Abstract: At the present time, climate change and antimicrobial resistance are considered as the most critical threats, affecting human, animal, plant, and environmental health. Although these terms may initially appear different, they are interconnected and share similarities in their causes (human interventions and natural cycles), health, and societal consequences. Climate change is associated through direct and indirect pathways with an increase in infectious diseases. Nonetheless, the association between global warming and antimicrobial resistance requires a comprehensive summary of evidence exploring it. Methods: A literature review was conducted to identify and describe the association between climate change and the rapid emergence and spread of antimicrobial resistance. The search was conducted in the following databases: PubMed, Web of Science, Scopus, Embase, Epistemonikos, and Google Scholar. The search period was restricted to articles published from January 2010 to June 2021. Additionally, a snowballing approach was conducted to identify any additional papers. Data extraction included study location, weather factors, environmental elements, antibiotics, and bacteria analysed, as well as the results. Results: 29 articles were included (ten literature or systematic reviews, eight experimental, six ecological, four observational, and one quasi-experimental). In terms of location, all the studies were conducted in countries between 35° and 75° north latitude. The results suggested some evidence of the effects of climate change (alterations in temperature, precipitation, and humidity) on the emergence and rapid spread of antimicrobial resistance in different environments (water, soil, cryosphere, and air). Temperature was described as a main effect of climate change that had effects on antibiotic resistance (increasing bacteria growth, altering metabolism, inducing crossprotection, and facilitating horizontal gene transfer between bacteria). Additionally, results also described the association between altered rain patterns and humidity and antimicrobial resistance, through the runoff of antibiotic molecules or the transport of antibiotic resistance mechanisms to other areas. Conclusions: This literature review has underscored the association between climate change and antimicrobial resistance. According to the results shown in the selected studies, the alterations in weather factors resulting from climate change have varying effects on the emergence and spread of antibiotic resistance. However, further research is imperative to decipher the complex interactions between other environmental processes, pollutants, patterns of antibiotic consumption, wastewater, animal migration, and regions below the latitudes covered in this literature review.

Abstract: Background: Multidrug resistant TB cases have been on the rise, risking advances in TB prevalence and control. Early diagnosis and targeted initial treatment are paramount for effective management and control of spreading of MDR/XDR-TB cases Methods: 161 isolates from patients with L-J culture confirmed TB in Lima, Peru, were tested with MODS+ assay, the diagnostic test and Sensititre, the reference standard. Analysis of growth patterns of bacteria in both methods were used to determine susceptibility/resistance of each isolate to three first line and six second line anti-TB agents, using two different critical concentrations (CC) for each antibiotic. Results: Agreement between susceptibility profiles and operational characteristics of diagnostic test yielded high performance and strong agreement with rifampicin 1μg/ml (agreement percent 90%, Kappa value 0.80) and amikacin 1μg/ml (agreement percent 96%, Kappa value 0.81), moderate for isoniazid 0.4μg/ml (agreement percent 89.4%, Kappa value 0.78), moxifloxacin at both CC’s 0.5μg/ml and 0.25μg/ml (agreement percent 93 and kappa values 0.73 for both), levofloxacin 2μg/ml (agreement 93%, kappa 0.69) and amikacin 2μg/ml (agreement 96%, Kappa 0.81), minimal for levofloxacin at CC 1.5μg/ml (agreement 90%, kappa 0.57) kanamycin at both CC’s 10μg/ml and 5μg/ml (agreement 87%, kappa 0.52) and ethionamide 5μg/ml (agreement 89%, kappa 0.46), weak for PAS 10μg/ml (agreement percent 93.9, kappa value 0.29), and none for ethambutol (Kappa value 0.02 for CC 10μg/ml, 0.07 for CC 5μg/ml). Conclusions: MODS+ assay is a cost-effective option for the diagnosis of TB and MDR/XDRTB, specially, in low resource settings with high TB incidence. Further operational research using lower CC’s, results read on different days and placed in settings with high and low TB and MDR/XDRTB burden could offer better sensitivities and wider applicability of results.

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.

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).

Insulin hormone is produced by pancreatic beta-cells and its biosynthesis, secretion, and intracellular degradation is tightly regulated. Newly formed SGs are preferentially released upon glucose stimulation while aged SGs are less competitive to be released and are more prompt to degradation mainly within lysosomes. The most assumed mechanism leading aged SGs to lysosome is autophagy, a degradation system for altered proteins and damaged organelles. The autophagic marker LC3 has facilitated the detection of autophagy through LC3-based biochemical and microscopic assays, as well as the possibility to experimentally manipulate the autophagy pathway. Here, we intended to establish a model for the further study of mechanism that target aged Ins-SNAPTMR-Star+ SGs to GFP-LC3+ autophagosomes in INS-1 cells by using three different approaches. Our results show that in INS-1 cells, modulation of autophagy with chemical agents can be detected by western blot. Likewise, TIRF Microscopy allowed for the detection of positive GFP-LC3+ aged Ins-SNAPTMR-Star+ objects in the cortical region of INS-1 cells. Additionally, we implemented SIM microscopy to gain more detail in the morphological aspect of autophagosomes vesicles. Despite some hints about the autophagosomal structures were uncovered through these approaches, further experiments should be performed to complement and confirm our findings. Thus, establishment of a suitable model for the study of autophagy, will allow us to further study the mechanisms behind the targeting process of aged SGs and to better understand how impairment of autophagy contributes to deterioration of pancreatic beta-cell function and subsequent onset of type 2 diabetes.

Waterborne diseases are transmitted by the faecal-oral route when water contaminated with faeces is ingested. Cryptosporidiosis is one of these diseases and is caused by one of the most widespread enteric parasites in the world; Cryptosporidium. To reduce the waterborne diseases, domestic wastewater needs to be treated sufficiently to reduce its pathogenic content. One of the recently introduced technologies for wastewater treatment is Aerobic Granular Sludge (AGS). AGS has proven to produce effluents with high chemical quality standards. However, little is known regarding the pathogen removal efficiencies or their removal mechanisms. In addition, there is a worldwide need to treat domestic wastewater appropriately to reduce pathogens causing waterborne diseases. The removal efficiencies and fate of some pathogens, such as Cryptosporidium, have not been studied in detail within wastewater treatment processes. Indicator microorganisms such as Escherichia coli (E. coli), have been used to understand the removal mechanisms and fate of pathogens in wastewater. However, it was found there is a miscorrelation between indicators and pathogens, and therefore there is a need for studies with pathogens themselves. Due to these reasons, this research aimed to develop a fluorescent staining method for E. coli and Cryptosporidium parvum (C. parvum) oocysts to allow their detection in AGS batch reactors, and evaluate the fate of fluorescently stained E. coli and C. parvum in these reactors. Pre-staining of E. coli and C. parvum was carried out using two fluorescent stains: dsGreen and SYBR. Experiments were carried out to test different pre-staining conditions. The stains were serial diluted, TWEEN was used to determine if it improved the staining, and the prestained microorganisms were incubated at 4 ºC, room temperature and 37 ºC. Two different batch reactors, 250 mL and 2 mL, were set up with AGS and were spiked with pre-stained microorganisms. Both reactors were run for 120 mins and sludge samples were collected and analysed using fluorescent microscopy. The filtered supernatant samples from the 250 mL were also analysed using the fluorescent microscope and the fluorescent cell count method. The best staining conditions for E. coli and C. parvum oocysts with dsGreen proved to be: 1,000x dilution of dye, incubation of stained microorganisms at room temperature for 15 mins and no need of TWEEN. SYBR photobleached rapidly and was therefore not an appropriate stain for this research. With the experiments in batch reactors, the fluorescent cell count method proved to be a generic and faster quantitative alternative to estimate E. coli concentrations in filtered supernatant samples than the E. coli agar plate method. In addition, it was qualitatively confirmed that fluorescently stained E. coli was removed by the predation of different species of protozoa. However, no conclusive results regarding protozoan predation of C. parvum oocysts were observed. Resumen: Las enfermedades transmitidas por el agua se transmiten por la ruta fecal-oral cuando se ingiere agua contaminada con heces. La criptosporidiosis es una de estas enfermedades y es causada por uno de los parásitos entéricos más extendidos del mundo; Cryptosporidium. Para reducir las enfermedades transmitidas por el agua, las aguas residuales domésticas deben tratarse lo suficiente como para reducir su contenido patógeno. Una de las tecnologías recientemente introducidas para el tratamiento de aguas residuales es el lodo granular aeróbico (AGS por sus siglas en inglés). AGS ha demostrado producir efluentes con altos estándares de calidad química. Sin embargo, se sabe poco sobre las eficiencias de eliminación de patógenos o sus mecanismos de eliminación. Además, existe una necesidad mundial de tratar las aguas residuales domésticas de manera adecuada para reducir los patógenos que causan enfermedades transmitidas por el agua. Las eficiencias de eliminación y el destino de algunos patógenos, como el Cryptosporidium, no se han estudiado en detalle en los procesos de tratamiento de aguas residuales. Se han utilizado microorganismos indicadores como Escherichia coli (E. coli) para comprender los mecanismos de eliminación y el destino de los patógenos en las aguas residuales. Sin embargo, se descubrió que existe una mala correlación entre los indicadores y los agentes patógenos y, por lo tanto, es necesario realizar estudios con los mismos agentes patógenos. Debido a estas razones, esta investigación tuvo como objetivo desarrollar un método de tinción fluorescente para E. coli y ooquistes de Cryptosporidium parvum (C. parvum) para permitir su detección en reactores discontinuos de AGS, y evaluar el destino de E. coli y C. parvum teñidos con fluorescencia en estos reactores. La tinción previa de E. coli y C. parvum se llevó a cabo utilizando dos tinciones fluorescentes: dsGreen y SYBR. Se llevaron a cabo experimentos para probar diferentes condiciones de pre-tinción. Las tintas se diluyeron en serie, se utilizó TWEEN para determinar si mejoraba la tinción, y los microorganismos pre-teñidos se incubaron a 4 ºC, temperatura ambiente y 37 ºC. Se prepararon dos reactores discontinuos diferentes, 250 ml y 2 ml, con AGS y se añadieron microorganismos previamente teñidos. Ambos reactores funcionaron durante 120 minutos y las muestras de lodo se recogieron y analizaron usando microscopía fluorescente. Las muestras de sobrenadante filtradas de 250 ml también se analizaron utilizando el microscopio fluorescente y el método de recuento de células fluorescentes. Las mejores condiciones de tinción para la E. coli y los ooquistes de C. parvum con dsGreen demostraron ser: dilución de colorante a 1,000x, incubación de microorganismos teñidos a temperatura ambiente durante 15 minutos y sin necesidad de TWEEN. SYBR se blanqueó rápidamente y, por lo tanto, no fue una tinta adecuada para esta investigación. Con los experimentos en reactores discontinuos, el método de recuento de células fluorescentes demostró ser una alternativa cuantitativa genérica y más rápida para estimar las concentraciones de E. coli en muestras de sobrenadante filtradas que el método de la placa de agar de E. coli. Además, se confirmó cualitativamente que E. coli teñida con fluorescencia se removió por la predación de diferentes especies de protozoos. Sin embargo, no se observaron resultados concluyentes con respecto a la predación de protozoos de los ooquistes de C. parvum.

In 2007, Mexico City legalized abortion in the first 12 weeks of pregnancy. By doing so, it became the first and only state in Mexico where abortion on demand is legal. In this paper, I use this natural experiment to estimate the effects of abortion legalization on child and maternal health. I perform Difference-In-Differences estimates using information from all births and deaths occurred between 2002 and 2012. My findings suggest that the change in the abortion legislation in Mexico City reduced the Infant Mortality Rate and the Under 5 Mortality Rate by approximately 2.3 and 2.4 deaths per 1,000 live births, respectively. Moreover, for the Maternal Mortality Rate I find that the estimations range from -5.49 to -6 deaths per 100,000 live births. These results are validated by the use of a more accurate control group generated by the Synthetic Control Method. To the best of my knowledge, this if the first paper that attempts to examine the effects of abortion legalization in Mexico City on child health. En el 2007, Ciudad de México legalizó el aborto en las 12 primeras semanas de gestación. Al hacerlo, se convirtió en el primero y único estado del país en donde el aborto voluntario es legal. En este artículo utilizo este experimento natural para estimar los efectos de la legalización del aborto en la salud materno infantil. Realizo estimaciones de Diferencias en Diferencias utilizando información de todos los nacimientos y muertes ocurridos entre 2002 y 2012. Mis hallazgos sugieren que el cambio en la legislación relativa el aborto en la Ciudad de México redujo la tasa de mortalidad Infantil y la tasa de mortalidad en menores de 5 años en aproximadamente 2.3 y 2.4 muertes por cada 1.000 nacidos vivos, respectivamente. Además, para la tasa de mortalidad materna, encuentro que las estimaciones oscilan entre -5,49 y -6 muertes por 100.000 nacidos vivos. Estos resultados se validan mediante el uso de un grupo de control más preciso, utilizando la metodología de control sintético. Según mi conocimiento, este es el primer artículo que intenta examinar los efectos de la legalización del aborto en la Ciudad de México sobre la salud infantil.

Se presenta la entrevista a Milagros Palma con la colaboración de Julio Heredia, desde París.

En este ensayo proponemos escudriñar lo más relevante de la obra de Doña Virginia Gutierrez de Pineda y analizar los aportes que a través de su larga trayectoria investigativa y académica fue realizando sobre la cambiante y dinámica institución familiar. Se busca conocer la utilización que ella hacía de la historia, la forma como la trabaja y los aportes realizados. Como punto de partida se hace una aproximación a la formación académica que ella recibió y la cual ayuda a entender su forma de trabajo, sus concepciones metodológicas y teóricas, además de su compromiso con la realidad del país. Sus aportes a la historia de la familia se pueden analizar desde dos vertientes diferentes: por una parte ella incursionó directamente en lo que podríamos llamar “historia de la familia” al plantearse como objetivo el recobrar las realidades de épocas pasadas mediante el uso de testimonios escritos, pero por otra parte, sus análisis sobre la familia del siglo XX, mediante la utilización de métodos eminentemente antropológicos o sociológicos, se convierten en textos de consulta obligatoria para cualquier estudioso de la historia colombiana del siglo XX y de manera especifica de la institución familiar.

Abstract: Functional Electrical Stimulation (FES) and robotic gait orthoses are rehabilitation technologies that help patients who have lost their normal gait function due to conditions such as spinal cord injury or stroke. FES promotes active muscle contractions that facilitate the rehabilitation process, while the Lokomat (an automated gait orthosis developed by Hocoma in collaboration with Balgrist University Hospital) provides passive limb movements that help to restore and increase mobility. The goal of this project was to combine both technologies in order to improve the beneficial effects that they provide individually. For that purpose, a control algorithm was developed for real-time Linux using an Iterative Learning Control approach in parallel with feedback control. The system was implemented on the ankle and knee joints. The ankle was controlled using a desired angle based on medical literature, while the knee was controlled using a reference force trajectory measured on subjects inside the Lokomat under high-effort conditions. As an alternative to force control on the knee, angle control was implemented for experiments in the lab. The controllers were tested on healthy subjects with and without the inclusion of voluntary movement. Based on these tests, we show the advantages and disadvantages of the control scheme and the physical setup, and give ideas for further improvement. Resumen: La estimulación eléctrica funcional (FES) y las ortesis de marcha robótica son tecnologías de rehabilitación que ayudan a los pacientes que han perdido su función de marcha normal debido a afecciones como una lesión de la médula espinal o un accidente cerebrovascular. FES promueve contracciones musculares activas que facilitan el proceso de rehabilitación, mientras que Lokomat (una órtesis de marcha automatizada desarrollada por Hocoma en colaboración con el Hospital Universitario Balgrist) proporciona movimientos pasivos de las extremidades que ayudan a restaurar y aumentar la movilidad. El objetivo de este proyecto fue combinar ambas tecnologías para mejorar los efectos beneficiosos que proporcionan individualmente. Para ello, se desarrolló un algoritmo de control para Linux en tiempo real utilizando un enfoque de control por aprendizaje iterativo en paralelo con el control de retroalimentación. El sistema se implementó en las articulaciones del tobillo y la rodilla. El tobillo se controló usando un ángulo deseado basado en la literatura médica, mientras que la rodilla se controló usando una trayectoria de fuerza de referencia medida en sujetos dentro del Lokomat bajo condiciones de alto esfuerzo. Como alternativa al control de fuerza en la rodilla, se implementó el control de ángulo para experimentos en el laboratorio. Los controladores se probaron en sujetos sanos con y sin la inclusión de movimiento voluntario. Con base en estas pruebas, mostramos las ventajas y desventajas del esquema de control y la configuración física, y brindamos ideas para mejoras adicionales.