Neanderthal introgression in SCN9A impacts mechanical pain sensitivity.

The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in SCN9A. We find that tracts of introgression occur on a Native American genomic background, have an average length of ~123 kb and overlap the M932L, V991L, and D1908G coding positions. Furthermore, we measured experimentally six pain thresholds in 1623 healthy Colombians. We found that Neanderthal ancestry in SCN9A is significantly associated with a lower mechanical pain threshold after sensitization with mustard oil and evidence of additivity of effects across Nav1.7 variants. Our findings support the reported association of Neanderthal Nav1.7 variants with clinical pain, define a specific sensory modality affected by archaic introgression in SCN9A and are consistent with independent effects of the Neanderthal variants on Nav1.7 function.

Automatic landmarking identifies new loci associated with face morphology and implicates Neanderthal introgression in human nasal shape.

We report a genome-wide association study of facial features in >6000 Latin Americans based on automatic landmarking of 2D portraits and testing for association with inter-landmark distances. We detected significant associations (P-value <5 × 10-8) at 42 genome regions, nine of which have been previously reported. In follow-up analyses, 26 of the 33 novel regions replicate in East Asians, Europeans, or Africans, and one mouse homologous region influences craniofacial morphology in mice. The novel region in 1q32.3 shows introgression from Neanderthals and we find that the introgressed tract increases nasal height (consistent with the differentiation between Neanderthals and modern humans). Novel regions include candidate genes and genome regulatory elements previously implicated in craniofacial development, and show preferential transcription in cranial neural crest cells. The automated approach used here should simplify the collection of large study samples from across the world, facilitating a cosmopolitan characterization of the genetics of facial features.

Diretivas antecipadas de vontade na percepção de estudantes de Medicina / Advance directives in the perception of Medical students

Resumo: Introdução: A autonomia do paciente na tomada de decisões a respeito da sua vida e das condutas diagnósticas e terapêuticas na sua saúde tem sido objeto de valorização social crescente. As diretivas antecipadas de vontade surgem, então, como um meio de o paciente expressar sua última vontade, salvaguardando o princípio da autonomia. No processo de aprendizagem acadêmica, na maioria das escolas médicas, o acadêmico se compromete com a vida, e toda a sua capacitação é fundamentada em aspectos técnicos, e apenas uma pequena parte do currículo, quando presente, abrange conteúdo específico voltado para a terminalidade da vida. A medicina evoluiu com importantes avanços tecnológicos que resultaram em melhorias na qualidade de vida, porém também trouxeram um prolongamento questionável da vida, com tratamentos muitas vezes injustificáveis e com a obstinação terapêutica de manter a vida a qualquer custo. Objetivo: Este estudo teve como objetivo analisar a percepção de estudantes de Medicina sobre as diretivas antecipadas de vontade. Método: O instrumento de pesquisa foi elaborado com uma entrevista individual e semiestruturada, aplicada pela plataforma de pesquisa Google Forms. Por causa do período de pandemia pelo Sars-CoV-2, a pesquisa foi realizada de forma não presencial em conformidade com a legislação vigente nacional. Após fechamento da amostra por exaustão, analisaram-se as respostas de 13 estudantes. Resultado: Em conformidade aos elementos, passos e critérios metodológicos, as informações obtidas foram classificadas e dispostas em duas categorias: dignidade da pessoa humana e autonomia do paciente; e conhecimento sobre diretivas antecipadas de vontade. Conclusão: Essa análise qualitativa trouxe à tona importantes temas, como a regulamentação que norteia as diretivas antecipadas de vontade e os princípios que envolvem a bioética, a fim de consolidar o respeito, a autonomia e a dignidade do paciente que está, ou estará, passando pela terminalidade da vida.

Abstract: Introduction: The patient's autonomy in making decisions about their life and about diagnostic and therapeutic approaches related to their health has been the object of growing social value. Then advanced directives appear to express the patient's last will, safeguarding the Principle of Autonomy. During the undergraduate learning process, students are committed to life, and all of their training is based on technical aspects. Only a small part of the curriculum covers specific contents focused on terminal illness, when present. Medicine has evolved with important technological advances that resulted in quality-of-life improvement, but also brought a questionable extension of life, with often unjustifiable treatments and a therapeutic obstinacy to maintain life at any cost. Objective: The aim of this study is to analyze the perception of medical students about end-of-life directives. Method: A descriptive qualitative research was carried out through an individual and semi-structured interview, applied through Google forms. Due to the period of pandemic caused by the SARS-CoV-2, the survey was carried out remotely, in accordance with current national legislation. After the target was attained through sample exhaustion, the responses of 13 students were analyzed. Results: In accordance with the elements, steps and methodological criteria, the obtained information was classified and arranged into two categories: Human Dignity and Patient Autonomy; Knowledge of Advance Will Directives. Conclusion: This qualitative analysis brought to light important topics such as the regulation that guides advance will directives and principles that involve bioethics, to consolidate the respect, autonomy and dignity of the patient who is, or will be, undergoing the terminality of life.

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans.

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

Treatment use and satisfaction in Australian women with endometriosis: a mixed-methods study.

AIMS: To document the frequency of conventional and complementary treatments used by Australian women with endometriosis and the perceived efficacy of these treatments, and to qualitatively explore women's treatment satisfaction. BACKGROUND: We do not adequately understand whether Australian women with endometriosis are satisfied with their medical care. METHODS: Using a mixed-methods design, 532 women with self-reported endometriosis were recruited from the community. Participants were asked about their medication, complementary and self-care treatment use, as well as perceived efficacy on a 0 (not effective) to 10 (extremely effective) numeric rating scale, and open-ended qualitative survey items about treatment satisfaction. RESULTS: Ninety-seven percent of women used medication for pain relief (mean perceived efficacy = 5.05) and 89% used complementary/self-care strategies (mean perceived efficacy = 3.70), with medication rated as significantly more effective (P < 0.001). Content analysis of the qualitative data identified that 36% of women were dissatisfied with treatment, 34% were somewhat satisfied and 24% were satisfied. We identified qualitative themes relating to: (i) barriers to treatment, which included lack of access, stigma and disappointment with medical professionals who were perceived as uncaring, unhelpful and, in some cases, psychologically damaging; (ii) the need for holistic, interdisciplinary care; and (iii) patient knowledge, advocacy and resilience in endometriosis management. CONCLUSIONS: Our findings reveal important limitations in the current Australian healthcare model, including the need for patient-centred interdisciplinary care that treats the biopsychosocial needs of people with endometriosis, and widespread pain education, spanning medical training to community awareness.

Prediction of eye, hair and skin colour in Latin Americans.

Here we evaluate the accuracy of prediction for eye, hair and skin pigmentation in a dataset of > 6500 individuals from Mexico, Colombia, Peru, Chile and Brazil (including genome-wide SNP data and quantitative/categorical pigmentation phenotypes - the CANDELA dataset CAN). We evaluated accuracy in relation to different analytical methods and various phenotypic predictors. As expected from statistical principles, we observe that quantitative traits are more sensitive to changes in the prediction models than categorical traits. We find that Random Forest or Linear Regression are generally the best performing methods. We also compare the prediction accuracy of SNP sets defined in the CAN dataset (including 56, 101 and 120 SNPs for eye, hair and skin colour prediction, respectively) to the well-established HIrisPlex-S SNP set (including 6, 22 and 36 SNPs for eye, hair and skin colour prediction respectively). When training prediction models on the CAN data, we observe remarkably similar performances for HIrisPlex-S and the larger CAN SNP sets for the prediction of hair (categorical) and eye (both categorical and quantitative), while the CAN sets outperform HIrisPlex-S for quantitative, but not for categorical skin pigmentation prediction. The performance of HIrisPlex-S, when models are trained in a world-wide sample (although consisting of 80% Europeans, https://hirisplex.erasmusmc.nl), is lower relative to training in the CAN data (particularly for hair and skin colour). Altogether, our observations are consistent with common variation of eye and hair colour having a relatively simple genetic architecture, which is well captured by HIrisPlex-S, even in admixed Latin Americans (with partial European ancestry). By contrast, since skin pigmentation is a more polygenic trait, accuracy is more sensitive to prediction SNP set size, although here this effect was only apparent for a quantitative measure of skin pigmentation. Our results support the use of HIrisPlex-S in the prediction of categorical pigmentation traits for forensic purposes in Latin America, while illustrating the impact of training datasets on its accuracy.

A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation.

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

Humanização em saúde na graduação em medicina e sua correlação com atividades da IFMSA Brazil / Humanization in healthcare at a medical undergraduate course and its correlation with IFMSA Brazil activities

Ao correlacionar humanização e graduação de medicina, estudantes filiados à Federação Internacional das Associações dos Estudantes de Medicina do Brasil (IFMSA Brazil), realizam atividades com o intuito de disseminar e implementar conhecimentos adquiridos em sua formação. O artigo objetiva identificar como a temática 'Humanização em Saúde' é desenvolvida nos programas da Federação, correlacionando-os com literatura científica. Realizou-se uma revisão integrativa e, posteriormente, analisou-se os relatórios referentes aos programas. Os artigos abordavam formas de inserir a humanização na graduação de medicina. Em relação aos programas, 15 possuíam as palavras 'Humanização', 'Arte' e/ou 'Empatia'. Reforça-se a importância da graduação médica com olhar holístico, voltado para o método clínico centrado na pessoa. A abordagem literária foi aplicada tanto pelo professor na graduação, em literatura científica, como por alunos da Federação. Evidencia-se que a humanização em saúde é abordada tanto em atividades curriculares como em extracurriculares na graduação de medicina.

When correlating humanization and the medical undergraduate course, students affiliated to the International Federation of Medical Students' Associations- Brazil (IFMSA Brazil) carry out activities to disseminate and implement the knowledge acquired in their undergraduate course. The objective of the study was to identify how 'Humanization in Healthcare' is developed in IFMSA Brazil's programs, correlating this with the scientific literature. First, an integrative review was performed, and then the reports related to the programs were analyzed. The articles addressed ways of inserting humanization in medical undergraduate courses. Regarding the programs, 15 had the words 'Humanization', 'Art' and/or 'Empathy'. The importance of the medical undergraduate course with a holistic view, focused on the person-centered clinical method, is reinforced. The literary approach was applied both by the professor at undergraduate level, in scientific literature, and by students of the Federation. It is evident that humanization in healthcare is addressed both in curricular and in extracurricular activities in medical school.

Al correlacionar humanización y graduación médica, los estudiantes afiliados a la Federación Internacional de las Asociaciones de los Estudiantes de Medicina de Brasil (IFMSA Brazil), realizan actividades con el intento de difundir e implementar los conocimientos adquiridos en su formación. Este trabajo objetiva identificar cómo se desarrolla la 'Humanización en salud' en los programas de IFMSA Brazil correlacionándolos con la literatura. Se realizó una búsqueda en la base de datos BVS y, posteriormente, se analizaron los informes de los programas. Los artículos abordaron formas de insertar la humanización en la graduación. En cuanto a los programas, 15 contenían las palabras "Humanización", "Arte" y/o "Empatía". Se refuerza la importancia de la enseñanza médica con enfoque en el método clínico que prioriza la persona. Es evidente que la humanización en salud se aborda en actividades curriculares y extracurriculares en la escuela médica.

A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia.

We report a genome-wide association scan in >6,000 Latin Americans for pigmentation of skin and eyes. We found eighteen signals of association at twelve genomic regions. These include one novel locus for skin pigmentation (in 10q26) and three novel loci for eye pigmentation (in 1q32, 20q13 and 22q12). We demonstrate the presence of multiple independent signals of association in the 11q14 and 15q13 regions (comprising the GRM5/TYR and HERC2/OCA2 genes, respectively) and several epistatic interactions among independently associated alleles. Strongest association with skin pigmentation at 19p13 was observed for an Y182H missense variant (common only in East Asians and Native Americans) in MFSD12, a gene recently associated with skin pigmentation in Africans. We show that the frequency of the derived allele at Y182H is significantly correlated with lower solar radiation intensity in East Asia and infer that MFSD12 was under selection in East Asians, probably after their split from Europeans.

Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance.

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the intermixing (admixture) of Native Americans, Europeans and Sub-Saharan Africans. Using novel haplotype-based methods, here we infer sub-continental ancestry in over 6,500 Latin Americans and evaluate the impact of regional ancestry variation on physical appearance. We find that Native American ancestry components in Latin Americans correspond geographically to the present-day genetic structure of Native groups, and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming mostly from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that ancestry related to highland (Central Andean) versus lowland (Mapuche) Natives is associated with variation in facial features, particularly nose morphology, and detect significant differences in allele frequencies between these groups at loci previously associated with nose morphology in this sample.

[Tuberculosis That Mimics Cancer: Cases Referred to the National Institute of Neoplastic Diseases, Lima-Peru]. / Tuberculosis que imita cáncer: casos derivados al Instituto Nacional de Enfermedades Neoplásicas, Lima-Perú.

Tuberculosis (TB) is a major public health problem that, due to the clinical variability of its presentation, can be confused with cancer. The aim of this study was to identify the clinical-radiological characteristics and to describe the methodology that allowed to achieve a TB diagnosis in patients referred to the National Institute of Neoplastic Diseases (INEN) with a presumed diagnosis of cancer between 2014 and 2016. The study included 170 patients (52.4% men) with an average age of 41.1 years; 18% presented a history of contact with TB, and 5.9% had had the disease previously. The TB was pulmonary in 22.4% and extrapulmonary in 77.7% of patients. The most frequent symptoms were respiratory, tumor, weight loss, and neurological. The cancer diagnoses most frequently discarded were lymphoma, lung cancer, and brain cancer. The lesions that suggested a neoplasm indicated an advanced clinical stage in 63.5%. Therefore, it follows that the symptoms and images associated with TB can be confused with malignant neoplasms.

La tuberculosis (TB) es un importante problema de salud pública que debido a la variabilidad clínica de su presentación, puede confundirse con una malignidad. El objetivo del estudio fue identificar las características clínico radiológicas y describir la metodología que permitió llegar al diagnóstico de TB en pacientes derivados con presunción diagnóstica de cáncer al Instituto Nacional de Enfermedades Neoplásicas (INEN) entre 2014 y 2016. Se incluyeron 170 pacientes (52,4 % hombres) con edad promedio de 41,1 años, 18 % presentaron antecedentes de contacto con TB y un 5,9 % tuvo previamente la enfermedad. La TB fue pulmonar en 22,4 % y extrapulmonar en 77,7 % de los pacientes. Los síntomas más frecuentes fueron respiratorios, tumoración, pérdida de peso y neurológicos. Los diagnósticos oncológicos descartados con mayor frecuencia fueron linfoma, cáncer pulmonar y cerebral. Las lesiones que sugerían una neoplasia indicaron un estadio clínico avanzado en el 63,5 %. Se concluye que los síntomas e imágenes asociados a TB pueden confundirse con neoplasias malignas.

Tuberculosis que imita cáncer: casos derivados al Instituto Nacional de Enfermedades Neoplásicas, Lima-Perú / Tuberculosis That Mimics Cancer: Cases Referred to the National Institute of Neoplastic Diseases, Lima-Peru

RESUMEN La tuberculosis (TB) es un importante problema de salud pública que debido a la variabilidad clínica de su presentación, puede confundirse con una malignidad. El objetivo del estudio fue identificar las características clínico radiológicas y describir la metodología que permitió llegar al diagnóstico de TB en pacientes derivados con presunción diagnóstica de cáncer al Instituto Nacional de Enfermedades Neoplásicas (INEN) entre 2014 y 2016. Se incluyeron 170 pacientes (52,4 % hombres) con edad promedio de 41,1 años, 18 % presentaron antecedentes de contacto con TB y un 5,9 % tuvo previamente la enfermedad. La TB fue pulmonar en 22,4 % y extrapulmonar en 77,7 % de los pacientes. Los síntomas más frecuentes fueron respiratorios, tumoración, pérdida de peso y neurológicos. Los diagnósticos oncológicos descartados con mayor frecuencia fueron linfoma, cáncer pulmonar y cerebral. Las lesiones que sugerían una neoplasia indicaron un estadio clínico avanzado en el 63,5 %. Se concluye que los síntomas e imágenes asociados a TB pueden confundirse con neoplasias malignas.

ABSTRACT Tuberculosis (TB) is a major public health problem that, due to the clinical variability of its presentation, can be confused with cancer. The aim of this study was to identify the clinical-radiological characteristics and to describe the methodology that allowed to achieve a TB diagnosis in patients referred to the National Institute of Neoplastic Diseases (INEN) with a presumed diagnosis of cancer between 2014 and 2016. The study included 170 patients (52.4% men) with an average age of 41.1 years; 18% presented a history of contact with TB, and 5.9% had had the disease previously. The TB was pulmonary in 22.4% and extrapulmonary in 77.7% of patients. The most frequent symptoms were respiratory, tumor, weight loss, and neurological. The cancer diagnoses most frequently discarded were lymphoma, lung cancer, and brain cancer. The lesions that suggested a neoplasm indicated an advanced clinical stage in 63.5%. Therefore, it follows that the symptoms and images associated with TB can be confused with malignant neoplasms.

A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation.

We report a genome-wide association scan for facial features in ∼6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P values<5 × 10(-8)) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar funtion.

A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features.

We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10(-8) to 3 × 10(-119)), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair.

A genome-wide association study identifies multiple loci for variation in human ear morphology.

Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10(-8) to 3 × 10(-14)). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1.