Abstract: Objective: Determine the population prevalence and trends of cleft lip and / or palate (CL/P) by department for Colombia in the period 2009 - 2015. Methods: Prevalence study based on Individual Registry of Health Services in general population from 2009 to 2015. All people diagnosed with CL/P were included for all ages, type of diagnosis and any type of health services in the mentioned period. The prevalence rate was calculated by period and point for each year, for each department and according to the type of cleft. Stationarity on time series was evaluated using (Dickey-Fuller) and (Phillips-Perron), the trends and prevalence ratios were calculated using Poisson regression. Results: 15,225 people with CL/P were identified, where 53.3% were men. The national period prevalence of CL/P is 3.37 per 10 000 (IC95%: 3.3-3.4) with upward trend (PR = 1.34 95% CI: 1.0 - 1.8 p = 0.05) and non-stationary behavior. The national period prevalence of CL is 0.93 per 10 000, CP 1.17 per 10 000 and CLP 1.26 per 10 000, where CLP is sub classify into CLPu (0.83 per 10 000), and CLPb (0.43 per 10 000). At the departmental level, the highest CL/P prevalence is Guaviare (11.2 95% CI: 8.6 – 14.2), followed by Guainía (8.4 95% CI:5.4 – 12.2) and the lowest Quindío (0.49 95% CI: 0.3 – 0.7) Conclusions: In Colombia, the national period prevalence of CL/P is 3.37 per 10 000 with upward trend at national level indicates an increase on prevalence from 2009 to 2015.

Abstract: Seasonal influenza is an infectious disease of multi-causal etiology and a major cause of mortality worldwide that has been associated with environmental factors. In the attempt to model and predict future outbreaks of seasonal influenza with multiple environmental factors, we face the challenge of increased dimensionality that makes the models more complex and unstable. In this paper, we propose a nowcasting and forecasting framework that compares the theoretical approaches of Single Environmental Factor and Multiple Environmental Factors. We introduce seven solutions to minimize the weaknesses associated with the increased dimensionality when predicting seasonal influenza activity levels using multiple environmental factors as external proxies. Our work provides evidence that using dimensionality reduction techniques as a strategy to combine multiple datasets improves seasonal influenza forecasting without the penalization of increased dimensionality.

Abstract: Cornelia de Lange Syndrome (CdLS) is a congenital autosomal dominant (NIPBL, SMC3 and RAD21) or Xlinked (SMC1A and HDAC8) disorder characterized by facial dysmorphism, pre and postnatal growth retardation, developmental delay and/or intellectual disability, and multiorgan involvement. Musculoskeletal malformations are usually bilateral and affect mainly the upper limbs; the range goes from brachyclinodactyly to severe reduction defects. Instead lower extremities are usually less and mildly involved. Here, we report on a 3-year-old Senegalese boy with typical craniofacial CdLS features, pre and postnatal growth retardation, atrial septal defect, developmental delay and right ipsilateral limb malformations, consistent with oligodactyly of the 3rd and 4th fingers, tibial agenesis and fibula hypoplasia. Exome sequencing and Sanger sequencing showed a novel missense mutation in NIPBL gene (c.6647A>G; p.(Tyr2216Cys)), which affects a conserved residue located within NIPBL HEAT repeat elements. Pyrosequencing analysis of NIPBL gene, disclosed similar levels of wild-type and mutated alleles in DNA and RNA samples from all tissues analyzed (oral mucosa epithelial cells, peripheral blood leukocytes and fibroblasts). These findings indicated the absence of somatic mosaicism, despite of the segmental asymmetry of the limbs, and confirmed biallelic expression for NIPBL transcripts, respectively. Additionally, conditions like Split-hand/foot malformation with long-bone deficiency secondary to duplication of BHLHA9 gene have been ruled out by the array-CGH and MLPA analysis. To our knowledge, this is the first CdLS patient described with major ipsilateral malformations of both the upper and lower extremities, that even though this finding could be due to a random event, expands the spectrum of limb reduction defects in CdLS.

Abstract: The disorders caused by mutations in genes encoding subunits and accessory proteins of cohesin complex are collectively termed as cohesinopathies. The best known cohesinopathy is Cornelia de Lange Syndrome (CdLS), which is a multisystem developmental disorder characterized by facial dysmorphism, limb malformations, growth and cognitive impairment. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), are responsible for ∼70% of CdLS cases. We describe a 16-year-old boy with facial dysmorphism, growth retardation, intellectual disability, hirsutism and small hands, who has a small Supernumerary Marker Chromosome (sSMC) present in mosaic form. sSMC is composed of two duplicated segments encompassing 17 genes including SMC1A gene, at the regions Xp11.22 and Xp11.21q11.1. Clinical comparison between our patient with a previously reported individual with a SMC1A duplication and four male carriers of similar sSMC reported in databases, suggest that they all share clinical features related to cohesinopathies. Although our patient does not have the classical CdLS craniofacial phenotype, he has pre and postnatal growth retardation, intellectual disability and mild musculoskeletal anomalies, features commonly seen in patients with cohesinopathies.

Abstract: Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. This platform might enable delivery of antibodies and other protein-based therapeutics to previously inaccessible intraneuronal targets. Resumen: El botulismo es causado por una potente neurotoxina que bloquea la transmisión neuromuscular, provocando la muerte por asfixiamiento. Actualmente, las opciones de tratamiento son limitadas y no existe un antídoto. En este artículo aprovechamos las propiedades estructurales y de tráfico neuronal de un derivado atóxico de la neurotoxina botulínica (BoNT) para transportar un anticuerpo que bloquea la función al citosol neuronal, donde puede inhibir la toxicidad molecular del serotipo A de la BoNT (BoNT /A1). El tratamiento post-sintomático alivió los signos tóxicos del botulismo y rescató de la muerte a ratones, conejillos de indias y primates no humanos después de la exposición letal a BoNT / A1. Esta plataforma podría permitir la administración de anticuerpos y otros terapéuticos basados en proteínas a blancos intraneuronales que previamente eran inaccesibles.

Abstract: Mixed microbial cultures have become a preferred choice of biocatalyst for chain elongation systems due to their ability to convert complex substrates into medium chain carboxylates. However, the complexity of the effects of process parameters on the microbial metabolic networks is a drawback that makes the task of optimizing product selectivity challenging. Here, we studied the effects of small air contaminations on the microbial community dynamics and the product formation in anaerobic bioreactors fed with lactate, acetate and H2/CO2. Two stirred tank reactors and two bubble column reactors were operated with H2/CO2 gas recirculation for 139 and 116 days, respectively, at pH 6.0 and 32°C with a hydraulic retention time of 14 days. One reactor of each type had periods with air contamination (between 97 ± 28 and 474 ± 33 mL O2 L−1 d−1, lasting from 4 to 32 days), while the control reactors were kept anoxic. During air contamination, production of n-caproate and CH4 was strongly inhibited, whereas no clear effect on nbutyrate production was observed. In a period with detectable O2 concentrations that went up to 18%, facultative anaerobes of the genus Rummeliibacillus became predominant and only n-butyrate was produced. However, at low air contamination rates and with O2 below the detection level, Coriobacteriia and Actinobacteria gained a competitive advantage over Clostridia and Methanobacteria, and propionate production rates increased to 0.8–1.8 mmol L−1 d−1 depending on the reactor (control reactors 0.1–0.8 mmol L−1 d−1). Moreover, i-butyrate production was observed, but only when Methanobacteria abundances were low and, consequently, H2 availability was high. After air contamination stopped completely, production of n-caproate and CH4 recovered, with n-caproate production rates of 1.4–1.8 mmol L−1 d−1 (control 0.7–2.1 mmol L−1 d−1). The results underline the importance of keeping strictly anaerobic conditions in fermenters when consistent n-caproate production is the goal. Beyond that, micro-aeration should be further tested as a controllable process parameter to shape the reactor microbiome. When odd-chain carboxylates are desired, further studies can develop strategies for their targeted production by applying micro-aerobic conditions.

El ambiente escolar es uno de los entornos más relevantes y significativos de nuestra vida, pues allí se tejen comportamientos, relaciones y hábitos que suelen modelar patrones de alimentación que impactan en nuestras preferencias de consumo. En este sentido, si bien es cierto que existe una combinación de factores individuales, como cuestiones psicológicas y culturales, que impactan en nuestros hábitos alimentarios, diversos estudios han demostrado el carácter determinante de los existen factores ambientales, entre ellos la disponibilidad, la accesibilidad y la invasiva publicidad de alimentos en los entornos donde nos relacionamos. Según UNICEF, en Colombia 3 de cada 10 niños y niñas entre 6 y 12 años padecen de sobrepeso. Esto lo confirman los datos recolectados por la ENSIN, reflejando que en 2005. El 4,3% de la población escolar (niños y niñas entre 5 y 12 años) tenía exceso de peso. Ya para el 2010 esta cifra habría aumentado a 18,8% y para el 2015 este porcentaje alcanzó el 24,4%. Este panorama es altamente preocupante, pues según la Organización Mundial de la Salud, la obesidad infantil se asocia con una mayor probabilidad de muerte prematura y discapacidad en la edad adulta. Esta cartilla resume los argumentos legales y de salud pública, por los cuales la regulación de venta y publicidad de ultraprocesados en entornos escolares es una política necesaria para favorecer la salud y la alimentación de los niños y niñas en Colombia. Descripción tomada de: https://www.dejusticia.org/publication/promoviendo-ambientes-escolares-libres-de-comida-chatarra-en-colombia/

Sala de cirugía de un hospital, al parecer se trata de una sala de partos. Posiblemente sea de algún hospital de Bogotá.

Mutations in PCDH19 gene are associated with Early Infantile Epileptic Encephalopathy type 9 (EIEE-9), a very rare disorder characterized by early onset of seizures, intellectual disability and psychiatric comorbidities with an unusual form of X-linked inheritance in which only females and mosaic male patients are affected. Materials and Methods: We report three patients, one male and two females carrying PCDH19 variants (D233G, V589Cfs*8 and N1103K) found by Whole exome sequencing (WES). One is a novel missense mutation (N1103K) while the others had been previously reported in female affected patients. Although, there is the first time that variant V589Cfs*8 is reported in a male patient. We performed a complete phenotype evaluation of our cases and establish the pathogenicity of each variant by in silico and functional analysis accessing many aspects of Protocadherin-19 including subcellular localization and protein expression. Results: Two of the three variants are predicted to be deleterious to protein function. The variant D233G is predicted to affect the calcium binding site and avoids cadherin strands swapping compromising the cell adhesion activity and the structural stability of the protein. While, the variant V589Cfs*8 introduced a premature stop codon which led to the loss of the transmembrane domain of the protein as well as to the cytoplasmic domain, including all predicted nuclear localization signals, suggesting the variant might affect the subcellular localization of Pcdh-19. The last findings were corroborated by western blotting and immunolabelling comparing the protein localization in patient and control fibroblasts. Conclusions: Our findings enhance understanding of molecular functions of Protocadherin-19, as well as highlighting the importance of functional testing of variants that emerge from NGS studies. Resumen: Las mutaciones en el gen PCDH19 están asociadas con la encefalopatía epiléptica infantil temprana tipo 9 (EIEE-9), un trastorno muy raro caracterizado por la aparición temprana de convulsiones, discapacidad intelectual y comorbilidades psiquiátricas con una forma inusual de herencia ligada al cromosoma X en la que solo las mujeres y mosaico pacientes masculinos se ven afectados. Materiales y métodos: Reportamos tres pacientes, un hombre y dos mujeres con variantes en el gen PCDH19 (D233G, V589Cfs*8 y N1103K) encontrados por secuenciación de exoma completo (WES). Una es una nueva mutación sin sentido (N1103K) mientras que las otras habían sido reportadas previamente en pacientes femeninas afectadas. Aunque, es la primera vez que se informa la variante V589Cfs*8 en un paciente masculino. Realizamos una evaluación completa del fenotipo de nuestros casos y establecimos la patogenicidad de cada variante mediante análisis in silico y funcional accediendo a muchos aspectos de la Protocadherin-19, incluida la localización subcelular y la expresión de proteínas. Resultados: se predice que dos de las tres variantes son perjudiciales para la función de la proteína. La variante D233G afecta el sitio de unión al calcio y evita el intercambio de hebras de caderina que comprometen la actividad de adhesión celular y la estabilidad estructural de la proteína. Mientras que la variante V589Cfs*8 introdujo un codón de parada prematuro que condujo a la pérdida del dominio transmembrana de la proteína, así como al dominio citoplasmático, incluidas todas las señales de localización nuclear esperadas, lo que sugiere que la variante podría afectar la localización subcelular de la proteína. Los últimos hallazgos fueron corroborados por Western blot e inmunomarcaje comparando la localización de la proteína en fibroblastos de pacientes y controles. Conclusiones: Nuestros hallazgos mejoran la comprensión de las funciones moleculares de Protocadherin-19, así como resaltan la importancia de las pruebas funcionales de las variantes que surgen de los estudios de secuenciación de siguiente generación (NGS).

This thesis examines the concept of medical futility and its importance for the practice of medicine nowadays. It presents an overview of the development of the concept throughout history and it discusses the main arguments in favor and against a determination of futile treatment in the clinical setting. The notion of futility, in broad terms, describes the situation in which certain medical interventions no longer benefit the patient and therefore, it follows that there must be a derived moral obligation to stop said intervention. Such an idea brings forward numerous problematic pitfalls that are discussed in this thesis, among which are the debate about the limits of medicine, the tension between the notions of patient autonomy and physician authority and the practice of medical rationing in hospitals. This thesis aims to provide a new perspective on the subject in hopes that it will help to keep the ongoing debate running so in the near future, more experts will decide to contribute themselves with their expertise. Situations where a medical intervention ceases to benefit the patient will continue to occur at the bedside; what is more, these ethical conundrums will become more and more problematic as the technological imperative intensifies and the possibilities of biotechnology increase. The leading question that directed the development of the thesis was “when enough it’s enough?” in other words, what are the ethical considerations on the limits of medicine? The paper concludes that the concept of medical futility has a heuristic value, and thus it has helped yield more clarity about relevant matters such as the differentiation between futility and rationing, the fact that more research is needed to test what works and what does not and it has brought to the spotlight the importance of more robust standards of practice that, for example, prevent physicians from practicing defensive medicine. Resumen: Esta tesis examina el concepto de futilidad médica y su importancia para la práctica de la medicina en la actualidad. Presenta una visión general del desarrollo del concepto a lo largo de la historia y discute los principales argumentos a favor y en contra de la determinación de un tratamiento fútil en el ámbito clínico. La noción de futilidad, en términos generales, describe la situación en la que ciertas intervenciones médicas ya no benefician al paciente y, por lo tanto, se deduce que debe existir una obligación moral derivada de detener dicha intervención. Esta idea plantea numerosos asuntos problemáticos que se discuten en esta tesis, entre los que se encuentran el debate sobre los límites de la medicina, la tensión entre las nociones de autonomía del paciente y autoridad del médico, y la práctica del racionamiento médico en los hospitales. Esta tesis pretende aportar una nueva perspectiva sobre el tema con la esperanza de que esta ayude a mantener el debate vigente, de manera que, en un futuro próximo, más expertos decidan aportar su experiencia. Las situaciones en las que una intervención médica deja de beneficiar al paciente seguirán; más aún, estos debates éticos se volverán cada vez más problemáticos a medida que se intensifique el imperativo tecnológico y aumenten las posibilidades de la biotecnología. La pregunta principal que dirigió el desarrollo de la tesis fue ""¿cuándo es momento de parar?"", es decir, ¿cuáles son las consideraciones éticas sobre los límites de la medicina? El documento concluye que el concepto de futilidad médica tiene un valor heurístico y, por lo tanto, ha contribuido a aclarar cuestiones pertinentes como la diferenciación entre futilidad y racionamiento, el hecho de que se necesita más investigación para probar lo que funciona y lo que no, y ha puesto de relieve la importancia de contar con normas de práctica más sólidas que, por ejemplo, impidan a los médicos practicar la medicina defensiva.