancy (Odds ratio= 2.2). Working with the hypothesis that in smokers a higher prevalence of lesions is expected when compared to the normal population, we conducted a thoracic computed tomography study in 239 volunteers over 38 years (103 men and 135 women), who had been consuming more than 15 cigarettes a day over more than 10 years. Data were analyzed with statistical parametric and multivariate analyses. Some types of lesions were found in 82.5 percent of men and in 87.4 percent of women, being lung (53.7 percent) and mediastinal (13.8 percent) injuries the most frequent ones. Among these, bulls, scars, mediastinal lymphadenopathy and nodules constituted the main lesions (between 21.4 percent and 44.7 percent of the injuries). Nodules accounted for 21.4 percent of lesions in men and 25.2 percent in women, which falls within the normal range as described in volunteers. The cluster analysis, applied in conjunction with Jaccard coefficient of association, showed that nodules do not exist in isolation but in conjunction with other signs, forming a cluster that contains bulls, nodules, scars, mediastinal lymphadenopathy, aortic calcifications, and pleural thickening. Among lesions of potential oncological relevance, an overall finding of 5.83 percent in men and 4.44 percent in women is documented. Solitary nodules were found in 12 males and in 29 females, of whom 7 (58.3 percent) and 10 (34.5 percent), respectively...

El hallazgo de nodulos pulmonares en tomografía computada es extremadamente común, habiéndose reportado prevalencias entre 8 y 51 por ciento en voluntarios, habitualmente alrededor de 25 por ciento; de éstos, 2 a 13 por ciento serían malignos. La edad, antecedente de cáncer extratorácico más de 5 años antes del nodulo, bordes espiculados, gran tamaño, localizador superior y antecedente de consumo de cigarrillos son los principales factores de riesgo de malignidad. El cigarrillo es uno de los más comunes, con conocido aumento del riesgo (Odds ratio= 2.2). Trabajando con la hipótesis que en fumadores se espera mayor prevalencia de lesiones que en la población normal, estudiamos con tomografía computada de tórax 239 voluntarios mayores de 38 años (103 hombres, 135 mujeres), consumidores de más de 15 cigarrillos diarios por más de 10 años. Se analizaron los datos con estadística paramétrica habitual y multivariada. Encontramos 82,5 por ciento hombres y 87,4 por ciento mujeres con alguna lesión; las más frecuentes: pulmonares (53,7 por ciento) y mediastínicas (13,8 por ciento); las principales: bulas, cicatrices, adenopatías mediastínicas y nodulos (21,4 a 44,7 por ciento de las lesiones). Los nodulos correspondieron a 21,4 por ciento de las lesiones en hombres y 25,2 por ciento en mujeres, en rango habitual para lo descrito en voluntarios. El análisis de conglomerados con índice de asociación Jaccard mostró: los nodulos no se presentan aislados, evidenciándose un conglomerado que contiene: bulas, nodulos, cicatrices, adenopatías mediastínicas, calcificaciones aórticas y engrosamiento pleural. Entre las lesiones de posible importancia oncológica destacan: 5,83 por ciento en hombres y 4,44 por ciento en mujeres; 12 nodulos solitarios en hombres y 29 en mujeres, de los cuales 7 (6,8 por ciento) y 10 (7,4 por ciento) constituirían indicaciones de acciones diagnóstico-terapéuticas de mayor agresividad.

Buscando una curva general de respuesta a la quimioterapia basada en la evaluación radiológica con criterio RECIST / Looking for a general response curve to chemotherapy based on radiological evaluation with RECIST criteria

Radiological evaluation of response to chemotherapy can be carried out by applying the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, currently considered the most objective method for monitoring lesions. Aimed at finding a general response curve, 21 patients with lung and kidney tumors, as well as colorectal carcinoma were studied between 2006 and 2008. Statistical proceedings included variance (ANOVA), co-variance (ANCOVA) and logarithmic regression analysis. Target-lesion size reduction, duration of response and overall response of different types of tumors did not differ significantly A general response curve was obtained: log (RR)= 1,897-0,0281, where RRt is the relative RECIST count, and t is time (expressed in months). As an expected outcome -because of variety of drugs, type of tumors and variability rates in individual response- the determination coefficient in regression was 10.9 percent. However, it constitutes a first approach to solid tumors response and proves the accuracy and usefulness of RECIST methodology.

La evaluación radiológica de respuesta a la quimioterapia se puede hacer con el criterio RECIST, considerado actualmente el método más objetivo de seguimiento de lesiones. Con el objetivo de buscar una curva general de respuesta, entre los años 2006 y 2008 estudiamos 21 pacientes con tumores pulmonares, renales y cáncer colo-rectal. La estadística consistió en análisis de varianza (ANOVA), covarianza (ANCOVA) y regresión logarítmica. La reducción en tamaño y el tiempo de respuesta no difirieron significativamente, así como tampoco la respuesta global de los diferentes cánceres. Se obtuvo una curva general de respuesta: log (RR)= 1,897 -0,028 t, (RR= evaluación RECIST actual dividida por inicial y t= tiempo en meses). El coeficiente de determinación de la regresión fue 10,9 por ciento, esperable por la diversidad de fármacos, tipo de tumor y respuesta individual; sin embargo constituye una primera aproximación a la respuesta esperada mostrando la utilidad y objetividad del método.