Background Retinopathy of prematurity is the major cause of blindness in children in Colombia. This cause of childhood blindness is irreversible when stablished, but 100% preventable with the adequate strategies put in place. This raises important questions concerning strategies to reduce the incidence of blindness as a result of ROP, which should ensure that all infants who are at risk of blinding ROP are examined in screening programmes. Aim The aim was to collect data in the neonatal intensive care units. This was used to evaluate the existing human and material resources for preventing, screening and treating ROP and rehabilitation of children suffering from ROP. The data helped to do an analysis of gaps in the service and allowed to present a proposal for a programme to prevent blindness due to ROP in the cities of Manizales, Pereira and Armenia, Colombia. Methods 7 NICUs were visited in the three cities. The study collected quantitative data on neonatal intensive care units, admission and survival of premature babies during 2010, human resources and infrastructure and data on knowledge of the Colombian guidelines on ROP. Results The survival rates vary according to the provider. They are higher in the private sector, and lower in the public sector. Overall, the available data allowed us to estimate that there are approximately 45,000 births per year (2010) in the region (95% occur in hospital) and 1.8% of all the births are less than 2,000g. Therefore, in the region, 810 babies per year weighing less than 2,000g are at risk of developing any type of ROP. The number of places, ventilators and monitors is sufficient. Staffing is adequate in the private NICUs, with a shortage of neonatologists in the public NICUs. The number of nurses monitoring babies is universally adequate, but the lack of knowledge in controlling risk factors of developing ROP such as monitoring oxygen in a constraint. An ROP screening programme is not available in public NICUs and in some of the mixed providers. The Kangaroo Mother programme lack of screening for ROP. Conclusions The unstable health system has allowed (i) unsustainable NICUs and programmes for ROP (ii) If available, programmes running without being monitored or evaluated, and, (iii) no screening in public and some mixed NICUs in Manizales, Pereira and Armenia. (iv) no screening for ROP in the Kangaroo Mother Programe As access and survival rates improve in the NICUS of these cities, ROP is likely to continue to be a significant cause of blindness in the region, despite the progress that has been achieved with the 2010 Colombian guidelines for screening and treating ROP. Recommendations The results suggest that the prevention of blinding ROP is a complex task in Colombia that requires concomitant strategies to be put in place: Firstly, national policies in screening for ROP and oxygen delivery for the babies in the NICUs are needed. Secondly, as a primary preventive strategy, training nurses in the NICUs to control and monitor the delivery of oxygen; as a secondary preventive strategy, ROP programmes offered to the public, mixed, private NICUs and to the Kangaro Mother Programme; as a tertiary strategy, rehabilitation providing a low vision centre for these children Thirdly, running ROP programmes need to be monitored and evaluated.

Background: Health care–associated infections (HAIs) are a public health problem that increase health care costs. This article aimed to systematically review the literature and meta-analyze studies investigating risk factors (RFs) independently associated with HAIs in hospitalized adults. Methods: Electronic databases (MEDLINE, Embase, and LILACS) were searched to identify studies from 2009-2016. Pooled risk ratios (RRs) or odds ratios (ORs) or mean differences (MDs) and 95% confidence intervals (CIs) were calculated and compared across the groups. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Results: Of 867 studies, 65 met the criteria for review, and the data of 18 were summarized in the meta-analysis. The major RFs independently associated with HAIs were diabetes mellitus (RR, 1.76; 95% CI, 1.27-2.44), immunosuppression (RR, 1.24; 95% CI, 1.04-1.47), body temperature (MD, 0.62; 95% CI, 0.41-0.83), surgery time in minutes (MD, 34.53; 95% CI, 22.17-46.89), reoperation (RR, 7.94; 95% CI, 5.49-11.48), cephalosporin exposure (RR, 1.77; 95% CI, 1.30-2.42), days of exposure to central venous catheter (MD, 5.20; 95% CI, 4.91-5.48), intensive care unit (ICU) admission (RR, 3.76; 95% CI, 1.79-7.92), ICU stay in days (MD, 21.30; 95% CI, 19.81-22.79), and mechanical ventilation (OR, 12.95; 95% CI, 6.28-26.73). Conclusions: Identifying RFs that contribute to develop HAIs may support the implementation of strategies for their prevention, therefore maximizing patient safety.

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).

Objective: To evaluate the effectiveness of the chemically assisted dissection with sodium 2-mercaptoethanesulfonate (MESNA), in the reduction of residual and recurrent cholesteatoma after mastoidectomy in children with chronic cholesteatomatous otitis media (CCOM). Study Design: Retrospective case–control study. Setting: Tertiary referral center. Population: One hundred forty mastoidectomies performed in patients under 18 years of age for the treatment of CCOM. Interventions: Chemically assisted dissection (CAD) with MESNA compared with surgical dissection without MESNA. Main Outcome Measures: Recidivism of cholesteatoma (recurrence and residual disease), variations in the average of bone conduction threshold after treatment, and complications. Results: Recidivism of cholesteatoma was significantly lower when CAD with MESNA was used (p<0.0001). No difference was found in the mean variation of the average of bone conduction thresholds between the groups, confirming its safety profile regarding auditory function. Meatoplasty stenosis after surgery was more prevalent within CAD with MESNA group (p: 0.049). Conclusion: Recurrent and residual cholesteatoma remains a problem, especially in children and despite surgical techniques such as canal wall down mastoidectomy and endoscopic ear surgery. CAD with MESNA can be safe and effective to reduce recurrence rates. Resumen. Objetivo: Evaluar la efectividad de la disección químicamente asistida con 2-mercaptoetanosulfonato de sodio (MESNA), en la reducción de colesteatoma residual y recurrente después de mastoidectomía en niños con otitis media colesteatomatosa crónica (OMCC). Diseño del estudio: Estudio retrospectivo de casos y controles. Lugar: Centro de referencia terciario pediatrico. Población: Ciento cuarenta mastoidectomías realizadas en pacientes menores de 18 años para el tratamiento de OMCC. Intervenciones: Disección químicamente asistida (DQA) con MESNA en comparación con disección quirúrgica sin MESNA. Principales medidas de resultado: Reincidencia de colesteatoma (recurrencia y enfermedad residual), variaciones en el promedio del umbral de conducción ósea después del tratamiento y complicaciones. Resultados: La reincidencia del colesteatoma fue significativamente menor cuando se utilizó DQA con MESNA (p <0,0001). No se encontraron diferencias en la variación media del promedio de los umbrales de conducción ósea entre los grupos, lo que confirma su perfil de seguridad con respecto a la función auditiva. La estenosis de la meatoplastia después de la cirugía fue más frecuente dentro del grupo de DQA con MESNA (p: 0.049). Conclusión: El colesteatoma recurrente y residual sigue siendo un problema, especialmente en niños y a pesar de las técnicas quirúrgicas, como la mastoidectomía radical y la cirugía endoscópica del oído. La DQA con MESNA puede ser segura y efectiva para reducir las tasas de recurrencia.

Background: Current scores do not adequately predict cardiovascular risk in patients with chronic kidney disease who are at a very high CV risk in short and medium term. Aim: The aim of our analysis was to create a Bayesian network to predict the 2-year occurrence of a cardiovascular event in patients with chronic kidney disease. Methods and results: The data originated from the observational and prospective Photo-Graphe V3 cohort. Sixty-two nephrologists in 20 French regions included 1144 non-dialysed patients with chronic kidney disease. Seven hundred and thirty patients with known medical status at 2 years were analysed. An initial Bayesian model was first built using 26 variables related to the characteristics of the patients, their medical background, and treatments. A cardiovascular event (heart failure, acute coronary syndrome, transient ischemic attack, stroke or cardiovascular death) occurred in 20.0% of the patients after two years of follow-up. The model was first optimized using synthetic data (created from the original database) to increase its reliability. The number of variables was then reduced using the 13 most informative variables to increase its clinical applicability. The10-fold cross validation showed that the optimized clinical model with 13 variables had an area under the ROC curve of 0.90+0.02, a sensitivity of 82.5+5.9%, a specificity of 80.6+5.1%, a predictive positive value of 81.2+3.4% and a negative predictive value of 82.5+4.4%. The percentage of misclassified subjects was 18.4+2.6%. Conclusion: Using artificial intelligence methods, a new clinical tool to predict cardiovascular events in patients with chronic kidney disease is proposed.

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: 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: Objective: To analyze the population prevalence and birth prevalence of oral clefts in Colombia from 2009 to 2017. Methods: A cross-sectional study using information from the National Administrative Records of Colombia. The data came from 2 types of administrative records (Surveillance System and the Individual Registry of Service Provision) and the oral health national survey. Population prevalence and birth prevalence by type of cleft lip and/or cleft (CL/P) ratios were calculated using Poisson distribution for count data and to assess stationary tests on time series (Dickey-Fuller) and (Phillips-Perron) was used. Results: Population prevalence in Colombia was 3.27 per 10 000 inhabitants (95% confidence interval [CI], 3.21-3.32) and birth prevalence was 6.0 per 10 000 live births (95% CI, 5.67-6.35). Bogot´a have the highest population prevalence with CL/P. In the analysis of trends for the prevalence proportion by type of clefts in newborn babies with cleft, it was observed that the highest proportion was for babies with CLP. Cleft lip (CL) has increased from 17.4% in 2014 to 34.2% in 2017, cleft palate (CP) has decreased from 32.9% to 20.2%; and CLP changed from 49.6% to 45.5% in the same period. Conclusions: The population prevalence was 3.27 per 10 000 inhabitants. Births prevalence was 6.0 per 10 000 live births, and Orinoquia and Amazonia have higher rates than the national average. The administrative registers are adequate systems to know the behavior of oral clefts. The CL/P had a nonstationary trend during the period 2014 to 2017.

Abstract: Background: Seasonal Influenza is considered to be a cyclic and ordered sequence of values, influenced by external factors that can be predicted and used to detect disease outbreaks and monitoring. In machine learning, the key challenges that limit these analyses are in model explainability and limitations associated with ecological bias. Aim: Determine the best environmental variable selection method to predict Seasonal Influenza in Norway, using an environmental medicine approach combined with machine learning techniques. Methods: This is a quasi-experimental study that compares three approaches (non-variable selection, isolate component, and multipollutant mixture), represented in five methods (univariable, bivariable, multivariable AME, multivariable PCA, multivariable LDA). Per method, the best co-variable combination will be performed, following the internal rules of each method. The best covariable combination is the result of three components: variable selection, validation data set and lag. The first one involves 13 environmental variables (temperature, relative humidity, specific humidity, air pressure, wind speed, precipitation, CO, NO, NO2, O3, PM10, PM2,5 and SO2); second one compares a test dataset compiled from the data from 2019, last year (2018) and a synthetic environmental (avg. 2013-2018) data set in the validation process; and the third one compares a combination of lag from 0 to 12. All the predictions are made using ARIMA algorithm. The evaluation is given in terms of MAE, MSE, RMSE, OR. The training set is from 2 Jun 2013 (week 22/2013) to 28 May 2018 (week 21/2018), and test set is from (week 22/2018) to (week 21/2019) with a window of predictions of 52 weeks. Results: The increment of dimensionality in the environmental variable selection introduce different noise levels and optimize the prediction. Considerations that impact the explainability, usability, ecological bias and performance will be described. Conclusion: The increment of dimensionality in the variable selection has a better impact on performance than using complex algorithms.