Why is the study important?

English: In Chile, cervical cancer causes the death of more than 600 women each year and is the second leading cause of death by cancer in women of fertile age. The mortality rate for this cancer (7.6/100,000 women) is four times higher than that in developed countries. In addition, the distribution of mortality presents a large socioeconomic inequality, principally affecting women with lower socioeconomic status, whose mortality rate is one of the highest in the world. Moreover, Chilean women have changed their sexual behaviour in recent years, increasing their risk factors for cervical cancer, such as earlier initiation of sexual activity and having more sexual partners. Furthermore, the incidence of infection by high-risk Human papillomaviruses (HPV), causal agent of cervical cancer, has been increasing in Chilean women. These facts could lead to an increase in this type of cancer in Chile. It is estimated that the incidence of cervical cancer in Latin America will increase more than 75% in the next 20 years, due to demographic changes. All of this highlights the importance of improving the effectiveness and equity of the national cervical cancer prevention programme. The Chilean programme uses Papanicolaou (Pap) every three years for screening women between 25 and 64 years old, but the diagnostic accuracy of this test has never been evaluated in the country. A screening strategy that has been thoroughly studied throughout the world uses a test that detects the presence of HPV, and has demonstrated a greater sensitivity than Pap and is currently being routinely used in some developed countries. This is the first study in Chile that has evaluated the sensitivity and specificity of Pap and HPV in the clinical practice of public health centres. The study demonstrated a very low sensitivity for Pap (22%) and a sensitivity four times better for HPV (93%), the latter detecting three times more high grade lesions.

Por qué es importante  el estudio?

Spanish: En Chile, el cáncer cervicouterino causa la muerte de más de 600 mujeres cada año y es la segunda causa de muerte por cáncer en mujeres en edad fértil. La tasa de mortalidad por este cáncer (7.6/100 000 mujeres) es cuatro veces más alta que la de países desarrollados. Además, la distribución de la mortalidad presenta una gran desigualdad socioeconómica, afectando principalmente a mujeres de bajo nivel, cuya tasa de mortalidad es de las más altas a nivel mundial. Por otro lado, las mujeres chilenas han cambiado su comportamiento sexual en los en los últimos años, incrementando sus factores de riesgo para cáncer cervicouterino, como son un inicio más temprano de la actividad sexual y un mayor número de parejas sexuales. Asimismo, la incidencia de la infección por virus papiloma humano (VPH) de alto riesgo, agente causal del cáncer cervicouterino, ha ido aumentando en la mujer chilena. Estos hechos podrían llevar a un incremento de este cáncer en Chile. Se estima que la incidencia de cáncer cervicouterino en América Latina incrementará en más de 75% en los próximos 20 años, debido a cambios demográficos. Todo esto resalta la importancia de mejorar la efectividad y equidad del programa nacional de prevención de cáncer cervicouterino. El programa chileno utiliza un Papanicolaou (Pap) cada tres años para el tamizaje de mujeres entre 25-64 años, pero nunca se ha evaluado la exactitud diagnóstica de este examen en el país. Una estrategia de tamizaje que ha sido ampliamente estudiada a nivel mundial es la utilización de un examen de detección del VPH, que ha demostrado tener una mayor sensibilidad que el Pap y está siendo utilizado actualmente en forma rutinaria en algunos países desarrollados. Éste es el primer estudio en Chile que ha evaluado la sensibilidad y especificidad del Pap y el VPH en la práctica clínica de centros de salud públicos. El estudio demostró una muy baja sensibilidad para el Pap (22%) y una sensibilidad cuatro veces mayor para el VPH (93%), el que detectó tres veces más lesiones de alto grado.

What is the technical difference between HPV and Pap; how do they work and how do they predict the presence of cancers? Why is HPV thought to be a more sensitive test?

English: The main difference is that Pap is analysed using a visual technique that results in a subjective qualitative judgement, while HPV is analysed via an automated method in which a machine produces an objective quantitative result.

The Pap smear, or conventional cervical cytology, consists of an inspection of cervical cells in order to identify cellular alterations that occur in precancerous lesions and cancer. For this test a sample of cervical cells is taken and transferred to a glass slide and sent to the laboratory for examination by a cytotechnologist or pathologist. The performance of Pap largely depends on the training and experience of both the person taking the sample and the person doing the analysis. Error can occur in different ways: at the time of sampling the spatula may not pass through the precise area of the lesion and miss the altered cells and, when inspecting the slide, it is possible that the altered cells are hidden under mucus or blood or the cytotechnologist does not exhaustively scan the slide and, therefore, may not observe them. Finally, a subjective judgment is given that depends on the criteria of the individual, who needs to assess whether what is being observed is normal or abnormal according to the shape and size of the cells’ nuclei and determine the magnitude of the lesion based on the quantity and distribution of the abnormal cells that are being observed. For these reasons the sensitivity of Pap testing varies greatly even in developing countries, with figures reported between 20% in Germany and 77% in England.

The HPV test consists of the detection in the cervix of DNA from the high-risk human papillomavirus group, the causal agent of cervical cancer, identifying, therefore, women that might be at risk of developing cancer (but do not necessarily have lesions). For this test, a sample of cells is taken from the cervix that is later put into a tube with transport medium and sent to the laboratory for analysis in special equipment. To be able to detect the DNA from HPV, only a single virus needs to be found in the sample, since the technique amplifies the signal of the genetic material, thus not requiring a sample of such high quality as the Pap. Furthermore, the sample  is read by machines that give a quantitative result with a predetermined cut-off point, which makes this technique highly reproducible. Because this analysis is automated, it reduces the subjectivity and the possibility of human error and, therefore, variation in the test performance. For this reason, while lower levels of sensitivity have been reported in developing countries, the sensitivity reported in developed countries is consistently high, around 97-99%.

¿Cuál es la diferencia técnica entre HPV y Pap; cómo trabajan y predicen la presencia de canceres?

Spanish: La principal diferencia es que el Pap se analiza mediante una técnica visual en que se emite un juicio cualitativo subjetivo, mientras que el VPH se analiza mediante una técnica automatizada en que una máquina emite un resultado cuantitativo objetivo.

El Pap, o citología convencional de cuello uterino, consiste en un estudio de las células del cuello uterino con el objetivo de identificar alteraciones celulares que ocurren en lesiones precancerosas y cáncer. Para este examen se toma una muestra de células del cuello uterino que luego se extiende en una placa de vidrio y se envía al laboratorio para su estudio por un citotecnólogo o patólogo. El desempeño del Pap depende en gran medida del entrenamiento y experiencia tanto de la persona que toma la muestra como del que la analiza. Se puede producir error en distintos puntos: en el momento de la toma de muestra es posible que la espátula no pase por el área precisa de la lesión y que no obtenga células alteradas y, al estudiar la placa, es posible que células alteradas queden ocultas bajo mucosidad o sangre o que el citotecnólogo no recorra exhaustivamente toda la placa y, por lo tanto, no pueda observarlas. Finalmente, se emite un juicio subjetivo que depende del criterio de la persona, quien debe calificar lo que está observando como normal o anormal según el tamaño y forma de los núcleos celulares y determinar la magnitud de una lesión según la cantidad y distribución de las células anormales que observe. Es por todo esto que la sensibilidad del Pap varía mucho incluso en países desarrollados, reportándose cifras desde 20% en Alemania hasta 77% en Inglaterra.

El examen de VPH consiste en la detección en el cuello uterino de ADN del grupo de virus papiloma humano de alto riesgo, agente causal del cáncer cervicouterino, identificando, por lo tanto, a mujeres que pueden estar en riesgo de desarrollar cáncer (pero no necesariamente tienen lesiones). Para este examen se toma una muestra de células del cuello uterino que luego se introduce en un tubo con medio de transporte y se envía al laboratorio para su análisis en un equipo especial. Para que se detecte el ADN de VPH, basta con que haya un solo virus en la muestra, ya que la técnica amplifica la señal del material genético, por lo que no se requiere una muestra de tan alta calidad como el Pap. Por otro lado, la muestra se lee en máquinas que dan un resultado cuantitativo, con un punto de corte previamente determinado, lo que hace que esta técnica sea altamente reproducible. Como este análisis es automatizado, se disminuye la subjetividad y posibilidad de error humano y, por tanto, la variabilidad en el desempeño. Es por esto que, aunque se han reportado cifras de sensibilidad menores en países en desarrollo, la sensibilidad reportada en países desarrollados es consistentemente alta, alrededor de 97-99%.

What are the contributing factors to the high cervical cancer rates in Chile/Latin America?

English: Women have a higher prevalence of risk factors for cervical cancer in Latin America, such as a greater number of children, early age of sexual initiation and high rate of male infidelity, contributing to an increased incidence; however, the main contributing factor to the high mortality rate in this region is the difficulty in implementing effective prevention programmes, mainly for economic reasons. The difficulties range from  reaching appropriate coverage – a study in Chile demonstrated that 48% of women with cancer hadn’t undergone Pap screening in at least 10 years – to achieving good follow-up of screen-positive women, with timely diagnosis and treatment – a study in Peru showed that only 25% of women with an abnormal Pap received  adequate follow-up.

¿Cuáles son los factores contribuyentes a la alta tasa de cáncer cervical en Chile/Latin América?

Spanish: En América Latina las mujeres tienen mayor prevalencia de factores de riesgo de cáncer cervicouterino, como son un mayor número de hijos, edad precoz de iniciación sexual y alta tasa de infidelidad masculina, lo que contribuye a una mayor incidencia; sin embargo, el factor que más contribuye a la alta tasa de mortalidad en esta región es la dificultad de implementar programas de prevención efectivos, principalmente por causas económicas. Las dificultades van desde el alcanzar una adecuada cobertura ─un estudio en Chile demostró que el 48% de las mujeres con cáncer no habían recibido un Pap en al menos 10 años─ hasta lograr un buen seguimiento de las mujeres con tamizaje positivo para obtener un diagnóstico y tratamiento oportuno ─un estudio en Perú demostró que sólo 25% de las mujeres con Pap anormales recibieron un seguimiento adecuado.

Has the National cervical cancer prevention program been thoroughly evaluated over the years? How effective do you think it is? Is the decline in cervical cancer rate over time due to the program or other factors?

English: The national cervical cancer prevention programme, based on Pap screening, was introduced as a pilot study in Santiago in 1987 and was later implemented as a national programme in 1994. The mortality for this cancer decreased during this period (rates per 100 000 women of 11.8 in 1990 and 7.6 in 2009); however, this coincided with great socioeconomic development in the Chilean population and it has been demonstrated that in Latin America, income per capita is a better predictor of mortality from cervical cancer than Pap coverage. Moreover, the Chilean women’s access to higher education has tripled in the period and the proportion of women in the workforce has doubled, leading to a decrease in the fertility rate (less  schooling and higher parity are considered risk factors for this cancer). Another factor that may have contributed to this decline in mortality is increased access to quality health care, including the implementation of a health reform (the AUGE plan), which means less waiting time and better follow-up care for women suspected of having cervical cancer.

Over the years, the national programme has been evaluated in terms of coverage, which increased steadily since its implementation, but has remained relatively stable in recent years (<70%), without reaching the goal of the Ministry of Health (80%). The instrument of the screening programme, the Pap test, had only been studied in terms of consistency between readings obtained at medical centre laboratories and at a reference laboratory, that is to say, if the interpretation is the same when assessing the same sample, but it had never been compared with a standard, such us colposcopy, to evaluate its sensitivity and specificity; this is the first study in Chile to do so.

¿Ha sido evaluado sistemáticamente el programa de prevención nacional de cáncer cervical  a través de los años?  ¿Qué tan efectivo crees que es?  ¿Corresponde la disminución en el tiempo de la tasa de cáncer cervical debido al programa  u otros factores?

Spanish: El programa nacional de prevención de cáncer cervicouterino, basado en tamizaje con Pap, se introdujo como piloto en Santiago en 1987 y luego se implementó como programa nacional en 1994. La mortalidad por este cáncer presentó una disminución en este período (tasas por 100 000 mujeres de 11.8 en 1990 y 7.6 en 2009); sin embargo, esto coincide con un gran desarrollo socioeconómico de la población chilena y se ha demostrado que, en América Latina, el ingreso per cápita es un mejor predictor de mortalidad por cáncer cervicouterino  que la cobertura del Pap. Por otra parte, el acceso de la mujer chilena a la educación superior se ha triplicado en el período y la proporción de mujeres en la fuerza de trabajo se ha duplicado, llevando a una disminución de la tasa de fertilidad (menor educación y mayor paridad se consideran factores de riesgo para este cáncer). Otro factor que puede haber aportado a este descenso en la mortalidad es un mayor acceso a atención de salud de calidad, incluyendo la implementación de una reforma en salud (Plan AUGE), que se traduce en menor tiempo de espera y mejor seguimiento de mujeres con sospecha de cáncer cervicouterino.

A través de los años, el programa nacional ha sido evaluado en cuanto a su cobertura, la que aumentó progresivamente desde su implementación, pero se ha mantenido relativamente estable en los últimos años (<70%), sin llegar a alcanzar el objetivo del Ministerio de Salud (80%). El instrumento de tamizaje del programa, el Pap, solo había sido estudiado en cuanto a la concordancia de la lectura entre los laboratorios de los centros asistenciales y de un laboratorio de referencia, es decir, si la interpretación es la misma al examinar una misma muestra, pero nunca se había comparado el Pap con un estándar, como es la colposcopía, para evaluar su sensibilidad y especificidad; éste es el primer estudio en Chile que lo ha hecho.

The cervical cancer mortality rate by socioeconomic status is intriguing.  Are the better rates in the middle classes due to education, or is this a marker for better medical treatment? What are the specific mechanisms? For example, is the environment more healthy for those better off (e.g. less pollution, better food, less stress etc?)

English: If you look at figure 3 in the article, you can see that in Chile the cervical cancer mortality rate follows a markedly unequal distribution between women with different levels of education. While women with less than eight years of education have one of the highest mortality rates in the world, women with more than 12 years of education have a mortality rate similar to developed countries (12.6 vs 1.2/100,000). Level of education is a marker of socioeconomic status. A contributing factor to the large inequality is that women from the higher levels make use of the private sector (30% of the population). The majority of private doctors carry out annual gynaecological checkups including Pap testing, which is different to practice in the public sector, where the cancer programme recommends a Pap test every three years. As shown in this study, the sensitivity of Pap is very low, but it is possible, given the slow progression of this cancer, that the Pap test repeated annually detects lesions that would have gone undetected in earlier tests, allowing women to receive treatment while the disease is still curable. On the other hand, women of low socioeconomic status have more risk factors (more children, early age of initial sexual intercourse) and a lower screening coverage (30% of female beneficiaries of the public health care system are not up to date with their Pap test).

La tasa de mortalidad de cáncer cervical por el factor socioeconómico es intrigante.  ¿Corresponde el resultado mejor en la clase media debido a la educación, o es un marcador para mejor tratamiento  médico? ¿Cuáles son los mecanismos específicos? Por ejemplo, ¿es el medio ambiente más saludable para la clase alta?  (ej.: menos contaminación, mejor calidad de comida, menos stress, etc.)

Spanish: Si se observa la figura 3 del artículo, se puede ver que en Chile la mortalidad por cáncer cervicouterino tiene una distribución marcadamente desigual entre mujeres con distintos niveles de escolaridad. Mientras que las mujeres con menos de ocho años de escolaridad tienen una mortalidad de las más altas a nivel mundial, las mujeres con más de 12 años de escolaridad tienen una mortalidad similar a la de países desarrollados (12.6 vs 1.2/100,000). El nivel de educación es un marcador de nivel socioeconómico. Un factor que puede estar contribuyendo a esta gran inequidad es que las mujeres de nivel alto se atienden en el sector privado (30% de la población). La mayoría de los médicos privados realizan controles ginecológicos con Pap anuales, a diferencia de lo que ocurre en el sector público, en que el programa de cáncer indica un Pap cada tres años. Como se demostró en este estudio, la sensibilidad del Pap es muy baja, pero es posible, dada la progresión lenta de este cáncer, que la repetición anual del Pap detecte lesiones que se habían perdido en exámenes anteriores, permitiendo que la mujer reciba tratamiento cuando aún es curable. Por otro lado, las mujeres de nivel socioeconómico bajo tienen una mayor frecuencia de factores de riesgo (mayor número de hijos, edad precoz de inicio sexual) y una menor cobertura de tamizaje con Pap (30% de las mujeres beneficiarias del sistema público no tienen su Pap al día).

Why has there been a reliance on Pap in Chile thus far?

English: This temporal correlation between the reduction in cervical cancer mortality and the implementation and increased coverage of the national programme has been interpreted, perhaps prematurely, as a success completely attributable to Pap. This test undoubtedly played a role, but as explained earlier, other factors may have had a significant influence (socioeconomic development). On the other hand, the programme has been considered more successful than it actually is, because what has been observed is the decrease in the mortality rate of the whole population; however a main contributor to the national mortality curve are women of high socioeconomic status who have a very low mortality rate, but they are seen in the private health sector, receiving annual Pap tests. In contrast, women with lower socioeconomic status, who attend the public health system and, therefore, are the beneficiaries of the national programme, still have very high mortality rates. Finally, we believe there has been some resistance from programme managers to review its impact; we hope that, in light of this study, they will take the decision to review in depth the effectiveness and cost-effectiveness of the national cervical cancer prevention programme.

¿Por qué  ha habido una dependencia del Pap en Chile hasta el momento?

Spanish: Esta coincidencia temporal entre la disminución de la mortalidad por cáncer cervicouterino y la implementación y aumento de cobertura del programa nacional ha sido interpretada, tal vez apresuradamente, como un éxito completamente atribuible al Pap. Éste indudablemente jugó un rol, pero, como se explicó anteriormente, hubo otros factores que pueden haber influido de forma significativa (desarrollo socioeconómico). Por otro lado, el programa se ha considerado más exitoso de lo que efectivamente es, ya que lo que se ha observado es el descenso de la tasa de mortalidad de toda la población; sin embargo, un gran contribuyente a la curva de mortalidad nacional lo constituyen las mujeres de nivel socioeconómico alto que tienen una muy baja mortalidad, pero ellas se atienden en el sector privado de salud, recibiendo Pap anuales. En cambio, las mujeres de nivel más bajo, que se atienden en el sistema público y, por tanto, son las beneficiarias del programa nacional, aún tienen una mortalidad muy elevada. Por último, nos parece que ha habido cierta resistencia por parte de los responsables del programa de revisar el impacto de éste; esperamos que, a la luz de este estudio, se tome una decisión de revisar en profundidad la efectividad y costoefectividad del programa nacional de prevención de cáncer cervicouterino.

Are there any reasons to think the results would differ in the regions outside Santiago?

English: We don’t believe that the results obtained in our study would not be replicated in other regions of the country.

¿Existen otros motivos para pensar que los resultados deferirían en las regiones fuera de Santiago?

Spanish: No creemos que haya motivos para que los resultados obtenidos en nuestro estudio no sean reproducibles en otras regiones del país.

Even though HPV outperformed Pap in this study, could another detection method improve on HPV in terms of sensitivity and specificity?

English: Other methods based on HPV do exist that could be more accurate, mainly by improving specificity. These methods, currently being studied internationally, include the detection of HPV RNA and oncoproteins.

Aunque HPV superó a Pap en este estudio, ¿podría otro método de detección mejorar en HPV en términos de sensibilidad y especificación?

Spanish: Existen otros métodos basados en VPH que podrían ser más precisos, fundamentalmente aumentando la especificidad. Estos métodos, que en la actualidad se están estudiando internacionalmente, incluyen la detección de oncoproteínas y de ARN de VPH.

What further research needs to be carried out to further improve cervical cancer detection in Chile?

English: The HPV test is being considered worldwide to replace the Pap smear in cervical cancer screening. Given the good results observed in our study using this test in three primary care centres in Santiago, it’s a very attractive alternative to be considered in Chile as well; however, given that HPV infections are very common and the majority disappear in a few years (only those that persist can lead to cancer), it is not possible to refer all the women who screen positive for HPV to a consultant for further diagnostic procedures, since it would create an unnecessary burden to the women and the health system. It is necessary, therefore, to implement a follow-up strategy for women who are HPV positive, with the aim of identifying the subgroup of women that do need to be referred for having a higher risk of lesions. Alternatives to this strategy could include visual inspection of the cervix, high quality cytology and various molecular techniques, among others. At present, we are participating in a study to determine which test is best to follow up HPV positive women.

¿Qué otro tipo de investigación es necesario para mejorar la detección de cáncer cervical en Chile?

Spanish: El examen de VPH está siendo considerado a nivel mundial para remplazar al Papanicolaou en el tamizaje para cáncer cervicouterino. Dados los buenos resultados observados en nuestro estudio al usar este examen en tres centros de atención primaria de Santiago, es una alternativa muy atractiva para ser considerada en Chile también; sin embargo, dado que la infección por VPH es muy frecuente y la mayoría desaparece en un par de años (sólo las que persisten pueden llevar a cáncer), no es posible derivar a todas las mujeres positivas para VPH a un especialista para procedimientos diagnósticos adicionales, ya que implicaría una sobrecarga innecesaria a la mujer y al sistema de salud. Es necesario, por lo tanto, implementar una estrategia de seguimiento de las mujeres que son positivas a VPH, con el objetivo de identificar el subgrupo de mujeres que sí deben ser derivadas por tener un mayor riesgo de presentar lesiones. Alternativas para esta estrategia podrían incluir inspección visual del cuello, citología de alta calidad y diversas técnicas moleculares, entre otras. En la actualidad nosotros estamos participando en un estudio que tiene este objetivo: determinar qué examen es el mejor para ser usado en el seguimiento de una mujer positiva para VPH.

What about treatment of cancer?

English: The treatment of cervical cancer has not been an area of our research, but there is a point that is important to note: The progression of this cancer is relatively slow; therefore, if the lesion is diagnosed early, treatment (excision, conization or hysterectomy) is curative in most cases. Hence the importance of an effective screening process, that could avoid a large number of deaths from this cancer.

¿Qué hay del tratamiento de cáncer?

Spanish: El tratamiento del cáncer cervicouterino no ha sido un área de investigación nuestra, pero hay un punto que es importante destacar: La evolución de este cáncer es relativamente lenta, por lo tanto, si la lesión es diagnosticada en etapas tempranas, el tratamiento (ablación, conización o histerectomía) es curativo en la gran mayoría de los casos. De ahí la importancia de un proceso de tamizaje efectivo, pudiendo evitarse un gran número de muertes por este cáncer.

Chile’s Research Planning
Aims High
IN THEIR LETTER “CHILE’S RESEARCH PLANNING
falls short” (27 April, p. 412), P. Astudillo et al. argue that CONICYT—Chile’s government funding agency for science and technology (S&T)—is insufficient and should be replaced by a ministry of science. In fact, it is a good time to be a scientist in Chile.

Most of the data Astudillo et al. cite were collected before 2010. The budget of CONICYT has increased almost 2.7 times since 2008, from US$182 million to US$485 million in 2012. Projects in basic science supported by FONDECYT (a subdivision of CONICYT) have increased by 50% since 2010. No discipline in S&T has funded less than 40% of proposals (1). Postdoctoral fellowships in Chile and abroad increased by more than 40% in the past year (2), and they are expected to increase again after the next call [increases to FONDECYT’s budget and Becas Chile are shown on p. 319 of the Budget of the Nation 2012 (3)]. Eleven recipients of the National Prize in Science, including the President of Academy of Science, applauded this change (4).

Contrary to the impression given by Astudillo et al., CONICYT has indeed made research plans, which have been published in the media and discussed in forums with university authorities and scientists (5). A major
share of CONICYT’s budget is devoted to the scholarship program Becas Chile, an effort amounting to about US$200 million in 2012, allowing 3240 Ph.D. students to complete studies in Chile or abroad in 150 universities and programs around the world (4). Estimates show that by 2014, more than 800 Ph.D.s per year will graduate from national and international universities and join the ranks of scientists in Chile’s universities, government, and private sector.

By the end of this year, CONICYT will implement a new fund (FONDEQUIP) aimed at increasing scientifi c competitiveness through access to modern laboratory equipment [(3), p. 320]. Moreover, all Chilean scientists and graduate students will have free electronic access to the major international journals at their universities. Recent data indicate that Chilean science exhibits the highest indicators among all Latin American countries in terms of papers published in journals with high ISI ratings per dollar invested and citations per paper (6). Fifty-three percent of ISI publications by Chilean scientists now have at least one foreign co-author (7).

Meanwhile, four international centers of excellence in the key areas of aquaculture biotechnology, communications and information research, mining, and pro-cessed foods have been launched in the past 2 years by INNOVA CORFO (the government innovation agency), attracting reputed institutions such as Fraunhofer, CSIRO, INRIA, and Wageningen University. By 2014, we expect that six more centers, which will receive a basal funding of up to US$20 million in 10 years, will be ready to start operation.

A good example of the new times for science and technology is astronomy. By 2020, Chile will host almost 70% of the observation capacity in the world, involving a foreign investment of close to US$5.8 billion (8). Chilean astronomers have rights to 10% of the observation time; thus, faculty at astronomy departments in Chilean universities have increased by 50% since 2007 and more than 80 Ph.D. and Master students are enrolled in their programs (9).

Ministries of Science and Technology (MSTs) are not the only alternative for policy and promotion of science. In many instances, MSTs are synonymous with bureaucracy and prone to political favoritism. Administrative costs in CONICYT constitute 3.8% of the budget, all programs have scientifi c advisory committees, and the top officials remained in their posts after the change in government in 2010. More important, CONICYT serves more than 10,000
scientists and graduate students in Chile and abroad. As is well known, this President has met with government authorities and the Congress to reassess the structure and role of CONICYT within the existing National Innovation System created in 2006 (10).

Chile is not at risk of research funding cuts or in desperate need of planning, as Astudillo et al. assert. Our efforts are now centered on increasing the number of scientists (presently around 4500) because empirical evidence (11) suggests that larger investments in R&D must be accompanied by minds and hands to accommodate the increase.

JOSE M. AGUILERA
CONICYT, Santiago, 7500788, Chile. E-mail: jmaguilera@conicyt.cl

References and Notes
1. CONICYT, “Scientifi c Panorama” (November 2011), vol. 25; www.fondecyt.cl/578/articles-27688_panorama_2011.pdf.
2. Becas CONICYT, Comparativo Adjudicaciones Becas Postdoctorado FONDECYT–Becas Chile 2008–2012 (www.becasconicyt.cl/index.php?option=com_content&view=article&id=383&Itemid=1).
3. Ley de Presupuestos del Sector Publico Año 2012 (www.dipres.gob.cl/572/articles-76644_pres_2012.pdf).
4. J. Allende et al., “Results of Fondecyt 2011,” El Mercurio,Letters to the Editor (11 January 2011), p. A2.
5. J. M. Aguilera, “Science and technology in Chile: Using the shortcut,” El Mercurio, special edition, “Science changes our lives” (29 September 2011), p. 2.
6. J. Larrain, M. O’Ryan, B. Santelices, “Scientifi c Productivity,” El Mercurio, Letters to the Editor (21 April 2012), p.
A2; http://blogs.elmercurio.com/columnasycartas/2012/04/21/productividad-cientifi ca.asp.
7. We searched Web of Knowledge/Thomson Reuters, database Web of Science (http://apps.webofknowledge.com/
WOS_GeneralSearch_input.do?SID=1FPGCJaHBfhBkF8K4BP&product=WOS&search_mode=GeneralSearch&prefe
rencesSaved=) for articles, reviews, and proceedings with affi liations from Chile for year 2010. Of 5379 ISI publications with an author affiliation in Chile, 2843 publications list coauthors with foreign affi liations and 2536 have only authors with affiliations in Chile. Hence, approximately 53% of publications have a foreign coauthor. Our data are available here: www.conicyt.cl/website/privado/colaboracion_2010_24por100_soloXChile.xls.
8. Foreign investment includes astronomical projects such as the Extremely Large Telescope (US$1.5 billion, the Large Synoptic Survey Telescope (US$500 million), the Giant Magellan Telescope (US$800 million), the Atacama Large Millimeter/Submillimeter Array (US$1.0 billion), the Very Large Telescope ($700 million), Gemini (US$300 million), and investments from Cornell and California Institute of Technology.
9. T. Feder, Phys. Today 65, 20 (2012).
10. Ministry of Economy, Chile, Plan of Innovation to 2014, Division of Innovation (March 2012), pp. 8, 9, and 16; www.economia.gob.cl/wp-content/uploads/2010/03/Plan-de-Innovacion-al-2014-Final.pdf.
11. W. T. H. Koha, P. K. Wong, Technol. Forecasting Soc.Change 72, 255 (2005).

Source:

PRESS RELEASE

KOCH AND COLLEAGUES REFUTE THE GUTTMACHER INSTITUTE AND REAFFIRM NULL IMPACT OF LEGAL ABORTION RESTRICTION ON MATERNAL MORTALITY IN CHILEAN STUDY.

Chile, Santiago, 05/25/2012. On May 23^rd, the Guttmacher Institute released an advisory comment (http://www.guttmacher.org/media/evidencecheck/2012/05/23/Guttmacher-Advisory.2012.05.23.pdf) attempting to debunk some conclusions of the article recently published in PLoS ONE by Koch et al. (http://dx.plos.org/10.1371/journal.pone.0036613). The authors elaborated a full point-by-point rebuttal document to the criticisms (http://es.scribd.com/doc/94847841), claiming erroneous and misleading information is being spread by the Guttmacher Institute, which may influence public opinion into disregarding important findings revealed in the controversial article.

Dr. Elard Koch, leading author of the article and fellow researcher of the Universidad de Chile and Universidad Católica de la Santísima Concepción, states that “the single conclusion that the Guttmacher Institute challenges appears to relate only to the null effect we found of abortion ban on maternal mortality trend in Chile, since this country already had restrictions of abortion in place before 1989”. Koch remarks, however, that the opinion of the Guttmacher Institute in terms of how restrictive the Chilean abortion law was before and after 1989 is essentially misinformed. Yet, even if the argumentation by the Guttmacher Institute experts stating, “Chile’s pre-1989 abortion law was already highly restrictive” was correct, this in no way invalidates that abortion restrictive laws had a null influence maternal mortality trends in Chile. “In fact, maternal mortality ratios steadily decreased over the last fifty years, mainly associated to an increase in educational level of women and maternal health facilities and regardless of the extent of abortion restrictions in the country” Koch says.

Furthermore, Koch indicates that researchers from the Guttmacher Institute failed to present any actual evidence in support of any severe methodological flaw in the PLoS ONE study. In fact, Chile has a robust and reliable registry of vital and socioeconomic data, with the Chilean National Institute of Statistics being recognized as a referent in Latin America by the World Health Organization, United Nations and the Organization for Economic Co-operation and Development. Moreover, Koch explains, “ours is the first in-depth analysis of parallel time series with a sufficient number of time points, year-by-year over fifty years, of maternal deaths and the simultaneous assessment of their determinants at a country level.”

Arguments by the Guttmacher Institute are mainly based on the idea that their own methodology, using data sources such as opinion surveys, can accurately estimate the amount of induced abortions in countries with abortion restrictive laws. Nevertheless, Koch et al. stress that opinion surveys are purely indirect approaches that may lead to under- or overestimations, and due to their subjective nature, can be extremely biased. “A completely different scenario is observed when calculating figures of illegal abortions on the basis of actual vital statistics, acknowledged epidemiological methods, and well known biological reproductive rates”, states Koch.

Koch and his colleagues extensively explored the potential discrepancies between these two methodologies when estimating figures of illegal abortion in several Latin American countries. Their findings have been recently published as a peer-review article last May 18^th (http://www.nietoeditores.com.mx/ginecologia-y-obstetricia-de-mexico/5/4883-sobrestimacion-del-aborto-inducido-en-colombia-y-otros-paises-latinoamericanos.html), just a few days after the controversial article published in PLoS ONE.

Koch indicates, “Not surprisingly, we found that the methodology developed by scientists from the Guttmacher Institute appears to grossly overestimate the number of possible induced abortions in developing countries.” For instance, induced abortion estimates by Koch et al. in Colombia (21,978) indicate that the Guttmacher Institute likely overestimates figures in this region (400,400) at least by 18-fold. “In other words, estimates drawn through the methodology developed by the Guttmacher Institute is beyond what is empirically possible”, Koch says.

In their full point-by-point rebuttal document to the criticisms by the Guttmacher Institute (link), Koch and colleagues conclude that “it is imperative to remark that, because abortion restrictive law in Chile is unrelated to maternal mortality and this country reached one of the lowest rates of maternal-related and abortion-related deaths of the world (at the present, 16.9 and 0.39 per 100,000 live births, respectively) without legalizing abortion, the Chilean fifty-year natural experiment provides strong evidence, for the first time, that a liberal law of abortion is unnecessary to improve maternal health: it is a matter of scientific fact in our study.”

Source: PlosONE

A new study published in the open access scientific journal PLoSONE has shown that the maternal mortality rate (MMR) in Chile has dramatically reduced over the last 50 years and now compares favourably with the rest of the American continent. Study figures suggest the rate now surpasses that of most regional countries including that of the US.

OFFICIAL PRESS RELEASE

"Concepción, Chile, May 5 - A scientific analysis of 50 years of maternal mortality data from Chile has found that the most important factor in reducing maternal mortality is the educational level of women. “Educating women enhances women’s ability to access existing health care resources, including skilled attendants for childbirth, and directly leads to a reduction in her risk of dying during pregnancy and childbirth,” according to Dr Elard Koch, epidemiologist and leading author of the study.

The research entitled  “Women’s Education Level, Maternal Health Facilities, Abortion Legislation and Maternal Deaths: a Natural Experiment in Chile from 1957 to 2007” was conducted on behalf of the Chilean Maternal Mortality Research Initiative (CMMRI) and published in the Friday, May 4 issue of PLoS ONE.

Using 50 years of official data from Chile’s National Institute of Statistic (1957-2007), the authors looked at factors likely to affect maternal mortality, such as years of education, per capita income, total fertility rate, birth order, clean water supply, sanitary sewer, and childbirth delivery by skilled attendants. They also analysed the effect of historical educational and maternal health policies, including legislation that has prohibited abortion in Chile since 1989, on maternal mortality.

During the fifty-year study period, the overall Maternal Mortality Ratio or MMR (the number of maternal deaths related to childbearing divided by the number of live births) dramatically declined by 93.8%, from 270.7 to 18.2 deaths per 100,000 live births between 1957 and 2007, making Chile a paragon for maternal health in other countries. “In fact, during 2008, the overall MMR declined again, to 16.5 per 100,000 live births, positioning Chile as the country with the second lowest MMR in the American continent after Canada and with at least two points lower MMR than the United States” said Koch.

One of the most significant findings is that, contrary to widely held assumptions, making abortion illegal in Chile did not result in an increase in maternal mortality. In fact, after abortion was made illegal in 1989, the MMR continued to decrease from 41.3 to 12.7 per 100,000 live births (69.2% reduction). “Definitively, the legal prohibition of abortion is unrelated to overall maternal mortality rates” emphasized Koch.

The variables affecting this decrease included the predictable factors of delivery by skilled attendants, complementary nutrition for pregnant women and their children in the primary care clinics and schools, clean facilities, and fertility. But the most important factor and the one that increased the effect of all others was the educational level of women. For every additional year of maternal education there was a corresponding decrease in the MMR of 29.3 per 100,000 live births.

The picture for Chile includes a transition of leading causes of death along with an accelerated decline of fertility and delayed motherhood. Koch explained that direct causes –those directly attributable to pregnancy condition– were the rule before 1990, but from then, indirect causes –i.e. non-obstetric chronic conditions such as hypertension and diabetes among others– arise as the most prevalent, hindering the decline on maternal mortality.

“This study uncovers an on-going ‘fertility paradox’ in maternal health: education is the major modulator that has helped Chile to reach one of the safest motherhood in the world, but also contributes to decrease fertility, excessively delaying motherhood and putting mothers at risk because of their older age.” Thus, an emerging problem nowadays “is not a question of how many children a mother has, but a question of when a mother has her children, specially the first of them” concluded Koch."

Professor  Koch, who is Principal Investigator and Director of Research at Universidad Católica de la Santísima Concepción and Universidad de Chile, spoke to chileno.co.uk about the significance of the ground-breaking study.

Relevance of the work

This is a landmark study since it shows an in-depth analysis of a large time series, year by year, of maternal deaths and their determinants, including years of education, per capita income, total fertility rate, birth order, clean water supply, sanitary sewer, and childbirth delivery by skilled attendants, and including simultaneously different historical policies. In this sense, it is a unique natural experiment conducted in a developing country. Thus, there is a rigorous analysis controlled by multiple confounders. It is not a matter of circumstantial or anecdotal evidence, but it is a matter of scientific data representing real vital events whose methodology has been published for the first time in a peer reviewed scientific journal.

As described in our paper, the study shows that the most important factor promoting the decrease in maternal mortality is the number of years in women’s education. Nevertheless, the study also places Chile as the second safest country in the American continent, following Canada, for maternal health during pregnancy and childbirth. The ranking was elaborated using official vital data from several countries during 2008, including the US. Noteworthy, when comparing official data with those of the most recent technical report from the World Health Organization (WHO), significant overestimations were found. For instance, the WHO global report overestimates maternal mortality ratios 28.3% for the US, 33.3% for Canada, 48.6% for Mexico, 57.6% for Chile, and 76.3% for Argentina. Thus, the WHO report underestimates the progress of several developing countries in improving maternal health.

Further directions of the research

The powerful statistical methodology developed to perform the published analysis allowed for simultaneous comparison of several factors and confounders, year by year. In addition we identified two clear changes in the slope of the decline from 1957 to 2007. Between 1965 and 1981, there was an accelerated reduction of 84% in the MMR of approximately -13.29 per 100,000 live births each year (rapid phase). Between 1981 and 2003, the slope became less pronounced, at -1.59 per 100,000 live births each year (slow phase). All mortality causes declined in parallel, but the proportion of maternal deaths due to indirect causes increased during the slower phase.

We noted that there is a transitional threshold in the decrease of maternal mortality ratio approximately situated between 40 and 50 maternal deaths per 100,000 living births separating the rapid and slow phase in the downward trend. A possible explanation for this transition from a rapid to a slower decline on maternal mortality is that, before 1990, causes of maternal death were of obstetric origin or directly attributable to complications of childbirth, such as haemorrhage, sepsis and obstructive labour. Since 1990, however, there has been a major change in the proportion of maternal death causes in Chile, moving towards pre-existing chronic conditions, unrelated to pregnancy. In fact, nowadays 40% of all causes of maternal deaths are related to indirect causes, such as hypertension, diabetes, obesity and cardiovascular diseases. This change suggests the apparition of a more complex residual pattern of maternal morbidity, which requires specialized, immediate medical services for decreasing the MMR trend.

More complexity is added to this issue due to the presence of an unavoidable “fertility paradox” in maternal health: education is the major modulator that has helped Chile to reach one of the safest motherhoods in the world, but also contributes to decreased fertility, excessively delaying pregnancy and putting mothers at risk because of their older age. Childbearing at advanced ages emerged progressively in Chile from 1985 and it continues to rapidly increase. We think that this paradox hinders further improving maternal health in Chile and, most likely, in several developed and developing countries. The actual deleterious effect of these phenomena requires further research in Chile and especially in developed nations where maternal mortality is increasing, such as in the case of the U.S.

Implications for policy

One of the interesting features of the article is that several policies were considered when interpreting trends observed in maternal mortality: 1) the passing of a law that mandates free education to a minimum of eight years for all Chilean population in 1965; 2) implementation of an extensive prenatal primary care program with a family planning component at the end of the 1960’s; and 3) prohibition of abortion in 1989. Completeness and quality of Chilean data provided a unique way to test, in hindsight, the relevance of such policies on maternal health.

In light of the analysed data, policies aimed to increase women’s school years, facilitate universal access to improved maternal health facilities (early prenatal care, delivery by skilled birth attendants, postnatal care, availability of emergency obstetric units and specialized obstetric care), provide complementary nutrition for pregnant women and their children in the primary care network and schools, and improve the sanitary system ―i.e. clean water supply and sanitary sewer access– greatly favoured maternal health. Furthermore, it is confirmed that women’s educational level appears to have an important modulating effect on other variables, especially promoting the utilization of maternal health facilities and modifying their reproductive behaviour. Consequently, we propose that these policies outlined in different United Nations’ Millennium Development Goals and implemented in different countries may act synergistically and efficiently decreasing maternal deaths in the developing world.

In contrast to wide held assumptions, abortion banning did not influence overall maternal mortality rates. Although our study definitively ruled out any deleterious influence of abortion prohibition on the maternal mortality trend, it cannot be immediately concluded that solely making abortion illegal is a direct causal factor for decreasing maternal mortality. Thus, one complex and important question remains: Does prohibition of abortion save lives? We can address this important issue from different perspectives.

First, from a Public Health view, restrictive laws are hypothesized to cause a dissuasive effect on the population, similar to restrictions on tobacco or alcohol use. We observed that reduction of maternal mortality in Chile was paralleled by the number of hospitalizations attributable to complications of clandestine abortions: while over 50% of all abortion-related hospitalizations were attributable to complications of clandestine abortions during the 1960’s decade, this proportion decreased rapidly in the following decades; indeed, only 12-19% of all hospitalization from abortion can be attributable to clandestine abortions between 2001 and 2008. These data suggest that throughout time, restrictive laws may have a restraining effect on the practice of abortion, promoting its decrease. In fact, Chile exhibits today one of the lowest abortion-related maternal deaths in the world, displaying 92.3% further decrease from 1989 and 99.1% accumulated decrease over fifty years.

Second, from the perspective of the human life, especially if a developing country is looking for simultaneously protecting the life of the mother and the unborn, a plausible hypothesis after the Chilean study is that abortion restriction may be effective when combined with public policies adequately implemented to increase the education level of women and improve access to maternal health facilities. A restrictive law may discourage practice, which is suggested by the decrease of hospitalizations due to clandestine abortions estimated in Chile.

Finally, from the perspective of protecting the human life from the very beginning, evidently, abortion restriction saves many lives, in contrast to countries where first-trimester elective –on demand– abortion is allowed, because in these countries all the unborn lose their lives. It is just a matter of simple logical reasoning if you are looking for protecting the human life during all the stages of the human development.

Join the abortion debate.

Source: Dossier – Programa de Formación de Capital Humano Avanzado: Eternos Problemas y Desafíos Actuales

More than 50% of the countries of the world possess some kind of Ministry of Science (red), some have no Ministry although do have Ministers (pink), others, including Chile have neither a Ministry nor Minister (blue).

In a recently published article in the highly respected academic journal Science a group of Chilean scientists has issued a warning that the country may be falling behind others in their planning and spending for research. The authors, lead by Pablo Astudillo of the pressure group mascienciaparachile (more science for Chile) made a call for improved bureaucratic administration, more political will and funding for Chilean researchers.

The letter Chile's Research Planning Falls Short details a number of potentially fundamental fissures in the Chilean system than could severely undermine the good growth and development that Chile has enjoyed over recent years. For example, although Chile has recently (2010) joined the club of developed countries (OECD) whose members account for approximately 80% of world trade and investment, there is currently no Ministry for Science in the country, which is in contrast to neighbouring Argentina and Brazil. Peru, which by most standards has a weaker economy than Chile, is also said to be tabling the idea of a new Ministry of Science and Technology.

A major concern is that research spending has been relatively poor in Chile, nearly 10 times less than the OECD average of per capita investment.

You can read the letter published in Science here. The Chilean science group, mascieciaparachile formed in 2010, following the model of the Save British Science campaign founded in 1986.

Credit: Simon Fraser/Newcastle Hospitals NS Trust/Science Photo Library

Caption: Meningitis. Coloured magnetic resonance imaging (MRI) scan of a section through the head of a 34 year old woman, showing meningitis (yellow). The brain is seen, with the folded cerebrum (at top), brainstem (centre), and cerebellum (centre right). The spinal cord passes into the neck. Meningitis infection is coloured yellow on surfaces of the brain and spinal cord. Meningitis is an inflam- mation of the meninges, the membranes that cover and protect the brain and spinal cord. It is caused by either bacterial or viral infection. Viral meningitis is a mild form; bacterial menin- gitis is very dangerous and requires antibiotics.


Meningitis, the inflammation of the protective lining around the brain and spinal cord, is a serious condition for young and old and can be fatal. Typically 1 in 10 victims will die in the UK, a process that can take as little as 4 hours in some cases. While vaccines have been developed for most known subtypes of the meningitis-causing bacteria, Neisseria meningitides, group B currently accounts for approximately 90% of all confirmed cases in the UK. The primary cause being that until now no suitable vaccine had existed for serogroup B. However, Chilean researchers at Universidad de Chile have recently conducted an important randomised controlled trial assessing a new vaccine developed to protect against the remaining  Neisseria meningitides b bacteria. The study was published in the prestigious medical journal The Lancet showing that the vaccine successfully caused the production of sufficient antibody levels to combat the bacteria. Project leader and Vice President of Research and Development Professor Miguel O'Ryan talked to chileno.co.uk about why the work is important:

The importance of the research
"Three bacteria are responsible for the great majority of severe invasive infections in children and healthy adults: Haemófilus influenza b, Streptococcus pneumonia, and Neisseria meningitides. Thanks to worldwide use of vaccines, the first has practically disappeared in most countries sparing thousands of lives and millions of hospitalizations and sequelae. More recently, vaccines against the most common S. pneumonia serotypes have been incorporated in a significant number of countries with a dramatic decrease in severe bacterial infections caused by these serotypes. For both bacteria the vaccine strategy has been to use capsular polysaccharide as the immunogen which has worked very well in conjugation with a protein carrier.  For N. meningitidis four main serogroups infect humans, namely A, B, C, W. Vaccines using the capsular polysaccharide strategy are available as sole or combined for groups A, C and W but not for B. The reason is because the B polysaccharide has an almost identical structure to polysaccharide located in the human brain. Thus, the immune system does not recognize as “different” this molecule and does not create a robust immune response.  N. meningitides b is thus the only remaining bacterial pathogen of the “big three” for which a vaccine was not available. It is a significant cause of bacterial meningitis and meningococcemia in many countries in Latin America, Europe and North America. Incidence goes from 0.5 up to 5-10 cases per 100.000 population with a lethality rate of 5-10% and sequelae (listening impairment, motor or cranial nerve palsies and others) that can affect an additional 10 to 15% of survivors.  Using a new approach, referred to as “reverse vaccinology”, the complete genome of the bacteria was sequenced, all structural proteins were identified, mice were inoculated with these proteins in order to determine which protein induced a robust immune response. Finally, a selection of “immunogenic proteins” located in the bacterial surface and present in a large group of different N. meningitides b subtypes lead to the vaccine of “protein nature” containing 4 main bacterial proteins.

Our study was a clinical evaluation of the vaccine in adolescents in order to determine immunogenicity and safety and to define how many doses would be required in this age group to produce a “protective immune response”. After enrolling over 1500 adolescents, receiving one, or two, or three doses of vaccine we concluded the two doses were highly immunogenic at month 7, better than one dose, and similar to three doses.  This study complements the studies done by other colleagues in young infants in which three doses proved to be better than two. The vaccine was moderately reactogenic, mostly at the local level (redness, pain at the vaccine site) albeit quite tolerable in the adolescents.

Thus, this new vaccine proved to be promising in “closing the loop” of the main bacterial pathogens causing severe infections in children and young healthy adults. Some questions remain, especially how long does immunity last, but this will probably have to be answered after vaccine introduction and use in different settings."

If you are enjoying this post why not follow us on twitter and like us on facebook using the buttons below.

Follow @chilenocouk

Future Directions
"I am currently Vice President for Research and Development at the University of Chile which takes most of my time. My research is currently focused on another bacteria, Helicobacter pylori, albeit at a more basic level. We are trying to understand the dynamics of infection in young children, and the possible impact of this early persistent infection in disease outcome further in life. Other groups continue with N. meningitides b performing clinical research in combined vaccines (including group B protein with the other groups which are polysaccharide remember, in order to create one vaccine for all groups), studies aimed to determine the duration of immunity (we have an extension study up to one year of age in finishing phase), and new possibly less reactogenic new generation vaccines (at earlier stages)."

Tean leader Xavier Bonfils explained, “Our new observations with HARPS mean that about 40% of all red dwarf stars have a super-Earth orbiting in the habitable zone where liquid water can exist on the surface of the planet...Because red dwarfs are so common — there are about 160 billion of them in the Milky Way — this leads us to the astonishing result that there are tens of billions of these planets in our galaxy alone.”

If such exoplanets have a rocky surface and contain water on the surface, then the prospect of some form of life existing on the planet, perhaps in abundance, is tantalising for us all. The new estimates also allow for a calculation of how many super-Earth planets may exist in the habitable zone around red dwarfs in close proximity to the sun; there may number as many as 100 within 30 light years.

One such planet discoverd by HARPS in Chile, Gliese 667 Cc, may well have water on the surface and so could support life. An artist's impression of the planet is shown below. Before we start packing our bags for an exo-holiday though, it should be remembered that the planet lies some 22 light years away from us, that is 22 years of travel at 186,000 miles per second!