Abstract: BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with significant morbidity and mortality that may affect over 5% of children and approximately 2.8% of adults worldwide. Pharmacological and behavioral therapies for ADHD exist, but critical symptoms such as dysexecutive deficits remain unaffected. In a randomized, sham-controlled, double-blind, crossover mechanistic study, we assessed the cognitive and physiological effects of transcranial direct current stimulation (tDCS) in 40 adult patients with ADHD in order to identify diagnostic (cross-sectional) and treatment biomarkers (targets). METHODS: Patients performed three experimental sessions in which they received 30 minutes of 2 mA anodal tDCS targeting the left dorsolateral prefrontal cortex, 30 minutes of 2 mA anodal tDCS targeting the right dorsolateral prefrontal cortex, and 30 minutes of sham. Before and after each session, half the patients completed the Eriksen flanker task and the other half completed the stop signal task while we assessed behavior (reaction time, accuracy) and neurophysiology (event-related potentials). RESULTS: Anodal tDCS to the left dorsolateral prefrontal cortex modulated cognitive (reaction time) and physiological (P300 amplitude) measures in the Eriksen flanker task in a state-dependent manner, but no effects were found in the stop signal reaction time of the stop signal task. CONCLUSIONS: These findings show procognitive effects in ADHD associated with the modulation of event-related potential signatures of cognitive control, linking target engagement with cognitive benefit, proving the value of eventrelated potentials as cross-sectional biomarkers of executive performance, and mechanistically supporting the statedependent nature of tDCS. We interpret these results as an improvement in cognitive control but not action cancellation, supporting the existence of different impulsivity constructs with overlapping but distinct anatomical substrates, and highlighting the implications for the development of individualized therapeutics.

Abstract: Introduction: The occlusion of coronary grafts used during myocardial revascularization surgery is a relatively frequent event. It has been described that between 7–15% are affected before 24 hours, and up to 30% per year being mainly related to technical errors. Pulsed Doppler offers the necessary requirements for an adequate intraoperative evaluation of grafts. The main objective of this study is to demonstrate it using the Fluxvisum prototype. Material and method: Longitudinal study carried out between March 2012 and June 2016 in surgically revascularized patients in which the elaborated coronary grafts were evaluated intraoperatively using pulsed Doppler. Results: 110 patients were studied, predominantly men older than 60 years, with a high prevalence of HT, DM and previous AMI, and diagnosis on admission to NSTEMI. The average measurements were: Qmed:31.7ml/min, PI:3.2, DFI:70.2. The Qmed was the flowmeter variable that was most statistically associated with the appearance of major cardiac events. In the logistic regression, the quality of LAD revascularization stood out as the main predictor of MACE (p=0.050, OR:2.599, 95%CI:0.972-6.947), death (p=0.004, OR:13.947, 95%CI:2,311-84,163), AMI (p=0.000, OR:11.331, 95%CI:2.995-42.867) and perioperative acute ischemia (p=0.049, OR:2.864, 95%CI:0.997-8.222). Conclusions: Pulsed Doppler flowmetry proved to be a tool with high prognostic power as a predictor of postoperative comorbidity and major cardiac events in surgically revascularized patients. Resumen: Introducción: La oclusión de los injertos coronarios utilizados durante la cirugía de revascularización miocárdica es un hecho relativamente frecuente. Se ha descrito que entre el 7–15% se afectan antes de las 24 horas, y hasta un 30% al año relacionándose principalmente con errores técnicos. El Doppler pulsado ofrece los requerimientos necesarios para una adecuada evaluación intraoperatoria de los injertos. El objetivo principal de este estudio es demostrarlo utilizando el prototipo Fluxvisum. Material y método: Estudio longitudinal realizado entre marzo de 2012 y junio del 2016 en pacientes revascularizados quirúrgicamente en los que los injertos coronarios elaborados fueron evaluados intraoperatoriamente utilizando Doppler pulsado. Resultados: Se estudiaron 110 enfermos predominantemente hombres mayores de 60 años, con una alta prevalencia de hipertensión arterial (HTA), diabetes mellitus (DM) e infarto agudo de miocardio (IMA) previo, y diagnostico al ingreso de SCASEST. Las mediciones promedio fueron: Qmed:31,7ml/min, IP:3,2, DFI:70,2. El Qmed fue la variable flujométrica que más se asoció estadísticamente con la aparición de eventos cardiacos mayores. En la regresión logística, la calidad de la revascularización de la DA destacó como el principal factor predictor de MACE (p=0,050, OR:2,599, CI95%:0,972–6,947), muerte (p=0,004, OR:13,947, CI95%:2,311–84,163), IMA (p=0,000, OR:11,331, CI95%:2,995–42,867) e isquemia aguda perioperatoria (p=0,049, OR:2,864, CI95%:0,997–8,222). Conclusiones: La flujometría con Doppler pulsado demostró ser una herramienta que tiene un alto poder pronóstico como predictor de comorbilidad posoperatoria y eventos cardiacos mayores en pacientes revascularizados quirúrgicamente.

Abstract: Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake of total, classes and subclasses of polyphenols and EOC risk in a large prospective study. The study was conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 309,129 adult women recruited mostly from the general population. Polyphenol intake was assessed through validated country-specific dietary questionnaires and the Phenol-Explorer database. During a mean follow-up of 14 years, 1469 first incident EOC cases (including 806 serous, 129 endometrioid, 102 mucinous, and 67 clear cell tumours) were identified. In multivariable-adjusted Cox regression models, the hazard ratio in the highest quartile of total polyphenol intake compared with the lowest quartile (HRQ4vsQ1) was 1.14 (95% CI 0.94–1.39; p-trend = 0.11). Similarly, the intake of most classes and subclasses of polyphenols were not related to either overall EOC risk or any EOC subtype. A borderline statistically significant positive association was observed between phenolic acid intake (HRQ4vsQ1 = 1.20, 95% CI 1.01–1.43; p-trend = 0.02) and EOC risk, especially for the serous subtype and in women with obesity, although these associations did not exceed the Bonferroni correction threshold. The current results do not support any association between polyphenol intake and EOC in our large European prospective study. Results regarding phenolic acid intake need further investigation.

Abstract: Biological and physiological changes in response to stress are crucial to achieving adaption to environmental constraints. Typical stress responses activate the sympathetic nervous system and the hypothalamic-pituitary-adrenal cortical axis, which aim to maintain homeostasis in response to demands and influence various biological responses at neuroendocrine, cellular, and immune levels. In particular, there is compelling evidence showing the devastating effects of high-stress levels on immune responses and brain functionality. In that sense, data suggest that a sustained stress-physiological response predicts decreases in immunity and leads to allostatic load, the wear, and tear of biological systems. Similarly, in cancer research, chronic stress levels have been reported to impair the bodysurveillance systems and be related to cancer incidence, progression, and mortality. Despite the evidence demonstrating the associations between stress and cancer, there are limited data on whether lifetime stress exposure relates to clinical indicators of cancer aggressiveness. Considering the evidence showing the adverse effects of prolonged stress exposure on cancer disease, this thesis aimed to explore the relationship between lifetime stress exposure and the clinical characteristics of tumor-aggressiveness in a cohort of patients affected with triple-negative breast cancer (TNBC). Likewise, as research has shown that coping responses moderate the stress-physiological response, we aimed to investigate the role of coping responses in moderating the association between tumor aggressiveness and lifetime stress exposure. According to the scientific literature, high-stress levels would increase physiological arousal and allostatic load favoring a debilitated immune system. Thus, we hypothesized finding positive associations between lifetime stress exposure and tumor-aggressiveness. In the same line, we suspected that adaptative coping styles would be negatively related to tumoraggressiveness. The participants of this study were 29 women diagnosed with TNBC who were treated in the University Hospital for Gynecology Pius-Hospital (Oldenburg, Germany). Correlation and moderation regression analyses with the use of composite scores were conducted. Overall, we could not demonstrate significant associations between lifetime stress exposure and coping responses on the clinical indicators of tumor aggressiveness in this cohort of patients. Possible explanations for these results are discussed, and suggestions for future research are provided. This study was the first to investigate the effect of lifetime stress exposure and coping response on the aggressive tumor characteristics of TNBC. We provided a deep theoretical framework to understand the interplay between biological and psychological aspects of cancer disease, and we hope that our recommendations may serve as a base for upcoming studies.

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.

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: 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.

Abstract: Latin American countries are experiencing a significant increase in the reports of mistreatment that women experience while using the maternity healthcare services, a phenomenon acknowledged as “Obstetric Violence” (OV). The Latin American region is crucial for the recognition of OV, not only because the term OV was originated there, but also because of its particular response to the matter. The present Scoping Review aimed to identify and review the available evidence about the response of Latin American countries to OV. As a result, it was found, firstly, that the emergence of the concept of OV in Latin America demonstrated to be a transformative tool useful to raise awareness about the mistreatment women face when giving birth. This OV concept also positions this problematic as subset of gendered violence and as a type of structural violence, through which the need to address it systemically is highlighted. Secondly, the used categorization of OV appears to be the broadest and more inclusive typology, emphasizing that OV might stem from both intentional and unintentional actions of healthcare professionals, as well as from conditions within healthcare organizations. Moreover, the identified variables that influence the response to OV in Latin America were synthetized into a theoretical framework, which offers insight into how the problem has been addressed until now and subsequently, provides useful lessons for other countries seeking approaches to combat mistreatment of women during childbirth. Lastly, it was determined that, in order to address OV and allow the progression of public policies to become regionally available, a broadened view encompassing a human rights-based approach is necessary. This research allowed to conclude that OV is a multi-faceted and complex phenomenon whose solution requires a multidimensional and multidisciplinary approach. Furthermore, OV should be understood as more than a simple act of mistreatment, but rather be viewed as a set of socially constructed symbolic, and violent, meanings allowing different stakeholders to reframe the abuse and violence that women undergoing childbirth experience as natural, expected, and accepted, reinforcing specific gender dynamics not merely in maternity care but in society overall. Finally, the framework to tackle OV within the human rights approach developed by the author is expected to be advantageous for the development of further research, programs, and policies to prevent OV in Latin America and beyond.

Abstract: Acute brain injuries are associated with high mortality rates and poor long-term functional outcomes. Measurement of cerebrospinal fluid (CSF) biomarkers in patients with acute brain injuries may help elucidate some ofthe pathophysiological pathways involved in the prognosis of these patients. We performed a systematic search and descriptive review using the MEDLINE database and the PubMed interface from inception up to June 29, 2021. Of the 39 studies that met our criteria, 30 reported that the biomarker concentration was associated with neurological outcome and 9 reported no association. In traumatic brain injury patients, increased extracellular concentrations of biomarkers related to neuronal cytoskeletal disruption, apoptosis and inflammation were associated with the severity of acute brain injury, early mortality and worse long-term functional outcome. Reduced concentrations of protein biomarkers related to impaired redox function were associated with increased risk of neurological deficit. In non-traumatic acute brain injury, concentrations of CSF protein biomarkers related to dysregulated inflammation and apoptosis were associated with a greater risk of vasospasm and a larger volume of brain ischemia. Resumen: Las lesiones cerebrales agudas se asocian con altas tasas de mortalidad y malos resultados funcionales a largo plazo. La medición de biomarcadores en el líquido cefalorraquídeo (LCR) en pacientes con lesiones cerebrales agudas puede ayudar a dilucidar algunas de las vías fisiopatológicas implicadas en el pronóstico de estos pacientes. Realizamos una búsqueda sistemática y revisión descriptiva utilizando la base de datos MEDLINE y la interfaz PubMed desde su inicio hasta el 29 de junio de 2021.De los 39 estudios que cumplieron con nuestros criterios de inclusión, 30 informaron que la concentración del biomarcador se asoció con el resultado neurológico y 9 no informaron ninguna asociación. En lesiones cerebrales traumáticas, el aumento de las concentraciones extracelulares de biomarcadores relacionados con la alteración del citoesqueleto neuronal, la apoptosis y la inflamación se asociaron con la gravedad de la lesión cerebral aguda, la mortalidad temprana y un peor resultado funcional a largo plazo. Las concentraciones reducidas de biomarcadores proteicos relacionados con la función redox deteriorada se asociaron con un mayor riesgo de déficit neurológico. En la lesión cerebral aguda no traumática, las concentraciones de biomarcadores proteicos del LCR relacionados con la inflamación desregulada y la apoptosis se asociaron con un mayor riesgo de vasoespasmo y un mayor volumen de isquemia cerebral.