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.

Nutritional Value and Antioxidant, Antimicrobial and Cytotoxic Activity of Wild Macrofungi.

Macrofungi are among the most promising sources of biologically active natural products with nutritional qualities and therapeutic values. In this work, the nutritional value of nine species of wild macrofungi from Ibague-Tolima (Colombia) was evaluated. In addition the antioxidant, antimicrobial and cytotoxic activities of an ethanol:water (70:30) extract of wild basidiomata were evaluated. The wild mushrooms' nutritional potential showed that the genus Pleurotus and Lentinus have the best protein percentages, with 18.4% and 18.5%. The nine extracts evaluated managed to stabilize the two radicals evaluated; however, lower IC50 was found for Phellinus gilvus and Ganoderma australe extracts. The results showed that Trametes coccinea, Pleurotus floridanus and Ganoderma australe extracts were the most effective as antimicrobials, with high inhibition percentages against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. Antifungal activity results against Rhizopus oryzae, Penicillium sp. and Aspergillus niger showed that the nine extracts were effective at the concentrations tested. Considering cell viability against isolated leukocytes, seven of the nine extracts showed percentages higher than 50% of cell viability. This research describes the nutritional value of nine wild macrofungi in Colombia and their potential for antimicrobial, cytotoxic and antioxidant activity.

Manejo de la hipoxia durante ventilación unipulmonar en un paciente con absceso mediastinal y mediastinitis para toracotomía abierta. Reporte de caso / Hypoxia Management during One-Lung Ventilation in a Patient with Mediastinal Abscess and Mediastinitis for Open Thoracotomy. Case Report

Introducción: la mayoría de los pacientes que se someten a cirugía torácica pueden ser clasificados en el grupo de alto riesgo para hipoxia, especialmente cuando se decide por una ventilación unipulmonar, debido al desequilibrio V/Q; por lo tanto, se han desa-rrollado nuevas estrategias ventilatorias y maniobras de rescate para hipoxia. Curso clínico: presentamos una paciente de 85 años de edad sin comorbilidades programada para toracotomía abierta y manejada con ventilación unipulmonar. Durante el mane-jo anestésico, se presenta hipoxia secundaria a desequilibrio V/Q y choque hipovolémi-co hemorrágico, con respuesta positiva a las maniobras de rescate para hipoxia. Con-clusión: es importante prevenir en la medida de lo posible la hipoxia en la ventilación unipulmonar, siguiendo las nuevas estrategias ventilatorias. Sin embargo, cuando se presenta una crisis, no debemos retrasar las maniobras de rescate de forma moderna. (AU)

Introduction: most of the patients undergoing thoracic surgery fit in the high risk group for hypoxia, especially when deciding to use one-lung ventilation due to the V/Q mis-match; therefore, new ventilation strategies and hypoxia rescue manoeuvres have been developed. Clinical course: we present an 85-year old female with no major co-morbidities scheduled for open thoracotomy and managed with one-lung ventilation. During the course of the anaesthetic management, hypoxia presents secondary to V/Q mismatch and haemorrhagic hypovolemic shock, with a positive response to hypoxia rescue manoeuvres. Conclusion: it is important to prevent as much as we can the hy-poxia in a one-lung ventilation following the new ventilation strategies. Although when facing a crisis, proper hypoxia management with a modern approach should not be de-layed. (AU)

In Vitro and In Vivo Evaluation of ABCG2 (BCRP) Inhibitors Derived from Ko143.

Breast cancer resistance protein (BCRP, ABCG2) is an efflux transporter that plays a crucial role in multidrug resistance to antineoplastic drugs. Ko143, an analogue of the natural product fumitremorgin C, is a potent inhibitor of ABCG2 but is rapidly hydrolyzed to an inactive metabolite in vivo. To identify ABCG2 inhibitors with improved metabolic stability, we have assessed a series of Ko143 analogues for their ability to inhibit ABCG2-mediated transport in ABCG2-transduced MDCK II cells and determined the stability of the most potent compounds in liver microsomes. The most promising analogues were evaluated in vivo by positron emission tomography. In vitro, three of the tested analogues were potent ABCG2 inhibitors and stable in microsomes. In vivo, they increased the distribution of the ABCG2/ABCB1 substrate [11C]tariquidar to the brain both in wild-type (with Abcb1a/b transport blocked by tariquidar) and Abcb1a/b(-/-) mice. One analogue was more potent than Ko143 in both animal models.

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.

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.

Utilidad clínica de la videocápsula endoscópica en el estudio de patologías de intestino delgado en Colombia: resultados de un registro nacional / Clinical utility of the small bowel capsule endoscopy in the study of small bowel diseases in Colombia: Results of a national registry

Introducción: La videocápsula endoscópica (VCE) ha revolucionado el estudio de las patologías de intestino delgado. El objetivo de este estudio es determinar las indicaciones, hallazgos y rendimiento diagnóstico de la VCE en un registro nacional. Pacientes y métodos: Se realizó un estudio observacional, de corte transversal analítico, analizando los registros de VCE en siete centros del país, se recolectaron diferentes variables. Resultados: Se evaluaron 1.883 estudios de VCE. La edad promedio fue 55,4 años (5,6-94,2). Las indicaciones más frecuentes fueron sospecha de sangrado de intestino delgado (SID) (64,4%), estudio enfermedad de Crohn (15,2%) y diarrea crónica (11,2%). El 54,3% de VCE se prepararon con laxantes. Las lesiones más frecuentes fueron erosiones/úlceras (31,6%), angiectasias (25,7%) y parasitosis (2,7%). El rendimiento diagnóstico (P1+P2, clasificación de Saurin) de VCE en SID fue 60,6%, siendo mayor en SID evidente (66,0%) comparado con SID oculto (56,0%) (P=0,003). Los estudios con mejor preparación presentaban mayor detección de lesiones (93,8% vs. 89,4%) (OR=1,8; IC: 95%: 1,2-2,6; P=0,004). La tasa de complicación de VCE fue 3,1%, con visualización completa del ID en 96,6% y tasa de retención en ID de 0,7%. El 81,5% de VCE se realizaron en forma ambulatoria, y presentaron mayor visualización completa de ID que las hospitalarias (97,1% vs. 94,3%) (OR=2,1; IC: 95%; 1,2-3,5; P=0,008). Conclusiones: Las indicaciones, hallazgos y rendimiento diagnóstico de VCE en Colombia son similares a los reportados en la literatura universal, con alto porcentaje de estudios completos y baja tasa de complicaciones.(AU)

Introduction: The small bowel capsule endoscopy (SBCE) has revolutionised the study of small bowel diseases. The objective of this study is to determine the indications, findings and diagnostic yield of SBCE in a national registry. Patients and methods: An observational, analytical cross-sectional study was carried out, analysing the SBCE records at seven centres in the country, where different variables were collected. Results: 1,883 SBCEs were evaluated. The average age was 55.4 years (5.6-94.2). The most frequent indications were suspicion of small bowel bleeding (SBB) (64.4%), study of Crohn's disease (15.2%) and chronic diarrhoea (11.2%). 54.3% were prepared with laxatives. The most frequent lesions found were erosions/ulcers (31.6%), angioectasias (25.7%) and parasitosis (2.7%). The diagnostic yield (P1+P2, Saurin classification) of SBCE in SBB was 60.6%, being higher in overt SBB (66.0%) compared to occult SBB (56.0%) (P=.003). The studies with better preparation showed higher detection of lesions (93.8% vs. 89.4%) (OR=1.8, CI: 95%: 1.2-2.6; P=.004). The SBCE complication rate was 3.1%, with complete SB visualisation at 96.6% and SB retention rate of 0.7%. 81.5% of SBCEs were performed on an outpatient basis, and presented a greater complete SB visualisation than hospital ones (97.1% vs. 94.3%) (OR=2.1, CI: 95%, 1.2-3.5; P=.008). Conclusions: The indications, findings and diagnostic performance of SBCEs in Colombia are similar to those reported in the literature, with a high percentage of complete studies and a low rate of complications.(AU)

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.

In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET.

PURPOSE: The co-stimulatory molecules CD80 and CD86 are upregulated on activated antigen-presenting cells (APC). We investigated whether local APC activation, induced by subcutaneous (s.c.) inoculation of lipopolysaccharides (LPS), can be imaged by positron emission tomography (PET) with CD80/CD86-targeting 64Cu-labelled abatacept. PROCEDURES: Mice were inoculated s.c. with extracellular-matrix gel containing either LPS or vehicle (PBS). Immune cell populations were analysed by flow cytometry and marker expression by RT-qPCR. 64Cu-NODAGA-abatacept distribution was analysed using PET/CT and ex vivo biodistribution. RESULTS: The number of CD80+ and CD86+ immune cells at the LPS inoculation site significantly increased a few days after inoculation. CD68 and CD86 expression were higher at the LPS than the PBS inoculation site, and CD80 was only increased at the LPS inoculation site. CTLA-4 was highest 10 days after LPS inoculation, when CD80/CD86 decreased again. A few days after inoculation, 64Cu-NODAGA-abatacept distribution to the inoculation site was significantly higher for LPS than PBS (4.2-fold). Co-administration of unlabelled abatacept or human immunoglobulin reduced tracer uptake. The latter reduced the number of CD86+ immune cells at the LPS inoculation site. CONCLUSIONS: CD80 and CD86 are upregulated in an LPS-induced local inflammation, indicating invasion of activated APCs. 64Cu-NODAGA-abatacept PET allowed following APC activation over time.

Clinical utility of the small bowel capsule endoscopy in the study of small bowel diseases in Colombia: Results of a national registry. / Utilidad clínica de la videocápsula endoscópica en el estudio de patologías de intestino delgado en Colombia: resultados de un registro nacional.

INTRODUCTION: The small bowel capsule endoscopy (SBCE) has revolutionised the study of small bowel diseases. The objective of this study is to determine the indications, findings and diagnostic yield of SBCE in a national registry. PATIENTS AND METHODS: An observational, analytical cross-sectional study was carried out, analysing the SBCE records at seven centres in the country, where different variables were collected. RESULTS: 1,883 SBCEs were evaluated. The average age was 55.4 years (5.6-94.2). The most frequent indications were suspicion of small bowel bleeding (SBB) (64.4%), study of Crohn's disease (15.2%) and chronic diarrhoea (11.2%). 54.3% were prepared with laxatives. The most frequent lesions found were erosions/ulcers (31.6%), angioectasias (25.7%) and parasitosis (2.7%). The diagnostic yield (P1+P2, Saurin classification) of SBCE in SBB was 60.6%, being higher in overt SBB (66.0%) compared to occult SBB (56.0%) (P=.003). The studies with better preparation showed higher detection of lesions (93.8% vs. 89.4%) (OR=1.8, CI: 95%: 1.2-2.6; P=.004). The SBCE complication rate was 3.1%, with complete SB visualisation at 96.6% and SB retention rate of 0.7%. 81.5% of SBCEs were performed on an outpatient basis, and presented a greater complete SB visualisation than hospital ones (97.1% vs. 94.3%) (OR=2.1, CI: 95%, 1.2-3.5; P=.008). CONCLUSIONS: The indications, findings and diagnostic performance of SBCEs in Colombia are similar to those reported in the literature, with a high percentage of complete studies and a low rate of complications.

Prevalencia y asociación de factores de riesgo cardiovascular en hombres con disfunción eréctil / Prevalence and association with cardiovascular risk in men with erectile dysfunction

Resumen Objetivo: estimar la prevalencia de los factores de riesgo para enfermedad cardiovascular en hombres con disfunción eréctil atendidos en un centro especializado en diferentes ciudades de Colombia y evaluar su asociación con el grado de severidad de la enfermedad. Métodos: estudio de corte transversal analítico. Se revisaron los registros clínicos de pacientes con diagnóstico de disfunción eréctil que fueron atendidos durante el primer semestre del año 2018. Se analizaron las características sociodemográficas y clínicas de los pacientes, y se estimó la prevalencia de los factores de riesgo cardiovascular. Se exploró la asociación entre estos factores y el grado de severidad de la disfunción eréctil por medio de modelos multivariados logísticos ordinales. Resultados: se incluyeron 2.484 pacientes que cumplieron los criterios de selección, con una edad promedio de 48,7 años (± 14,1). 2.112 sujetos presentaron uno o más factores de riesgo cardiovascular, para una prevalencia global de 85,2%. La prevalencia estimada para factor evaluado fue la siguiente: sobrepeso y obesidad 70,9%, edad superior a 45 años 60,0%, hiperlipidemia 25,1%, hipertensión 21,4%, consumo de tabaco 17,7%, diabetes 16,7%, infarto agudo de miocardio 2,21% y antecedente de alguna enfermedad cardiovascular diferente a infarto 1,68%. En el análisis multivariado se observó que la diabetes y la edad son factores que aumentan el riesgo de severidad de la disfunción eréctil. Conclusiones: es alta la prevalencia de factores de riesgo cardiovascular en hombres colombianos con disfunción eréctil. En ese sentido, el sobrepeso u obesidad es el factor modificable más frecuente en esta población. El grado de disfunción puede estar asociado con la edad y la diabetes.

Abstract Objective: To estimate the prevalence of risk factors of cardiovascular disease in men with erectile dysfunction attending a specialist clinic in different cities in Colombia, as well as their association with the level of severity of the disorder. Methods: A cross-sectional analytical study was conducted using a review of the medical records of patients diagnosed with erectile dysfunction and seen during the first six months of 2018. An analysis was made of the socio-demographic and clinical characteristics of the patients, and the prevalence of cardiovascular risk factors was calculated. The association between these factors and the level of severity of the erectile dysfunction was determined using ordinal multivariate logistic models. Results: The study included a total of 2,484 patients that met the selection criteria. The mean age was 48.7 (± 14.1) years. The majority (2.112) of subjects had one or more cardiovascular risk factors, with an overall prevalence of 85.2%. The estimated prevalence for a factor evaluated was as follows: overweight and obesity; 70.9%, age greater than 45 years; 60.0%, hyperlipidaemia; 25.1%, hypertension; 21.4%, smoking; 17.7%, diabetes; 16.7%, acute myocardial infarction; 2.21%, and a history of any cardiovascular disease other than an infarction; 1.68%. In the multivariate analysis it was observed that diabetes and age are factors that increase the risk of severity of erectile dysfunction. Conclusions: The prevalence of cardiovascular risk factors is high in Colombian men with erectile dysfunction. As regards this, overweight or obesity is the most common modifiable factor in this population. The level of dysfunction may be associated with age and diabetes.

Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography.

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure-affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [11C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [11C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

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.

Chronic bronchitis: High prevalence in never smokers and underdiagnosis- A population-based study in Colombia.

The objective of the article was to establish the prevalence, underdiagnosis, and risk factors of chronic bronchitis (CB) in a general population in five Colombian cities. Cross-sectional study using a probabilistic sampling technique in five Colombian cities was adopted. The CB definition was "cough and expectoration for three or more months per year for at least two consecutive years." Underdiagnosis was considered in subjects with clinical definition without previous medical diagnosis. Univariate χ2 or Student's t-test and logistic regression analysis were used. The study included 5539 subjects. The prevalence was 5.5%, the underdiagnosis 50.3%, and 33.7% of the cases were in nonsmokers (53.6% in women vs. 16.9% in men, p < 0.001). The adjusted risk factors were living in Bogota, current smoking, male, age ≥ 64 years, low education, indoor wood smoke exposure, and occupational exposure to vapors, gases, dust, and fumes. CB is a common disease among adults in Colombia. The underdiagnosis was high and there were a large proportion of cases in nonsmokers, particularly in women. Our findings support the association of CB with indoor wood smoke and occupational exposures.

Developmental pathways inferred from modularity, morphological integration and fluctuating asymmetry patterns in the human face.

Facial asymmetries are usually measured and interpreted as proxies to developmental noise. However, analyses focused on its developmental and genetic architecture are scarce. To advance on this topic, studies based on a comprehensive and simultaneous analysis of modularity, morphological integration and facial asymmetries including both phenotypic and genomic information are needed. Here we explore several modularity hypotheses on a sample of Latin American mestizos, in order to test if modularity and integration patterns differ across several genomic ancestry backgrounds. To do so, 4104 individuals were analyzed using 3D photogrammetry reconstructions and a set of 34 facial landmarks placed on each individual. We found a pattern of modularity and integration that is conserved across sub-samples differing in their genomic ancestry background. Specifically, a signal of modularity based on functional demands and organization of the face is regularly observed across the whole sample. Our results shed more light on previous evidence obtained from Genome Wide Association Studies performed on the same samples, indicating the action of different genomic regions contributing to the expression of the nose and mouth facial phenotypes. Our results also indicate that large samples including phenotypic and genomic metadata enable a better understanding of the developmental and genetic architecture of craniofacial phenotypes.

Contrapulsación externa aumentada, un tratamiento no invasivo recomendado para la angina refractaria, valoración de la clase funcional y la calidad de vida / Enhanced external counterpulsation, a non-invasive therapy recommended for refractory angina. Functional class and quality of life

Resumen Introducción: La enfermedad coronaria es una causa importante de la morbilidad y la mortalidad en el mundo. Dentro de este grupo, se encuentran los pacientes con angina refractaria. Objetivo: El objetivo de la investigación fue evaluar la eficacia y seguridad de la contrapulsación externa aumentada con 35 sesiones de una hora, en una población atendida desde diciembre de 2013 hasta noviembre de 2015. Materiales y métodos: Se realizó un estudio observacional analítico de cohorte concurrente. Se seleccionaron los pacientes que fueron remitidos para contrapulsación. A todos se les realizó una evaluación incial y a los seis meses de la clase funcional de angina según la Canadian Cardiovascular Society y disnea de la New York Heart Association, se valoraron los medicamentos recibidos y procedimientos realizados. Se aplicó el cuestionario de calidad de vida EQ - 5 D antes y a los seis meses. Para establecer la presencia de diferencias en el seguimiento en la clase funcional, la calidad de vida al inicio y a los seis meses, se utilizó la prueba no paramétrica de Wilcoxon para datos pareados, con un nivel de significación menor de 0,05. Las estadísticas fueron analizadas con el programa SPSS versión 20,0. Resultados: El análisis inicial de 74 pacientes, 50 hombres (67,6%), el promedio de edad 65,5 años. Al inicio de la terapia el 74,4% de los pacientes, se encontraban con disnea clase II - III de la New York Heart Association y el 77% con angina II - III de la Canadian Cardiovascular Society. La mediana de la fracción de eyección fue 50,5% (35,0 - 60,0). Los antecedentes más importantes fueron: la hipertensión arterial 62 (83,8%) y la diabetes mellitus 28 (37,8%). Medicamentos recibidos para la angina y procedimientos realizados: betabloqueadores 74 (100%), estatinas 71 (95,9%), aspirina 67 (90,5%), inhibidores de la enzima convertidora de angiotensina/bloqueadores de los receptores de angiotensina 64 (86,5%), trimetazidina 56 (75,7%), nitratos 37 (50%), calcioantagonistas 20 (27%), ivabradina 15 (20,3%), revascularización quirúrgica 41 (55,4%), revascularización percutánea 51 (68,9%), rehabilitación cardiovascular 45 (60,8%) y uso de dispositivos como el marcapasos, el cardiodesfibrilador o el Cardiodesfibrilador con resincronizador 19 (25,6%). A los seis meses se analizaron 45 pacientes que habían terminado el tratamiento, encontrando que el 91,1% estaba en clase I - II de disnea de la New York Heart Association y el 93,2% clase I - II de angina de la Canadian Cardiovascular Society (p < 0,01 para ambos). En la evaluación de la calidad de vida se revisaron 36 pacientes que llenaron el instrumento EQ - 5 D, encontrando una mejoría significativa en la variable de movilidad (p = 0,021) y en la escala visual análoga de salud, con una mediana inicial de 70,0 (RIQ: 50,0 - 80,0), que mejoró a los 6 meses a 80 (RIQ: 70,0 - 90,0), p = 0,003. No se encontraron complicaciones con la contrapulsación. Conclusiones: La terapia de contrapulsación externa aumentada, mejora la calidad de vida y la clase funcional de angina y disnea en pacientes con angina refractaria y se convierte en un procedimiento no invasivo seguro y eficaz.

Abstract Introduction: Coronary disease is an important cause for morbidity and mortality worldwide. Within this group there are patients with refractory angina. Objective: The goal of this investigation was to assess efficiency and security of enhanced external counterpulsation (EECP) with 35 one-hour sessions, in a population assisted between December 2013 and November 2015. Material and methods: Analytical observational recurrent cohort study. Patients who were referred for counterpulsation were selected. All of them were assessed in the beginning and after six months of the functional class of angina according to the Canadian Cardiovascular Society (CCS) and dyspnoea to the New York Heart Association (NYHA). Medication received and the procedures carried out were evaluated. The EQ-5D quality of life questionnaire was applied before and after six months. In order to establish the presence of differences in the follow-up of the functional class, the quality of life in the beginning and after six months, the Wilcoxon nonparametric test for paired data was used, with a significance level below 0.05. Data were analysed using SPSS version 20.0. Results: Initial analysis of 74 patients, 50 men (67.6%), with an average age of 65.5 years. In the beginning of the therapy 74.4% of patients had class II - III dyspnoea (NYHA) and 77% class II - III angina (CCS). The median ejection fraction was 50.5% (35.0 - 60.0). The most important previous conditions were arterial hypertension 62 (83.8%) and diabetes mellitus 28 (37.8%). Medication received for angina and conducted procedures: betablockers 74 (100%), statins 71 (95.9%), aspirin 67 (90.5%), angiotensin-converting-enzyme inhibitors/angiotensin receptor antagonists 64 (86.5%), trimetazidine 56 (75.7%), nitrates 37 (50%), calcium antagonists 20 (27%), ivabradine 15 (20.3%), surgical revascularisation 41 (55.4%), percutaneous revascularisation 51 (68.9%), cardiovascular rehabilitation 45 (60.8%) and use of devices such as pacemakers, implantable cardioverter-defibrillators (CDI) or ICDs with synchronizers 19 (25.6%). After six months 45 patients who had finished the treatment were analysed, revealing that 91.1% was in class I - II dyspnoea (NYHA) and 93.2% were class I - II angina (CCS) (p < 0.01 for both). For the quality of life assessment 36 patients who has filled out the EQ-5D were reviewed, thus finding a significant improvement in the mobility variable (p = 0.021) and the visual analogue scale, with an initial median of 70.0 (RIQ: 50.0 - 80.0), that improved after six months to 80 (RIQ: 70.0 - 90.0), p = 0.003. No complications for counterpulsation were found. Conclusions: Enhanced external counterpulsation therapy improves quality of life and functional class of angina and dyspnoea in patients with refractory angina and becomes a non-invasive, safe and efficient procedure.

Toward in vitro-to-in vivo translation of monoclonal antibody pharmacokinetics: Application of a neonatal Fc receptor-mediated transcytosis assay to understand the interplaying clearance mechanisms.

Monoclonal antibodies (mAbs) are a rapidly growing drug class for which great efforts have been made to optimize certain molecular features to achieve the desired pharmacokinetic (PK) properties. One approach is to engineer the interactions of the mAb with the neonatal Fc receptor (FcRn) by introducing specific amino acid sequence mutations, and to assess their effect on the PK profile with in vivo studies. Indeed, FcRn protects mAbs from intracellular degradation, thereby prolongs antibody circulation time in plasma and modulates its systemic clearance. To allow more efficient and focused mAb optimization, in vitro input that helps to identify and quantitatively predict the contribution of different processes driving non-target mediated mAb clearance in vivo and supporting translational PK modeling activities is essential. With this aim, we evaluated the applicability and in vivo-relevance of an in vitro cellular FcRn-mediated transcytosis assay to explain the PK behavior of 25 mAbs in rat or monkey. The assay was able to capture species-specific differences in IgG-FcRn interactions and overall correctly ranked Fc mutants according to their in vivo clearance. However, it could not explain the PK behavior of all tested IgGs, indicating that mAb disposition in vivo is a complex interplay of additional processes besides the FcRn interaction. Overall, the transcytosis assay was considered suitable to rank mAb candidates for their FcRn-mediated clearance component before extensive in vivo testing, and represents a first step toward a multi-factorial in vivo clearance prediction approach based on in vitro data.

Correction: Socioeconomic Status Is Not Related with Facial Fluctuating Asymmetry: Evidence from Latin-American Populations.

[This corrects the article DOI: 10.1371/journal.pone.0169287.].

Factores asociados a la presencia de sangrado clasificados por el Bleeding Academic Research Consortium, en pacientes con síndrome coronario agudo sometidos a intervención coronaria percutánea / Factors associated with presence of bleeding classified by Bleeding Academic Research Consortium in patients with acute coronary syndrome undergoing percutaneous coronary intervention

Resumen Fundamentos y objetivos: El sangrado es la principal complicación no cardiaca relacionada con la intervención coronaria percutánea y se asocia a un aumento en el riesgo de eventos adversos. Actualmente existen varias escalas para definir riesgo de sangrado y varias definiciones de sangrado. El objetivo es determinar los factores asociados con la presencia de sangrado en pacientes con síndrome coronario agudo sometidos a intervención coronaria percutánea, utilizando la escala de Bleeding Academic Research Consortium y posteriormente ofrecer recomendaciones. Materiales y Métodos: estudio observacional analítico tipo casos y controles en pacientes con síndrome coronario agudo sometidos a intervención coronaria percutánea a quienes se aplicó la escala de Bleeding Academic Research Consortium. Los casos fueron definidos por pacientes que presentaron sangrado posterior al procedimiento (Bleeding Academic Research Consortium tipo 1-5) y los controles por pacientes que no presentaron sangrado (Bleeding Academic Research Consortium tipo 0). Resultados: Se seleccionaron 366 pacientes (121 casos, 245 controles). El 33% de pacientes presentaron algún tipo de sangrado distribuidos así: tipo 1: 12%, tipo 2: 13,4%, tipo 3: 7,3% y tipo 5: 0,3%. En el análisis multivariado los predictores más importantes de sangrado estadísticamente significativos fueron: sexo femenino, tratamiento con warfarina y uso de tirofiban durante la intervención coronaria percutánea. Conclusiones: El sangrado es un evento frecuente en la intervención coronaria percutánea, encontrando que utilizando la clasificación de Bleeding Academic Research Consortium la mayoría de los sangrados fueron tipo 1 y 2. Los factores de riesgo para sangrado descritos a nivel mundial, son parecidos a los del estudio. El sexo femenino, el uso de warfarina y uso de tirofibán fueron estadísticamente significativos. Consideramos que un buen instrumento para definir tipo de sangrado es la escala de Bleeding Academic Research Consortium.

Abstract Background and objectives: Bleeding is the main non-cardiac complication related to percutaneous coronary intervention and it is associated to an increase of the risk of adverse events. Nowadays there are multiple scales to define risk of bleeding and several definitions for bleeding. The goal is to determine factors associated to the presence of bleeding in patients with acute coronary syndrome undergoing percutaneus coronary intervention, using the the Bleeding Academic Research Consortium scale to then issue recommendations. Material and methods: Case-control analytical observational study in patients with acute coronary syndrome undergoing percutaneous coronary intervention applying the Bleeding Academic Research Consortium scale. Cases were defined by patients who presented bleeding following the surgery (Bleeding Academic Research Consortium type 1-5) and controls by patients who did not show bleeding (Bleeding Academic Research Consortium type 0). Results: 366 were selected (121 cases, 245 controls). 33% of the patients showed some type of bleeding, divided into: type 1: 12%; type 2: 13.4%; type 3: 7.3% and type 5: 0.3%. Multivariate analysis of most important predictive factors for bleeding that were statistically significant were: female gender, warfarin treatment and use of Tirobifan during percutaneus coronary intervention. Conclusions: Bleeding is a frequent event during percutaneus coronary intervention. According to the Bleeding Academic Research Consortium classification, most bleedings were of types 1 and 2. Risk factors for bleeding described worldwide are similar to those of this study. Female gender, warfarin treatment and use of Tirobifan were statistically significant. Bleeding Academic Research Consortium scale is considered a good indicator to define bleeding types.