The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio  = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Systematic review: fluid biomarkers and machine learning methods to improve the diagnosis from mild cognitive impairment to Alzheimer's disease.

Mild cognitive impairment (MCI) is often considered an early stage of dementia, with estimated rates of progression to dementia up to 80-90% after approximately 6 years from the initial diagnosis. Diagnosis of cognitive impairment in dementia is typically based on clinical evaluation, neuropsychological assessments, cerebrospinal fluid (CSF) biomarkers, and neuroimaging. The main goal of diagnosing MCI is to determine its cause, particularly whether it is due to Alzheimer's disease (AD). However, only a limited percentage of the population has access to etiological confirmation, which has led to the emergence of peripheral fluid biomarkers as a diagnostic tool for dementias, including MCI due to AD. Recent advances in biofluid assays have enabled the use of sophisticated statistical models and multimodal machine learning (ML) algorithms for the diagnosis of MCI based on fluid biomarkers from CSF, peripheral blood, and saliva, among others. This approach has shown promise for identifying specific causes of MCI, including AD. After a PRISMA analysis, 29 articles revealed a trend towards using multimodal algorithms that incorporate additional biomarkers such as neuroimaging, neuropsychological tests, and genetic information. Particularly, neuroimaging is commonly used in conjunction with fluid biomarkers for both cross-sectional and longitudinal studies. Our systematic review suggests that cost-effective longitudinal multimodal monitoring data, representative of diverse cultural populations and utilizing white-box ML algorithms, could be a valuable contribution to the development of diagnostic models for AD due to MCI. Clinical assessment and biomarkers, together with ML techniques, could prove pivotal in improving diagnostic tools for MCI due to AD.

Biomarkers for dementia in Latin American countries: Gaps and opportunities.

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.

Humanization of birth, women's empowerment, and midwives' actions and knowledge: experiences from Quebec and Chile / A humanização do nascimento, o empoderamento das mulheres e a reapropriação de ações e conhecimentos das parteiras: experiências do Québec e do Chile

ABSTRACT Whether in pre-pregnancy, pregnancy, birth and/or the postnatal and neonatal periods, midwives' practices are underpinned by humanism. However, in this era of postmodernity, there is an ever-growing need for rehumanization. This article adopts an auto-ethnographic approach in order to undertake a reflective analysis on the humanization of birth based on the practice of midwifery in two different contexts, namely Quebec (Canada) and Chile. In light of the evolution of the profession in these two countries, and the influence of health policies and social movements, there are factors such as the systematic use of technology and the hypermedicalization of reproductive processes which are maintaining women's ignorance and keeping them from being able to participate in their maternity process. Women's autonomy and empowerment become a key element for their participation in decisions regarding their maternity, assistance methods, or type of care. Concurrently, midwives' autonomy is a prerequisite for fully exercising their role in supporting and assisting women in this re-appropriation of their power by means of a comprehensive approach that takes into account psychological and social aspects as well as biomedical ones.

RESUMO Seja na pré-gravidez, na gravidez, no nascimento, seja nos períodos pós-natal e neonatal, as práticas das parteiras são sustentadas pelo humanismo. Entretanto, na atual era de pós-modernidade, há uma necessidade cada vez maior de reumanização. Este artigo adota uma abordagem autoetnográfica, a fim de realizar análise reflexiva sobre a humanização do nascimento baseada na prática da obstetrícia em dois contextos diferentes: Quebec (Canadá) e Chile. À luz da evolução da profissão nestes dois países e da influência das políticas de saúde e dos movimentos sociais, existem fatores, como o uso sistemático da tecnologia e a hipermedicalização dos processos reprodutivos, que estão mantendo as mulheres desinformadas e impedindo-as de participar de seu processo de maternidade. A autonomia e o empoderamento das mulheres tornam-se um elemento-chave para sua participação nas decisões relativas à sua maternidade, métodos de assistência ou tipo de cuidado. Ao mesmo tempo, a autonomia das parteiras é um requisito para o pleno exercício de seu papel de apoio e assistência às mulheres nesta reapropriação de seu poder, por meio de uma abordagem abrangente, que leve em conta tanto aspectos psicológicos e sociais quanto biomédicos.

Systematic Review: Genetic, Neuroimaging, and Fluids Biomarkers for Frontotemporal Dementia Across Latin America Countries.

Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.

Evaluación de un programa kinésico de fortalecimiento muscular en adultos mayores con alteración del equilibrio / Assessment of a Kinesthetic Program for Muscle Strengthening in Older Adults with Balance Impartment

Introducción: El aumento de la población adulta mayor es uno de los grandes cambios demográficos en Chile, por lo que resulta necesario establecer abordajes terapéuticos eficaces para prevenir caídas y, consecuentemente, la dependencia funcional en este grupo etario. Objetivo: Evaluar la eficacia de un programa kinésico de prevención de caídas mediante fortalecimiento muscular de extremidad inferior en adultos mayores de 65 años con alteración del equilibrio, en comparación con el programa kinésico convencional. Métodos: Ensayo clínico aleatorizado no farmacológico, incluyó un grupo experimental y un grupo control con 25 participantes en cada grupo. La modalidad del tratamiento experimental es más educativa y participativa que el convencional. La eficacia de cada tratamiento fue evaluada mediante la variación de parámetros de equilibrio estático y dinámico al segundo y tercer mes de tratamiento (resultados principales). Resultados: Los resultados secundarios fueron: fuerza, potencia y diámetro pierna - muslo. Se evaluó la eficacia de ambos programas por el modelo multinivel, se consideraron las variables tiempo y tratamiento. Resultados: Hubo mejorías significativas en parámetros de equilibrio estático y dinámico con ambos tratamientos. La eficacia del tratamiento experimental fue superior a la del convencional en parámetros de potencia muscular y aumento de diámetros de ambos muslos y pierna izquierda. El factor tiempo de tratamiento aportó significativamente a la eficacia. Conclusiones: Ambos tratamientos mejoran los parámetros de equilibrio, pero el tratamiento experimental es más eficaz sobre parámetros de potencia muscular. Con su modalidad educativa y participativa este tratamiento podría optimizar resultados para prevenir caídas del adulto mayor en el nivel primario de atención(AU)

Introduction: The increase in the older adult population is one of the great demographic changes in Chile, a reason why it is necessary to establish effective therapeutic approaches to prevent falls and, consequently, functional dependence in this age group. Objective: To assess the efficacy of a kinesthetic program for the prevention of falls through lower limb muscle strengthening in adults over 65 years of age with impaired balance, in comparison with the conventional kinesthetic program. Methods: Nonpharmacological randomized clinical trial including an experimental group and a control group, with 25 participants each. The modality of experimental treatment is more educational and participatory than the conventional one. The efficacy of each treatment was assessed based on the variation of static and dynamic balance parameters at the second and third months of treatment (main results). Secondary outcomes included strength, power, and leg-thigh diameter. The efficacy of both programs was assessed using the multilevel model; the variables time and treatment were considered. Results: There were significant improvements in static and dynamic balance parameters with both treatments. The efficacy of the experimental treatment was higher than the conventional one in parameters of muscular power and increase in diameters of both thighs and the left leg. The factor time of treatment contributed significantly to efficacy. Conclusions: Both treatments improve balance parameters, but the experimental treatment is more effective regarding muscle power parameters. With its educational and participatory modality, this treatment could optimize results to prevent falls in the older adult at the primary level of care(AU).

Systematic Review: microRNAs as Potential Biomarkers in Mild Cognitive Impairment Diagnosis.

The rate of progression from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD) is estimated at >10% per year, reaching up to 80-90% after 6 years. MCI is considered an indicator of early-stage AD. In this context, the diagnostic screening of MCI is crucial for detecting individuals at high risk of AD before they progress and manifest further severe symptoms. Typically, MCI has been determined using neuropsychological assessment tools such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental Status Examination (MMSE). Unfortunately, other diagnostic methods are not available or are unable to identify MCI in its early stages. Therefore, identifying new biomarkers for MCI diagnosis and prognosis is a significant challenge. In this framework, miRNAs in serum, plasma, and other body fluids have emerged as a promising source of biomarkers for MCI and AD-related cognitive impairments. Interestingly, miRNAs can regulate several signaling pathways via multiple and diverse targets in response to pathophysiological stimuli. This systematic review aims to describe the current state of the art regarding AD-related target genes modulated by differentially expressed miRNAs in peripheral fluids samples in MCI subjects to identify potential miRNA biomarkers in the early stages of AD. We found 30 articles that described five miRNA expression profiles from peripheral fluid in MCI subjects, showing possible candidates for miRNA biomarkers that may be followed up as fluid biomarkers or therapeutic targets of early-stage AD. However, additional research is needed to validate these miRNAs and characterize the precise neuropathological mechanisms.

GERO Cohort Protocol, Chile, 2017-2022: Community-based Cohort of Functional Decline in Subjective Cognitive Complaint elderly.

BACKGROUND: With the global population aging and life expectancy increasing, dementia has turned a priority in the health care system. In Chile, dementia is one of the most important causes of disability in the elderly and the most rapidly growing cause of death in the last 20 years. Cognitive complaint is considered a predictor for cognitive and functional decline, incident mild cognitive impairment, and incident dementia. The GERO cohort is the Chilean core clinical project of the Geroscience Center for Brain Health and Metabolism (GERO). The objective of the GERO cohort is to analyze the rate of functional decline and progression to clinical dementia and their associated risk factors in a community-dwelling elderly with subjective cognitive complaint, through a population-based study. We also aim to undertake clinical research on brain ageing and dementia disorders, to create data and biobanks with the appropriate infrastructure to conduct other studies and facilitate to the national and international scientific community access to the data and samples for research. METHODS: The GERO cohort aims the recruitment of 300 elderly subjects (> 70 years) from Santiago (Chile), following them up for at least 3 years. Eligible people are adults not diagnosed with dementia with subjective cognitive complaint, which are reported either by the participant, a proxy or both. Participants are identified through a household census. The protocol for evaluation is based on a multidimensional approach including socio-demographic, biomedical, psychosocial, neuropsychological, neuropsychiatric and motor assessments. Neuroimaging, blood and stool samples are also obtained. This multidimensional evaluation is carried out in a baseline and 2 follow-ups assessments, at 18 and 36 months. In addition, in months 6, 12, 24, and 30, a telephone interview is performed in order to keep contact with the participants and to assess general well-being. DISCUSSION: Our work will allow us to determine multidimensional risks factors associated with functional decline and conversion to dementia in elderly with subjective cognitive complain. The aim of our GERO group is to establish the capacity to foster cutting edge and multidisciplinary research on aging in Chile including basic and clinical research. TRIAL REGISTRATION: NCT04265482 in ClinicalTrials.gov. Registration Date: February 11, 2020. Retrospectively Registered.

Empathic decline and training in nursing students.

OBJECTIVE: The objective of this article is to examine whether the levels of empathy fit the concept of empathic decline. METHOD: This was a non-experimental and cross-sectional study. Two populations of nursing students in two nursing programs were studied: Universidad San Sebastián (Santiago, Chile) and Universidad Mayor (Temuco, Chile). The original data on empathy, assessed by the Jefferson Scale of Empathy, were combined into a single data base. They were then analyzed by means of normality tests and homoscedasticity, Cronbach's alpha, analysis of variance; the standard deviation of the dependent outcome measure (Sy.x) and the coefficient of determination (R2) were estimated. RESULTS: The sample sizes from the two programs were 479 and 277, respectively. It was found that the distributions of the averages over the course of study for empathy (and its components) were constant, and in some cases increased. CONCLUSION: It was found that the distribution of the means of empathy in the nursing students analyzed did not conform to the classical empathic decline observed in other studies. Therefore, it is inferred that the traditional factors identified as causes of empathic erosion were not operating in the same way in the studied context.

Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry.

Lynch syndrome (LS) is associated with the highest risk of colorectal (CRC) and several extracolonic cancers. In our effort to characterize LS families from Latin America, this study aimed to describe the spectrum of neoplasms and cancer risk by gender, age and gene, and survival in 34 Chilean LS families. Of them, 59% harbored path_MLH1, 23% path_MSH2, 12% path_PMS2 and 6% path_EPCAM variants. A total of 866 individuals at risk were identified, of which 213 (24.6%) developed 308 neoplasms. In males, CRC was the most common cancer (72.6%), while females showed a greater frequency of extracolonic cancers (58.4%), including uterus and breast (p < 0.0001). The cumulative incidence of extracolonic cancers was higher in females than males (p = 0.001). Path_MLH1 variants are significantly more associated with the development of CRC than extracolonic tumors (59.5% vs. 40.5%) when compared to path_MSH2 (47.5% vs. 52.5%) variants (p = 0.05018). The cumulative incidence of CRC was higher in path_MLH1/path_MSH2 carriers compared to path_PMS2 carriers (p = 0.03). In addition, path_MSH2 carriers showed higher risk of extracolonic tumors (p = 0.002). In conclusion, this study provides a snapshot of the LS profile from Chile and the current LS-associated diagnostic practice and output in Chile. Categorizing cancer risks associated with each population is relevant in the genetic counselling of LS patients.

Empathic decline and training in nursing students / Declinación empática y formación de estudiantes de enfermería / Declínio de empatia e formação de estudantes de enfermagem

ABSTRACT Objective The objective of this article is to examine whether the levels of empathy fit the concept of empathic decline. Method This was a non-experimental and cross-sectional study. Two populations of nursing students in two nursing programs were studied: Universidad San Sebastián (Santiago, Chile) and Universidad Mayor (Temuco, Chile). The original data on empathy, assessed by the Jefferson Scale of Empathy, were combined into a single data base. They were then analyzed by means of normality tests and homoscedasticity, Cronbach's alpha, analysis of variance; the standard deviation of the dependent outcome measure (Sy.x) and the coefficient of determination (R2) were estimated. Results The sample sizes from the two programs were 479 and 277, respectively. It was found that the distributions of the averages over the course of study for empathy (and its components) were constant, and in some cases increased. Conclusion It was found that the distribution of the means of empathy in the nursing students analyzed did not conform to the classical empathic decline observed in other studies. Therefore, it is inferred that the traditional factors identified as causes of empathic erosion were not operating in the same way in the studied context.

RESUMEN Objetivo El objetivo del artículo es analizar si los niveles de empatía se ajustan al concepto de declinación empática. Método Estudio no experimental y transversal. Fueron estudiadas dos poblaciones de estudiantes de enfermería de dos facultades de enfermería: Universidad San Sebastián (Santiago, Chile) y Universidad Mayor (Temuco, Chile). Los datos originales de empatía, evaluados por el Jefferson Scale of Empathy, fueron reunidos en un único grupo y analizados con pruebas de normalidad y homocedasticidad, alfa de Cronbach, análisis de varianza; también fueron estimados el desvío estándar de la medida de resultado dependiente (Sy.x) y el coeficiente de determinación (R2). Resultados Las muestras de las dos facultades constaron de 479 y 277 participantes, respectivamente. Se comprobó que las distribuciones de medias del curso de estudio para empatía (y sus componentes) fueron constantes, y en algunos casos aumentaron. Conclusión Se determinó que la distribución de medias de empatía en los estudiantes de enfermería analizados no se ajusta a la disminución empática clásica observada en otros estudios, infiriéndose que los factores tradicionales considerados como causas de la erosión empática no operan de la misma manera en el contexto estudiado.

RESUMO Objetivo O objetivo do presente artigo é investigar se os níveis de empatia são consistentes com o conceito de declínio de empatia. Método Um estudo não-experimental e transversal foi conduzido com duas populações de alunos de enfermagem de dois programas de enfermagem distintos, da Universidad San Sebastián (Santiago, Chile) e da Universidad Mayor (Temuco, Chile). Os dados originais sobre empatia, avaliados pela Jefferson Scale of Empathy, e reunidos em um único banco de dados. Os dados foram então analisados através de testes de normalidade e homocedasticidade, Cronbach's alpha e análise de variância. Foram calculados o desvio padrão da variável dependente (Sy.x) e o coeficiente de determinação (R2). Resultados As amostras dos dois programas tiveram 479 e 277 participantes, respectivamente. As distribuições das médias de empatia (e seus componentes) ao longo do curso foram constantes, com um aumento em alguns casos. Conclusão A distribuição das médias de empatia nos alunos de enfermagem estudados não foi consistente com o declínio clássico de empatia observado em outros estudos. Sendo assim, os dados indicam que os fatores tradicionais identificados como causas de erosão empática não funcionam da mesma forma no contexto avaliado.

Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile.

METHODS: Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. RESULTS: We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. CONCLUSION: Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.

Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile / Atrofia muscular espinal en Chile, resultados de un programa de atención médica nacional

ABSTRACT Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. Methods This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. Results We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. Conclusion Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.

La Atrofia Muscular Espinal (AME) ha concitado mucha atención en los últimos 2 años debido a la aprobación del primer tratamiento intratecal para esta enfermedad neurodegenerativa. América Latina necesita desarrollar la demografía de AME, un acceso oportuno al diagnóstico y un seguimiento apropiado de los pacientes que incorporen los estándares de atención recomendados por expertos. Estos son pasos esenciales para orientar las futuras políticas de salud en esta enfermedad. Métodos Este es un estudio descriptivo de una cohorte de pacientes con AME de todo el país. Se analizaron los datos clínicos, motores, funcionales, sociales y el estado nutricional, respiratorio y esquelético de los pacientes. También medimos el número de copias del gen SMN2 en esta población. Resultados se reclutaron 92 pacientes, 50 varones; 23 AME tipo 1, 36 AME tipo 2 y 33 AME tipo 3. La edad media al diagnóstico genético fue de 5, 24 y 132 meses respectivamente. Evaluamos el número de copias de SMN2 en 57 pacientes. Un 69,6% de los pacientes con AME tipo 1 estaban traqueostomízados y gastrostomizados , un 65% de los pacientes con AME tipo 2 usaban ventilación nocturna no invasiva y el 37% de toda la cohorte presentaba una cirugía de escoliosis. Conclusión Esta cohorte chilena de pacientes con AME tuvo acceso oportuno al diagnóstico genético, asistencia ventilatoria, apoyo nutricional y cirugía de escoliosis, sin embargo, la atención ventilatoria para AME tipo 1 continúa aun basándose principalmente en la traqueostomía. En esta serie, AME tipo 1 está subrepresentada, probablemente debido a las restricciones en el acceso al diagnóstico temprano y la tasa de mortalidad alta y temprana.

Differential expression profile of CXCR3 splicing variants is associated with thyroid neoplasia. Potential role in papillary thyroid carcinoma oncogenesis?

Papillary thyroid cancer (PTC) is the most prevalent endocrine neoplasia. The increased incidence of PTC in patients with thyroiditis and the frequent immune infiltrate found in PTC suggest that inflammation might be a risk factor for PTC development. The CXCR3-ligand system is involved in thyroid inflammation and CXCR3 has been found upregulated in many tumors, suggesting its pro-tumorigenic role under the inflammatory microenvironment. CXCR3 ligands (CXCL4, CXCL9, CXCL10 and CXCL11) trigger antagonistic responses partly due to the presence of two splice variants, CXCR3A and CXCR3B. Whereas CXCR3A promotes cell proliferation, CXCR3B induces apoptosis. However, the relation between CXCR3 variant expression with chronic inflammation and PTC development remains unknown. Here, we characterized the expression pattern of CXCR3 variants and their ligands in benign tumors and PTC. We found that CXCR3A and CXCL10 mRNA levels were increased in non-metastatic PTC when compared to non-neoplastic tissue. This increment was also observed in a PTC epithelial cell line (TPC-1). Although elevated protein levels of both isoforms were detected in benign and malignant tumors, the CXCR3A expression remained greater than CXCR3B and promoted proliferation in Nthy-ori-3-1 cells. In non-metastatic PTC, inflammation was conditioning for the CXCR3 ligands increased availability. Consistently, CXCL10 was strongly induced by interferon gamma in normal and tumor thyrocytes. Our results suggest that persistent inflammation upregulates CXCL10 expression favoring tumor development via enhanced CXCR3A-CXCL10 signaling. These findings may help to further understand the contribution of inflammation as a risk factor in PTC development and set the basis for potential therapeutic studies.

EGFR pathway subgroups in Chilean colorectal cancer patients, detected by mutational and expression profiles, associated to different clinicopathological features.

Colorectal cancer is a multistep process affecting several signaling pathways including EGFR (epidermal growth factor receptor), a therapeutic target for metastatic disease. Our aim was to characterize the mutational and expression profiles of the EGFR pathway in colorectal tumors and to integrate these results according to five previously defined groups. We screened seven genes for mutations ( KRAS-BRAF-PIK3CA-PIK3R1-AKT1-MAP2K1-PTEN) and six proteins (EGFR-p110α-p85α-PTEN-phosphoAKT-phosphoMEK1) by immunohistochemistry, PTEN deletion, and MSI. At least one mutated gene was observed in 68% of tumors ( KRAS 45%, PIK3CA 21%, BRAF 14%, and PTEN 7%). PTEN deletion was observed in 10.7% of tumors and 19.6% were MSI-High. In all, 54% of tumors showed a high EGFR expression, 48% p110α, 4.4% phosphoAKT, and 22% phosphoMEK1; and 43% showed low PTEN expression and 22% p85α. In total, five groups of tumors were defined based on MSI, BRAF, and KRAS mutations. Three groups gather mainly early-stage tumors, whereas a fourth group is mostly conformed by advanced tumors. We described here that 71.4% of tumors from one group have a mutated PI3K/PTEN pathway, in comparison to other groups having 32%, 27%, and 25%. In addition, the five groups are differentiated by molecular features such as EGFR, p85α, p110α, and PTEN, showing variable expression among tumor groups. In conclusion, alterations on the EGFR pathway were found in a high percentage of colorectal cancer patients. Using the integration of diverse molecular markers, we ratified previous classification in an ethnic group having relevant genetic differences and living in a different environmental background, adding complementary molecular targets related to therapy.

Increase in Preterm Birth during Demographic Transition in Chile from 1991 to 2012.

INTRODUCTION: Universally mothers at 35 years or more have had higher maternal and perinatal risks. This study analyzed the trend of this group in maternal population and determined their risk of having premature children, during the demographic transition period in Chile. MATERIALS AND METHODS: Epidemiological study conducted in the population of simple live births registered in the Chilean National Database Births of 1991-2012. Analyses were performed in three categories of maternal age: 35 or more, under 35, and 20 to 29 years. The risk of prematurity was measured by crude and Adjusted Odds Ratio from logistic regression model. RESULTS: Mothers aged 35 and older increased in population from 10.6% in 1991 to 16.7% in 2012 and presented an overall prevalence of preterm delivery of 6.7%, higher prevalence than 20-29 age group (4.7%). In aging mothers, the Odds Ratio for preterm birth adjusted for education, marital status, and parity was 1.68 (95% CI (1.66-1.70)) compared to mothers aged 20-29. All differences were significant (p < 0.001). CONCLUSIONS: During Chilean demographic transition, mothers aged 35 or older increased steadily and significantly maintaining higher risks of preterm births. Policies to prevent and monitor the late motherhood could contribute to stopping the current trend.

Activating PIK3CA somatic mutation in congenital unilateral isolated muscle overgrowth of the upper extremity.

Congenital unilateral overgrowth of the upper extremity affecting only the muscle tissue is rare. We describe on the clinical, histopathological, and neuroimaging findings in a 6-year-old girl with a congenital, non-progressive muscle enlargement of the entire left upper limb with an ipsilateral hand deformity. No cutaneous stigmata or additional features were detected. Sanger sequencing for the AKT1, PIK3CA, and PTEN genes identified an activating c.3140A>G, p.H1047R mutation in the PIK3CA gene from the affected muscle DNA. We demonstrate that isolated congenital muscular upper limb overgrowth with aberrant hand muscles is another condition related genetically to the PIK3CA-related overgrowth spectrum.

Mutación homocigota en la línea germinal del gen MUTYH en una paciente chilena con poliposis adenomatosa familiar / Homozygous germline mutation in MUTYH gene in familial adenomatous polyposis

Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation.

Síndrome de Lynch: selección de pacientes para el estudio genético mediante análisis de inestabilidad microsatelital e inmunohistoquímica / Lynch syndrome: selection of families by microsatellite instability and immunohistochemistry

Background: Selection of patients with Lynch Syndrome (LS) for a genetic study involves the application of clinical criteria. To increase the rate of identification of mutations, the use of molecular studies as Microsatellite Instability (MSI) and Im-munohistochemistry (IHC) in the tumor has been proposed. Aim: To demonstrate the usefulness of MSI and IHC in the detection of mutations in patients with LS. Material and Methods: From our Familial Colorectal Cancer Registry, families suspected of LS were selected according to Amsterdam or Bethesda clinical criteria. Screening of germline mutations of MLH1, MSH2 and MSH6 genes was performed. In addition, analysis of MSI and IHC were performed in colorectal tumors. Results: A total of 35 families were studied (19 met Amsterdam and 16 met Bethesda criteria). Twenty one families harbored a germline alteration in MLH1, MSH2 or MSH6 (18 Amsterdam and 3 Bethesda). In these families, eighteen different alterations were found, 15 of which were mutations and 3 corresponded to variants of uncertain pathogenicity. On the other hand, 80% of the tumors showed positive microsatellite instability (27 MSI-high and 1 MSI-low), and immunohistochemical testing showed that 77% of tumors had the loss of a protein. Correlation between results of tumor molecular studies and the finding of germline nucleotide change showed that IHC and MSI predicted mutations in 81 and 100% of patients, respectively. Conclusions: MSI and IHC can efficiently select patients with a high probability of carrying a mutation in DNA repair genes.

[A screening program for colorectal cancer in Chilean subjects aged fifty years or more]. / Programa de detección de neoplasias colorrectales en población mayor de 50 años.

BACKGROUND: Mortality from colorectal cancer (CCR) in Chile has nearly doubled over the past 15 years. International studies have shown that CCR screening programs based on fecal occult blood test (FOBT) reduce CCR mortality. AIM: To analyze the results from a CCR screening model in people over 50 years. MATERIAL AND METHODS: Between 2007 and 2009, a prospective multicenter study was performed in seven major Chilean cities. FOBT using an immunological method, was measured in asymptomatic subjects aged 50 years or more, without risk factors. In patients with a positive FOBT, with symptoms or with family risk factors, a colonoscopy was indicated. RESULTS: A total of 6348 subjects were assessed, FOBT was performed in 4938 of them, with a compliance of 77%. The result was positive in 9.6%. A total of 2359 colonoscopies were ordered, with an overall compliance of 50.1%. Of the 1184 colonoscopies performed, adenomas and high risk adenomas were found in 304 (26%) and 75 (6%) patients, respectively. Thirteen patients were diagnosed with stage I and IICCR. Three of these lesions were excised endoscopically and 10 surgically. The detection rate of polyps, high risk adenomas and cancer was 75, 12 and 2 per 1000 screened individuals, respectively. CONCLUSIONS: This program allowed the early detection of an important number of high risk colon lesions, and all patients with CCR were diagnosed at early stages.