Trends in incidence rates of head and neck squamous cell carcinomas overall and by potential relatedness to human papillomavirus, Costa Rica 2006 to 2015.

In Costa Rica (CR), only one report on head and neck cancer (HNC) incidence trends (1985-2007) has been published and no investigations on the epidemiology of potentially human papillomavirus (HPV)-related and HPV-unrelated HNCs have been done. We examined the age-standardized incidence rates (IRs) and trends of head and neck squamous cell carcinomas (HNSCC) and compared incidence trends of potentially HPV-related and HPV-unrelated HNSCCs. We obtained all available HNC cases for the period 2006-2015 from the Costa Rican National Cancer Registry of Tumors and the population estimates from the Costa Rican National Institute of Statistics and Census. The analysis was restricted to invasive HNSCCs (n = 1577). IRs and incidence rate ratios were calculated using SEER*Stat software and were age-standardized for the 2010 Costa Rican population. Joinpoint regression analysis program was used to calculate trends and annual percent changes (APCs) in rates. For all HNSCCs, the age-standardized IR was 34.0/million person-years; 95% CI 32.4, 35.8. There was a significant decline in the incidence of nasopharyngeal cancer (APC: -5.9% per year; 95% CI -10.8, -0.7) and laryngeal cancer (APC: -5.4% per year; -9.2, 1.5). The incidence trends for hypopharyngeal, oropharyngeal and oral cavity cancers each remained stable over time. HNSCCs were categorized by their potential relatedness to HPV infection. Though the APCs were not statistically significant, IRs of potentially HPV-related HNSCCs trended upward, while HPV-unrelated HNSCCs trended downward. HNSCCs are uncommon in CR and decreased over time. We observed a divergent pattern of decreasing HPV-unrelated with increasing HPV-related HNSCCs that should be further informed by HPV genotyping tumor samples.

Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial.

BACKGROUND: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+). METHODS: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464. FINDINGS: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine. INTERPRETATION: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable. FUNDING: US National Cancer Institute.

Cervical cancer incidence after screening with HPV, cytology, and visual methods: 18-Year follow-up of the Guanacaste cohort.

Testing negative for human papillomavirus (HPV) predicts long-term reassurance against invasive cervical cancer (ICC). To provide realistic estimates of effectiveness for new screening programs, we studied ICC risk after a 7-year repeated multimethod screening effort. In 1993-1994, 10,049 women aged 18-97 years were enrolled into a population-based cohort study of cervical HPV in Guanacaste, Costa Rica. Women were screened at different intervals according to enrollment results. Each visit (mean 3.2, 90% attendance) included split-sample conventional, automated, and liquid-based cytology, visual inspection, cervicography, and PCR-based HPV testing. Abnormal screening led to colposcopy and excisional treatment as appropriate during the study. Referral to colposcopy for HPV in the absence of other findings was introduced only at the last visit. Population-based Costa Rica Cancer Registry linkage identified cohort women diagnosed with ICC in the 18 years following cohort enrollment. The ICC cumulative risk was 0.4% (n = 38); 18 were diagnosed with ICC after study participation. Of these, 9 were missed at the screening step (negative screening or below the referral threshold, refused screening or colposcopy), 5 attended colposcopy but were not diagnosed as CIN2+, and 4 were treated for CIN2/3 but progressed to ICC nonetheless. Decreasing age-standardized ICC rates for the 1993-2011 period were observed in Guanacaste; cohort women showed additional 31% ICC incidence reduction with apparent downstaging of cancers that occurred. ICC risk following negative HPV testing in the optimal age range 30-50 years was extremely low. Real-life screening effectiveness following introduction is lower than the potential near-complete efficacy predicted by HPV natural history.

[ETHICS OF THE LIMITATION OF LIFE-SUSTAINING TREATMENTS]. / ÉTICA DE LA LIMITACIÓN DEL ESFUERZO TERAPÉUTICO.

The development over the last half century of the Life Support Technologies and the advent of the Intensive Care Units, have raised a wide range of new problems for ethical reflection. It is not by chance that the birth of Bioethics coincided with the birth of the Intensive Care Units. The first and most important of these problems is the withholding or withdrawing of the life support measures. In this article it is argued that the decision to limit life-sustaining treatments may be justified in four different ways, according with the four bioethical principles: by the expressed will of the patient or his/her representative, considering the procedure "extraordinary" for them (principle of autonomy); due to the lack of efficacy of the technique in question, which makes it "non-indicated" or "contraindicated" (principle of non-maleficence); due to problems of efficiency in the distribution of resources, which can make "disproportionate" the cost/benefit ratio of an specific treatment (principle of justice); and finally, due to the lack of effectiveness of some therapeutic procedures in concrete situations, which makes them "futile" (principle of beneficence).

Pediatric Hearing Aid Management: Experiences and Perspectives of Spanish-Speaking Parents.

PURPOSE: The purpose of the study was twofold: (a) to explore hearing aid management experiences of Spanish-speaking parents who have young children using hearing aids and (b) to explore parents' access to the Internet and perceptions about remote audiology services. METHOD: The study used a mixed methods design. Data were collected through a phone interview. RESULTS: Eleven mothers of children aged 14-60 months participated. Most of the children (9/11) had a bilateral hearing loss, and two had an additional disability. Three themes emerged for hearing aid management experiences: audiology services, routines, and emotional challenges/supports. Parents had variable levels of confidence in their skills ranging from no confidence to complete confidence, with the greatest variability for three items: (a) using the listening tube to make sure that the sound quality of the hearing aid is good, (b) removing moisture from the earmold tubing, and (c) troubleshooting problems when your child's hearing aids are not working. All participants reported having consistent Internet access and had positive perceptions about the possibility of remote audiology services. CONCLUSIONS: This study provided insights into hearing aid management experiences and perceptions of Spanish-speaking parents. Parents described variability for audiology services, routines for hearing aid use and care, and access to other parents of children with hearing loss. Spanish-speaking parents present additional elements in the hearing care process that need to be incorporated in planning. Remote services may be an opportunity to enhance access to support that could improve effectiveness of hearing aid management.

Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America: an analysis within the ESTAMPA study.

Background: Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30-64 years participating in the ESTAMPA study. Methods: Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated. Findings: 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0-53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3-96.7). Specificity was 96.5% (95% CI: 96.3-96.7) using cytology and 88.7% (95% CI: 88.3-89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%-100% and 83.6-90.8%, respectively). Interpretation: The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America. Funding: IARC/WHO, UNDP, HRP/WHO, NCI and local funders.

Low risk of type-specific carcinogenic HPV re-appearance with subsequent cervical intraepithelial neoplasia grade 2/3.

Carcinogenic human papillomavirus (HPV) infections are very common after sexual debut and nearly all become undetectable ("clear") within a few years. Following clearance, the long-term risks of type-specific HPV re-appearance and subsequent risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are not well defined. In the 7-year, population-based cohort study in Guanacaste, Costa Rica, we studied how often type-specific carcinogenic HPV infections re-appeared after clearance and how often re-appearance led to CIN2+. We considered 1,740 carcinogenic HPV infections detected by MY09/11 PCR among 2,805 women (18-91 years old, median 34) who were actively followed at 6- or 12-month intervals. We identified women with one or more type-specific HPV infections that cleared and re-appeared and further defined a subgroup of "definite clearance and re-appearance" (≥2 intervening negative results over a period of ≥1 year). We determined the absolute risk of CIN2+ among the different groups. p values are two-sided. Only 7.7% (81/1,052) of HPV-infected women had intervening negative results. Very few (3.7%, 39/1,052) had "definite clearance and re-appearance", of which 5.1% (2/39) subsequently persisted to a diagnosis of CIN2. There were zero CIN3+ lesions. Extremely few women (2/2,805 of women in our cohort) had a type-specific carcinogenic HPV infection clear, re-appear and lead to CIN2+. If confirmed, this argues against vaccination to avoid re-appearance that leads to precursor lesions and against the need of frequent HPV screening after initial negative results.

A competitive serological assay shows naturally acquired immunity to human papillomavirus infections in the Guanacaste Natural History Study.

BACKGROUND: A competitive Luminex Immunoassay (cLIA) has been developed to measure neutralizing antibodies against human papillomavirus (HPV) types 6, 11, 16 and 18. METHODS: In a cohort of 974 women from the Guanacaste Natural History Study, we studied the relationship of baseline cLIA and virus-like particle (VLP) enzyme-linked immunosorbent assay (ELISA) (HPV16 and HPV18 only) seropositivity to measures of HPV exposure, HPV DNA positivity, number of sexual partners, cytology findings, and age. We then studied immunity against subsequent infection with HPV6, 11, 16, 18 and related types over a 7-year period. RESULTS: cLIA seroprevalence varied with previous exposure; the prevalence of cLIA results positive for HPV16 and HPV18 was lower than the prevalence of positive VLP ELISA responses. cLIA and VLP ELISA positivity predicted protection from subsequent infections with concordant types. The combined odds ratio for HPV16 and HPV18 cLIA positivity was 0.41 (95% confidence interval [CI], 0.21-0.80), and the combined odds ratio for the HPV16 and HPV18 VLP ELISA positivity was 0.65 (95% CI, 0.46-0.93). Of individual types, statistical significance was only reached for HPV16 cLIA positivity (odds ratio, 0.44; 95% CI, 0.15-0.94). CONCLUSIONS: Both assays showed an association between positive results and significant protection from subsequent infections for HPV16 and HPV18 combined. cLIA seroprevalence was lower than VLP ELISA, suggesting that the assay detects a subset of antibodies following natural infection that are specifically linked to immunity against subsequent HPV infection.

Performance of Cervical Screening a Decade Following HPV Vaccination: The Costa Rica Vaccine Trial.

BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.

Simulation of the Mechanical Behaviour of Metal Gyroids for Bone Tissue Application.

Additive manufacturing is a valid solution to build complex geometries, including lightweight structures. Among these, gyroids offer a viable concept for bone tissue application, although many preliminary trials would be required to validate the design before actual implantation. In this frame, this study is aimed at presenting the background and the steps to build a numerical simulation to extract the mechanical behaviour of the structure, thus reducing the experimental effort. The results of the simulation are compared to the actual outcome resulting from quasi-static compressive tests and the effectiveness of the model is measured with reference to similar studies presented in the literature about other lightweight structures.

[The academies: remembering the past, programming the future]. / Las academias: recuerdo del pasado y programa de futuro.

Since the foundation of the first Academy by Plato the year 338 b.C. until now, Academies have gone through different periods. The first covered the centuries between Plato and the Renaissance. During this time, Academies were understood as centers for the culture of Humanities. At the beginning of the 17th Century a new period began, with Academies of a new style, aimed at either to the promotion of experimental scientific research (British model) or to the advisory of States in scientific questions (French model). The Spanish Academies founded in the 18th century followed the French model, neglecting at some extent the first goal, i.e. the leadership and promotion of scientific research. Looking to the future, Spanish Academies should increase their role as the main national centers for promotion and discussion of scientific research and developments.

Neither one-time negative screening tests nor negative colposcopy provides absolute reassurance against cervical cancer.

A population sample of 10,049 women living in Guanacaste, Costa Rica, was recruited into a natural history of human papillomavirus (HPV) and cervical neoplasia study in 1993-1994. At the enrollment visit, we applied multiple state-of-the-art cervical cancer screening methods to detect prevalent cervical cancer and to prevent subsequent cervical cancers by the timely detection and treatment of precancerous lesions. Women were screened at enrollment with 3 kinds of cytology (often reviewed by more than one pathologist), visual inspection and cervicography. Any positive screening test led to colposcopic referral and biopsy and/or excisional treatment of CIN2 or worse. We retrospectively tested stored specimens with an early HPV test (hybrid capture tube test) and for >40 HPV genotypes using a research PCR assay. We followed women typically 5-7 years and some up to 11 years. Nonetheless, 16 cases of invasive cervical cancer were diagnosed during follow-up. Six cancer cases were failures at enrollment to detect abnormalities by cytology screening; 3 of the 6 were also negative at enrollment by sensitive HPV DNA testing. Seven cancers represent failures of colposcopy to diagnose cancer or a precancerous lesion in screen-positive women. Finally, 3 cases arose despite attempted excisional treatment of precancerous lesions. Based on this evidence, we suggest that no current secondary cervical cancer prevention technologies applied once in a previously under-screened population is likely to be 100% efficacious in preventing incident diagnoses of invasive cervical cancer.

[Discreet follies. Variations on Don Quixote's folly]. / Discretas locuras. Variaciones en torno al tema de la locura de don Quijote.

Physicians and psychiatrists have been discussing through centuries about the madness of Don Quixote. The first in doing that was Philippe Pinel, followed immediately by many others. They all agreed in diagnosing Don Quixote as "monomaniac". Cervantes was considered an excellent "nosographer", and the novel a paradigmatic description of this mental disorder. After the Kraepelin's work, the old Pinelian nosography was substituted by a new system of classification of mental diseases, and Don Quixote was considered "paranoid". Finally, after the DSM IV, the usual diagnostic is "delusional disorder". Throughout history there have been two different types of mental disorders, being only one of them considered pathological. This difference appears in English in words like "crazy" and "mad." The thesis of this essay is that Don Quixote is more a crazy than a mad man. He is trying to achieve a world full of peace, justice and love. His moral ideal is to make possible the triumph of this perfect world. This crazy goal was deeply influenced by the Erasmian ideology. And Erasmus of Rotterdam was the author of a very famous book entitled The Praise of Folly, published the year 1509, almost a century before the novel of Cervantes. In this work, the word opposite to "loco" (crazy, mad, insane) is "discreto", a word of difficult translation to English, which means at the same time "shrewd," "discreet" and "ingenious". Cervantes says at the beginning of the second part of his work, that Don Quixote is doing in it "discretas locuras" ("discreet follies", trans. Thomas Shelton, 1620; "ingenious follies", trans. Tobias G. Smollet, 1755; "shrewd lunacies", trans. John Ormsby, 1885). This mixture of cleverness and lack of moderation is considered by the author the interpretation's key of the work.

Performance of self-collected cervical samples in screening for future precancer using human papillomavirus DNA testing.

BACKGROUND: Self-collected human papillomavirus (HPV) testing could reduce barriers to cervical cancer screening, with performance comparable to clinician-collected specimens. The ability of self-collected specimens to cross-sectionally and prospectively detect precursor lesions was investigated in an HPV vaccine randomized trial in Costa Rica. METHODS: In the trial, 7466 women age 18 to 25 years received an HPV16/18 or control vaccine and were followed at least annually for four years. In this secondary analysis, we included all women who provided a self-collected cervicovaginal specimen six months after enrollment (5109 women = full analytical cohort). A subset (615 women = restricted cohort) also had clinician-collected specimens at the six-month postenrollment visit. High-grade squamous intraepithelial lesion or repeat low-grade squamous intraepithelial lesion prompted colposcopic referral throughout the study. HPV testing was performed with SPF10PCR/DEIA/LiPA25. Cross-sectional and prospective sensitivity, specificity, and predictive values were estimated. RESULTS: In the full cohort, one-time HPV testing on self-collected samples detected prevalent CIN2+ with a sensitivity of 88.7% (95% confidence interval [CI] =77.0% to 95.7%) and a specificity of 68.9% (95% CI = 67.6% to 70.1%). For predicting incident CIN2+ in the subsequent four years, sensitivity was 73.9% (95% CI = 65.8% to 81.0%) and specificity 69.4% (95% CI = 68.1% to 70.7%). In the restricted cohort, for incident CIN2+, self-collected HPV was much more sensitive than cytology (80.0% vs 10.0%); relative sensitivity was 0.1 (95% CI = 0.03% to 0.5%). Furthermore, three times more women with normal baseline cytology developed incident CIN2+ than those with negative self-collected HPV. Self-collected and clinician-collected HPV testing had comparable performance. Agreement between self- and clinician-collected samples was 89.7% (kappa = 0.78, McNemar χ2 = 0.62) for carcinogenic HPV types. CONCLUSIONS: Self-collected specimens can be used for HPV-based screening, providing sensitivity and specificity comparable with clinician-collected specimens and detecting disease earlier than cytology.

Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica.

The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines.

[Michael Servetus: symphony in <>]. / Miguel servet: sinfonía en re mayor.

On October 27th 1553, the physician and religious reformer Miguel Servet was burnt at stake. The 450th anniversary of his death took place, therefore, a few months ago. This is a fact which deserves being taken into account, not only because of the importance of the individual, but also, and mainly, because during the last years some important historiographical advances have changed the traditional approach, giving place to a new and more accurate analysis to his life and work. The topic image of Servet spread by the Spanish historiography of the 19th and most of the 20th Centuries has been that of a scientific genius, discoverer of the pulmonary circulation of blood, but also that of a crazy theologian with absurd ideas about some basic Christian dogmas, specially the Holy Trinity. This image is now considered absolutely misleading. The historiography of the complex religious movements of the 16th Century has shown that Servet, far from being a crazy theologian absolutely disconnected of the religious movements of the Century, was instead one of the leaders of an important Christian movement which G. H. Williams called <> He consecrated all his life to this goal, which also was the reason of his death, always showing an absolute and admirable intellectual and human coherence. To these goals he subdued any other objective, as well as the study and the exercise of medicine. This gives the basis to correctly understand the fact, never explained convincingly until now, why his great scientific discovery, the pulmonary circulation of blood, appeared as a minimal part in the heart of a theological book.