Teleconsulta médica. Análisis y recomendaciones del Departamento de Ética del Colegio Médico de Chile

The possibility of allowing patients access to health professionals, has been greatly facilitated by advances in technology. Indeed, nowadays it is possible not only direct contact between one health professional with another, but also the possibility of sending images and other tests to consult distant colleagues. This has undoubtedly enabled better health care for many patients. It is also possible for a patient to consult a doctor directly in a remote and synchronous way with oral and visual contact, thus establishing a new form of medical consultation. It is this last way of relationship, which has already spread as a practice in normal times, which arouses apprehensions about the ethical requirements that a consultation must meet. This work by the Ethics Department of the Chilean Medical Association seeks to reflect on the ethical demands of a medical consultation and on the shortcomings that teleconsultation has. It also aims to propose several recommendations, so that this new form of doctor-patient relationship serves as a complement to traditional care, without jeopardizing the objectives of a medical action.

Quantitative interactions between Candida albicans and the mutans streptococci in patients with Down Syndrome

BACKGROUND: Oral microorganisms produce damage through the transfer to bloodstream, colonizing other tissues or direct damage in the oral cavity. Aim to study the quantitative interactions between C. albicans and the mutans streptococci and ms serotypes in the saliva of the oral cavity of patients with Down syndrome (DS). MATERIAL AND METHODS: Included 120 patients of both genders, 60 patients with Down syndrome (DS) and 60 patients as a control group (CG). Samples of saliva were taken, and bacteria and fungi were grown on TYCSB and Saboureaud agar. Microbiological, serological and quantitative analyses were performed to determine the kind of isolated of microorganisms corresponding to the ms c, e, f and k for species S. mutans and d and g for S. sobrinus and C. albicans. Electronic scanning microscopy was employed to visualize and confirm the colonies under study. Statistics analysis included t-test proofs for matched data test, Scheffé and ANOVA. RESULTS: Forming units (CFU) per mL of saliva of C. albicans a significant difference was observed among DS < CG groups. A correlation of the C. albicans quantity and the ms count was found by age intervals however, tendencies were different in SD and CG. Also, the CFU of C. albicans was different among the serotypes of ms (c, e, f, k < d, g, h, < notyped). CONCLUSIONS: These results show a significant non-random association between these two commensal microorganisms in different patient groups

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[Medical teleconsultation. Analysis and recommendations from the ethics department of the Chilean medical association]. / Teleconsulta médica. Análisis y recomendaciones del Departamento de Ética del Colegio Médico de Chile.

The possibility of allowing patients access to health professionals, has been greatly facilitated by advances in technology. Indeed, nowadays it is possible not only direct contact between one health professional with another, but also the possibility of sending images and other tests to consult distant colleagues. This has undoubtedly enabled better health care for many patients. It is also possible for a patient to consult a doctor directly in a remote and synchronous way with oral and visual contact, thus establishing a new form of medical consultation. It is this last way of relationship, which has already spread as a practice in normal times, which arouses apprehensions about the ethical requirements that a consultation must meet. This work by the Ethics Department of the Chilean Medical Association seeks to reflect on the ethical demands of a medical consultation and on the shortcomings that teleconsultation has. It also aims to propose several recommendations, so that this new form of doctor-patient relationship serves as a complement to traditional care, without jeopardizing the objectives of a medical action.

Development of a small panel of SNPs to infer ancestry in Chileans that distinguishes Aymara and Mapuche components.

BACKGROUND: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. RESULTS: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. CONCLUSIONS: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.

Argumentos éticos a favor y en contra de la participación del profesional médico en la muerte asistida. Análisis del Departamento de Ética del Colegio Médico de Chile / Ethical arguments for and against the participation of the medical profession in assisted death: analysis of the Ethics Department of the Chilean Medical Association

The discussion of a bill that allows medically assisted death (MAD) in Chile, revived the debate about the ethics of this practice. The Department of Ethics of the Chilean Medical Association herein analyzes arguments in favor or against the participation of the medical profession in MAD. Among the main arguments against the participation of physicians in this practice are that MAD conflicts with the basic ethical principles of medical practice, that it is contrary to the purposes of medicine and that it could erode the patients' and society's confidence in physicians. The arguments in favor are related to physician´s compassion and non-abandonment of patients during their illness, choosing palliative care and ushering them to the final instance. Additionally, there is social expectation that this practice will be carried out by trained physicians who can verify that the strict criteria established by the legislation are met, guarantee that it obeys to a repeated request of a fully capable patient, and who is able to deal with the complications of the procedure. In this document we aimed to represent the different perspectives about physicians' participation in MAD, offering arguments to colleagues and stimulating their participation in this important debate.

Development of a small panel of SNPs to infer ancestry in Chileans that distinguishes Aymara and Mapuche components

BACKGROUND: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. RESULTS: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. CONCLUSIONS: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.

Aspectos éticos de la conducta del médico ante personas en huelga de hambre: opinión del Departamento de Ética del Colegio Médico de Chile / Ethical aspects of the doctors' behavior towards people on hunger strike: position paper from the Ethics Department of the Chilean Medical Association

Every so often, in Chile there is a discussion about the role of physicians in the care of people on hunger strike (HS). In this document, we review the ethical aspects of health care for persons in HS, aiming to provide guidelines to medical doctors who are required to attend them. First, we make an important distinction between HS and suicide, since the former is used as a protest and denunciation tool, while suicide seeks deliberately to end a life. Then we describe the three roles that the health professional can fulfill: as a treating doctor, as an expert or as an official of a prison. The respect for the autonomy and dignity of the person in HS must prevail whatever the role of the physician. Therefore, we maintain that under no circumstances, people who have autonomously decided to be in HS should be fed by force. Due to the complexity of the issue, we make special considerations about the management of minors and the non-competent persons in HS. In conclusion, we adhere to the principles that inspire the Declaration of Malta, which indicate that it would be preferable to "allow a person on hunger strike to die in dignity, rather than subjecting them to repeated interventions against their will".

[Ethical aspects of the doctors' behavior towards people on hunger strike: position paper from the Ethics Department of the Chilean Medical Association]. / Aspectos éticos de la conducta del médico ante personas en huelga de hambre: opinión del Departamento de Ética del Colegio Médico de Chile.

Every so often, in Chile there is a discussion about the role of physicians in the care of people on hunger strike (HS). In this document, we review the ethical aspects of health care for persons in HS, aiming to provide guidelines to medical doctors who are required to attend them. First, we make an important distinction between HS and suicide, since the former is used as a protest and denunciation tool, while suicide seeks deliberately to end a life. Then we describe the three roles that the health professional can fulfill: as a treating doctor, as an expert or as an official of a prison. The respect for the autonomy and dignity of the person in HS must prevail whatever the role of the physician. Therefore, we maintain that under no circumstances, people who have autonomously decided to be in HS should be fed by force. Due to the complexity of the issue, we make special considerations about the management of minors and the non-competent persons in HS. In conclusion, we adhere to the principles that inspire the Declaration of Malta, which indicate that it would be preferable to "allow a person on hunger strike to die in dignity, rather than subjecting them to repeated interventions against their will".

Selective intra-dinucleotide interactions and periodicities of bases separated by K sites: a new vision and tool for phylogeny analyses.

Direct tests of the random or non-random distribution of nucleotides on genomes have been devised to test the hypothesis of neutral, nearly-neutral or selective evolution. These tests are based on the direct base distribution and are independent of the functional (coding or non-coding) or structural (repeated or unique sequences) properties of the DNA. The first approach described the longitudinal distribution of bases in tandem repeats under the Bose-Einstein statistics. A huge deviation from randomness was found. A second approach was the study of the base distribution within dinucleotides whose bases were separated by 0, 1, 2… K nucleotides. Again an enormous difference from the random distribution was found with significances out of tables and programs. These test values were periodical and included the 16 dinucleotides. For example a high "positive" (more observed than expected dinucleotides) value, found in dinucleotides whose bases were separated by (3K + 2) sites, was preceded by two smaller "negative" (less observed than expected dinucleotides) values, whose bases were separated by (3K) or (3K + 1) sites. We examined mtDNAs, prokaryote genomes and some eukaryote chromosomes and found that the significant non-random interactions and periodicities were present up to 1000 or more sites of base separation and in human chromosome 21 until separations of more than 10 millions sites. Each nucleotide has its own significant value of its distance to neutrality; this yields 16 hierarchical significances. A three dimensional table with the number of sites of separation between the bases and the 16 significances (the third dimension is the dinucleotide, individual or taxon involved) gives directly an evolutionary state of the analyzed genome that can be used to obtain phylogenies. An example is provided.

Selective intra-dinucleotide interactions and periodicities of bases separated by K sites: a new vision and tool for phylogeny analyses

Direct tests of the random or non-random distribution of nucleotides on genomes have been devised to test the hypothesis of neutral, nearly-neutral or selective evolution. These tests are based on the direct base distribution and are independent of the functional (coding or non-coding) or structural (repeated or unique sequences) properties of the DNA. The first approach described the longitudinal distribution of bases in tandem repeats under the Bose-Einstein statistics. A huge deviation from randomness was found. A second approach was the study of the base distribution within dinucleotides whose bases were separated by 0, 1, 2... K nucleotides. Again an enormous difference from the random distribution was found with significances out of tables and programs. These test values were periodical and included the 16 dinucleotides. For example a high ¨positive¨ (more observed than expected dinucleotides) value, found in dinucleotides whose bases were separated by (3K + 2) sites, was preceded by two smaller ¨negative¨ (less observed than expected dinucleotides) values, whose bases were separated by (3K) or (3K + 1) sites. We examined mtDNAs, prokaryote genomes and some eukaryote chromosomes and found that the significant non-random interactions and periodicities were present up to 1000 or more sites of base separation and in human chromosome 21 until separations of more than 10 millions sites. Each nucleotide has its own significant value of its distance to neutrality; this yields 16 hierarchical significances. A three dimensional table with the number of sites of separation between the bases and the 16 significances (the third dimension is the dinucleotide, individual or taxon involved) gives directly an evolutionary state of the analyzed genome that can be used to obtain phylogenies. An example is provided.

Aproximación ética científica al doble efecto o único bien posible en el aborto terapéutico / Scientific ethical approach to double effect or only possible good in therapeutic abortion / Aproximação ética científica ao duplo efeito ou único bem possível no aborto terapêutico

El estudio muestra como la doctrina o principio del doble efecto (DDE) de una acción con efecto secundario negativo no puede aplicarse a todos los casos de aborto terapéutico (AT). Con el análisis de las causas e indicación de AT se demuestra que solo algunos de estos corresponden a DDE. Cuando no es el feto el que lleva a la madre a tener un embarazo de alto riesgo con amenaza de daño severo o muerte para ella, el caso puede adscribirse a la DDE; cuando es el feto directa o indirectamente el que causa a lleva a ese riesgo materno, el caso no se adscribe a la DDE. Si el feto es la causa de la muerte inminente de la madre, la remoción de la causa, que es la terapia adecuada, coincide con matarlo; entonces la acción buena (salvar a la madre tratándola causalmente) es la misma que la mala (matar al feto), situación que no puede asimilarse sea a la DDE o a la doctrina del mal menor. Más aún, decidir no interrumpir el embarazo produciría la muerte de la madre y el feto. El caso debería adscribirse al principio del único bien posible.

This study shows the inapplicability of the doctrine of double effect (DDE) to all the cases of therapeutic abortion (TA). The causes of the maternal risk define cases that cannot be included in the DDE. When it is not the embryo or fetus that produces the mother pathology the case can be assigned to the DDE. When the embryo or fetus produces directly or indirectly the process that threatens the mother’s life the case cannot be assigned to the DDE. If the fetus is the cause of the imminent mother’s death, the removal of the cause, that is the proper therapy, coincides with killing him or her; then the good action (to save therapeutically the mother) is the same to the bad action (to kill the fetus) and this situation cannot be assimilated either to the DDE or to the doctrine of the lesser evil. Deciding not to kill the fetus will produce the death of the mother and the fetus. So this situation should be ascribed to the principle of the unique possible well.

O estudo mostra como a doutrina ou princípio do duplo efeito (DDE) de uma ação com efeito secundário negativo não pode aplicar-se a todos os casos de aborto terapêutico (AT). Com a análise das causas e indicação de AT se demonstra que só alguns destes correspondem a DDE. Quando não é o feto que leva a mãe a ter uma gravidez de alto risco com ameaça de dano severo ou morte para ela, o caso pode circunscrever-se à DDE; quando é o feto direta ou indiretamente quem causa ou leva a esse risco materno, o caso não se circunscreve a DDE. Se o feto é a causa da morte iminente da mãe, a remoção da causa, que é a terapia adequada, coincide em matá-lo; então a ação boa (salvar a mãe tratando-a causalmente) é a mesma que a má (matar o feto), situação que não pode assimilar-se à DDE ou à doutrina do mal menor. Mais ainda, decidir não interromper a gravidez produziria a morte da mãe e do feto. O caso deveria circunscrever-se ao princípio do único bem possível.

[Position paper from the Department of Ethics of the Chilean College of Physicians about conscientious objection]. / El médico y la objeción de conciencia: Opinión del Departamento de Ética del Colegio Médico de Chile A. G.

The Chilean bill that regulates abortion for three cases (Bulletin Nº 9895-11) includes the possibility that health professionals may manifest their conscientious objection (CO) to perform this procedure. Due to the broad impact that the issue of C O had, the Ethics Department of the Chilean College of Physicians considered important to review this concept and its ethical and legal basis, especially in the field of sexual and reproductive health. In the present document, we define the practical limit s of CO, both for the proper fulfillment of the medical profession obligations, and for the due respect and non-discrimination that the professional objector deserves. We analyze the denial of some health institutions to perform abortions if it is legalize d, and we end with recommendations adjusted to the Chilean reality. Specifically, we recognize the right to conscientious objection that all physicians who directly participate in a professional act have. But we a lso recognize that physicians have ineludib le obligations towards their patients, including the obligation to inform about the existence of this service, how to access to it and -as set out in our code of ethics- to ensure that another colleague will continue attending the patient.

El médico y la objeción de conciencia: opinión del Departamento de Ética del Colegio Médico de Chile A. G. / Position paper from the Department of Ethics of the Chilean College of Physicians about conscientious objection

The Chilean bill that regulates abortion for three cases (Bulletin Nº 9895-11) includes the possibility that health professionals may manifest their conscientious objection (CO) to perform this procedure. Due to the broad impact that the issue of C O had, the Ethics Department of the Chilean College of Physicians considered important to review this concept and its ethical and legal basis, especially in the field of sexual and reproductive health. In the present document, we define the practical limit s of CO, both for the proper fulfillment of the medical profession obligations, and for the due respect and non-discrimination that the professional objector deserves. We analyze the denial of some health institutions to perform abortions if it is legalize d, and we end with recommendations adjusted to the Chilean reality. Specifically, we recognize the right to conscientious objection that all physicians who directly participate in a professional act have. But we a lso recognize that physicians have ineludib le obligations towards their patients, including the obligation to inform about the existence of this service, how to access to it and -as set out in our code of ethics- to ensure that another colleague will continue attending the patient.

Malignant melanoma in Chile: different site distribution between private and state patients.

BACKGROUND: The body site location of primary Malignant Melanoma (MM) has been correlated with prognosis and survival. Ethnic, genetics, sun exposure factors are related to the anatomical distribution of MM. Low and high socioeconomic strata in Chile differ in ethnic, genetic and cultural conditions. The purpose of this study was to analyze the anatomical MM distribution in the Chilean population in both strata searching for differences due to their ethno-genetic-cultural differences. Records of 1148 MM, 575 cases from state hospitals (Low Socioeconomic Strata, LSS) and 573 cases from private clinics (High Socioeconomic Strata, HSS) were analyzed by body site. RESULTS: Females from LSS showed a higher number of MM in soles, cheeks, and around the eye area. Females from the HSS showed a higher number of MM in dorsal feet and dorsal hands. Males from LSS showed a higher number of MM in soles, around the eye area, and cheeks. However, males from HSS showed a higher number of MM in the trunk, and in the arms. Acral MM was significantly higher in LSS than in the HSS in both sexes. The Chilean population from the HSS and LSS showed differences in the distribution of MM by site. Furthermore, gender differences in the proportion of MM analyzed by anatomical site are observed in both strata. CONCLUSIONS: Results show evidence that differential genetics factors, sun exposure, or other environmental or cultural factors of both strata may account for these differences.

The structure of selective dinucleotide interactions and periodicities in D melanogaster mtDNA.

BACKGROUND: We found a strong selective 3-sites periodicity of deviations from randomness of the dinucleotide (DN) distribution, where both bases of DN were separated by 1, 2, K sites in prokaryotes and mtDNA. Three main aspects are studied. I) the specific 3 K-sites periodic structure of the 16 DN. II) to discard the possibility that the periodicity was produced by the highly nonrandom interactive association of contiguous bases, by studying the interaction of non-contiguous bases, the first one chosen each I sites and the second chosen J sites downstream. III) the difference between this selective periodicity of association (distance to randomness) of the four bases with the described fixed periodicities of base sequences. RESULTS: I) The 16 pairs presented a consistent periodicity in the strength of association of both bases of the pairs; the most deviated pairs are those where G and C are involved and the least deviated ones are those where A and T are involved. II) we found significant non-random interactions when the first nucleotide is chosen every I sites and the second J sites downstream until I=J=76. III) we showed conclusive differences between these internucleotide association periodicities and sequence periodicities. CONCLUSIONS: This relational selective periodicity is different from sequence periodicities and indicates that any base strongly interacts with the bases of the residual genome; this interaction and periodicity is highly structured and systematic for every pair of bases. This interaction should be destroyed in few generations by recurrent mutation; it is only compatible with the Synthetic Theory of Evolution and agrees with the Wright's adaptive landscape conception and evolution by shifting balanced adaptive peaks.

The structure of selective dinucleotide interactions and periodicities in D melanogaster mtDNA

BACKGROUND: We found a strong selective 3-sites periodicity of deviations from randomness of the dinucleotide (DN) distribution, where both bases of DN were separated by 1, 2, K sites in prokaryotes and mtDNA. Three main aspects are studied. I) the specific 3 K-sites periodic structure of the 16 DN. II) to discard the possibility that the periodicity was produced by the highly nonrandom interactive association of contiguous bases, by studying the interaction of non-contiguous bases, the first one chosen each I sites and the second chosen J sites downstream. III) the difference between this selective periodicity of association (distance to randomness) of the four bases with the described fixed periodicities of base sequences. RESULTS: I) The 16 pairs presented a consistent periodicity in the strength of association of both bases of the pairs; the most deviated pairs are those where G and C are involved and the least deviated ones are those where A and T are involved. II) we found significant non-random interactions when the first nucleotide is chosen every I sites and the second J sites downstream until I=J=76. III) we showed conclusive differences between these internucleotide association periodicities and sequence periodicities. CONCLUSIONS: This relational selective periodicity is different from sequence periodicities and indicates that any base strongly interacts with the bases of the residual genome; this interaction and periodicity is highly structured and systematic for every pair of bases. This interaction should be destroyed in few generations by recurrent mutation; it is only compatible with the Synthetic Theory of Evolution and agrees with the Wright's adaptive landscape conception and evolution by shifting balanced adaptive peaks.

Malignant melanoma in Chile: different site distribution between private and state patients

BACKGROUND: The body site location of primary Malignant Melanoma (MM) has been correlated with prognosis and survival. Ethnic, genetics, sun exposure factors are related to the anatomical distribution of MM. Low and high socioeconomic strata in Chile differ in ethnic, genetic and cultural conditions. The purpose of this study was to analyze the anatomical MM distribution in the Chilean population in both strata searching for differences due to their ethno-genetic-cultural differences. Records of 1148 MM, 575cases from state hospitals (Low Socioeconomic Strata, LSS) and 573 cases from private clinics (High Socioeconomic Strata, HSS) were analyzed by body site. RESULTS: Females from LSS showed a higher number of MM in soles, cheeks, and around the eye area. Females from the HSS showed a higher number of MM in dorsal feet and dorsal hands. Males from LSS showed a higher number of MM in soles, around the eye area, and cheeks. However, males from HSS showed a higher number of MM in the trunk, and in the arms. Acral MM was significantly higher in LSS than in the HSS in both sexes. The Chilean population from the HSS and LSS showed differences in the distribution of MM by site. Furthermore, gender differences in the proportion of MM analyzed by anatomical site are observed in both strata. CONCLUSIONS: Results show evidence that differential genetics factors, sun exposure, or other environmental or cultural factors of both strata may account for these differences.

Foundational errors in the Neutral and Nearly-Neutral theories of evolution in relation to the Synthetic Theory: is a new evolutionary paradigm necessary?

The Neutral Theory of Evolution (NTE) proposes mutation and random genetic drift as the most important evolutionary factors. The most conspicuous feature of evolution is the genomic stability during paleontological eras and lack of variation among taxa; 98% or more of nucleotide sites are monomorphic within a species. NTE explains this homology by random fixation of neutral bases and negative selection (purifying selection) that does not contribute either to evolution or polymorphisms. Purifying selection is insufficient to account for this evolutionary feature and the Nearly-Neutral Theory of Evolution (N-NTE) included negative selection with coefficients as low as mutation rate. These NTE and N-NTE propositions are thermodynamically (tendency to random distributions, second law), biotically (recurrent mutation), logically and mathematically (resilient equilibria instead of fixation by drift) untenable. Recurrent forward and backward mutation and random fluctuations of base frequencies alone in a site make life organization and fixations impossible. Drift is not a directional evolutionary factor, but a directional tendency of matter-energy processes (second law) which threatens the biotic organization. Drift cannot drive evolution. In a site, the mutation rates among bases and selection coefficients determine the resilient equilibrium frequency of bases that genetic drift cannot change. The expected neutral random interaction among nucleotides is zero; however, huge interactions and periodicities were found between bases of dinucleotides separated by 1, 2... and more than 1,000 sites. Every base is co-adapted with the whole genome. Neutralists found that neutral evolution is independent of population size (N); thus neutral evolution should be independent of drift, because drift effect is dependent upon N. Also, chromosome size and shape as well as protein size are far from random.

The monthly rhythm of incidence and age at menarche: thirty five years of research. The circa-vacation-study expectancy rhythm of incidence and age at menarche.

The hypothesis that the vacation-study-expectancy scholar regime produces most of the monthly rhythm of the age at menarche (AaM) was tested. Studies on monthly menarche incidence (MI) refuted climatic factors as a main factor in this rhythm, and indicated that the main factor of this rhythm is the succession of expectancies of study (Stu-months) or vacation (Vac-months) months within a year. Thus the hypothesis of seasonal circa-annual rhythm should be modified to the circa-[vacation (fiesta)]-[study (non-fiesta)]-expectancies rhythm for the MI and age at menarche annual rhythms. In several countries Vac-months had higher MI than Stu-months. The high MI of Vac-months was followed by a large decrease when girls started their studies and a MI increase occurred as vacations approached. The hypothesis proposes that at the end of vacations and at the beginning of the study period the AaM should be lowest, and then the mean of AaM should increase because of the menarche delay of girls whose menarche was arrested by the initiation of school work. This pattern was found in four independent samples, from Chile, Colombia, USA and Brazil. The probability that this result be due to random fluctuation of means is extraordinarily low (P<10⁻8). I conclude that the influence of the expectancy of vacation and study periods on the monthly rhythm of the age at menarche is a real process that accounts for most of this rhythm.