Background: Data are rare about the incidence of severe Fontan-associated liver disease (FALD) and its association with mortality. We sought to: (1) estimate the probability of developing severe FALD in patients who undergo the Fontan procedure (Fontan patients), compared with severe liver complications in patients with a ventricular septal defect; (2) assess the severe FALD-mortality association; and (3) identify risk factors for developing severe FALD. Methods and Results: Using the Quebec Congenital Heart Disease database, a total of 512 Fontan patients and 10232 patients with a ventricular septal defect were identified. Kaplan-Meier curves demonstrated significantly higher cumulative risk of severe FALD in Fontan patients (11.95% and 52.24% at 10 and 35years, respectively), than the risk of severe liver complica- tions in patients with a ventricular septal defect (0.50% and 2.75%, respectively). At 5years, the cumulative risk of death was 12.60% in patients with severe FALD versus 3.70% in Fontan patients without FALD (log-rank P=0.0171). Cox proportional hazard models identified significant associations between the development of severe FALD and congestive heart failure and supraventricular tachycardia, with hazard ratios (HRs) of 2.36 (95% CI, 1.38–4.02) and 2.45 (95% CI, 1.37–4.39), respectively. More recent Fontan completion was related to reduced risks of severe FALD, with an HR of 0.95 (95% CI, 0.93–0.97) for each more recent year. Conclusions: This large-scale population-based study documents that severe FALD in Fontan patients was associated with a >3-fold increase in mortality. The risk of FALD is time-dependent and can reach >50% by 35years after the Fontan operation. Conditions promoting poor Fontan hemodynamics were associated with severe FALD development.

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.

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/

Abstract: Objective: To investigate opportunities for task shifting to decongest an outpatient neurology clinic in Zambia by describing current patient flow through the clinic and potential nodes for intervention using process mapping. Background: Zambia has a population of approximately 18 million people with 4 full-time adult neurologists, as of 2018, who all practice at the University Teaching Hospital (UTH), the main tertiary care center in the country. As a result of this provider-to-patient ratio, the outpatient neurology clinic is overcrowded and overbooked. Task-shifting programs have shown to improve efficiency, access and quality of care through the use of less specialized healthcare workers in low- and middle-income countries (LMIC). Methods: We evaluated patient flow in the UTH neurology outpatient clinic through the development and analysis of a process map. The characteristics of the clinic population between 2014 and 2018 were retrospectively reviewed from the clinic register. Between July and August 2018, we prospectively collected appointment lag times and time each patient spent waiting at various points in the clinic process. We conducted interviews with clinic staff and neurologists to generate a detailed process map of current pathways to care within the clinic. We then devised task- shifting strategies to help reduce patient wait times based on the overview of clinic process mapping and patient demographics. Results: From 2014 to 2018, there were 4701 outpatients seen in the neurology clinic. The most common neurologi- cal diagnoses were epilepsy (39.2%), headache (21.5%) and cerebrovascular disease (16.7%). During prospective data collection, patients waited an average of 57.8 (SD 73.4) days to be seen by a neurologist. The average wait time from arrival in the clinic to departure was 4.0 (SD 2.5) h. The process map and interviews with clinic staff revealed long waiting times due to a paucity of providers. Nurses and clerks represent an influential stakeholder group, but are not actively involved in any activity to reduce wait times. A large proportion of follow-up patients were stable and seen solely to obtain medication refills. Conclusions: Epilepsy, headache, and stroke make up the largest percentage of outpatient neurological illness in Zambia. Targeting stable patients in these diagnostic categories for a task-shifting intervention may lead to substan- tially decreased patient wait times. Potential interventions include shifting clinical follow-ups and medication refills to less specialized healthcare workers.

Abstract: Objective: To investigate opportunities for task shifting to decongest an outpatient neurology clinic in Zambia by describing current patient flow through the clinic and potential nodes for intervention using process mapping. Background: Zambia has a population of approximately 18 million people with 4 full-time adult neurologists, as of 2018, who all practice at the University Teaching Hospital (UTH), the main tertiary care center in the country. As a result of this provider-to-patient ratio, the outpatient neurology clinic is overcrowded and overbooked. Task-shifting programs have shown to improve efficiency, access and quality of care through the use of less specialized healthcare workers in low- and middle-income countries (LMIC). Methods: We evaluated patient flow in the UTH neurology outpatient clinic through the development and analysis of a process map. The characteristics of the clinic population between 2014 and 2018 were retrospectively reviewed from the clinic register. Between July and August 2018, we prospectively collected appointment lag times and time each patient spent waiting at various points in the clinic process. We conducted interviews with clinic staff and neurologists to generate a detailed process map of current pathways to care within the clinic. We then devised task- shifting strategies to help reduce patient wait times based on the overview of clinic process mapping and patient demographics. Results: From 2014 to 2018, there were 4701 outpatients seen in the neurology clinic. The most common neurologi- cal diagnoses were epilepsy (39.2%), headache (21.5%) and cerebrovascular disease (16.7%). During prospective data collection, patients waited an average of 57.8 (SD 73.4) days to be seen by a neurologist. The average wait time from arrival in the clinic to departure was 4.0 (SD 2.5) h. The process map and interviews with clinic staff revealed long waiting times due to a paucity of providers. Nurses and clerks represent an influential stakeholder group, but are not actively involved in any activity to reduce wait times. A large proportion of follow-up patients were stable and seen solely to obtain medication refills. Conclusions: Epilepsy, headache, and stroke make up the largest percentage of outpatient neurological illness in Zambia. Targeting stable patients in these diagnostic categories for a task-shifting intervention may lead to substan- tially decreased patient wait times. Potential interventions include shifting clinical follow-ups and medication refills to less specialized healthcare workers.

Abstract: Cornelia de Lange syndrome (CdLS) is a dominant inherited congenital developmental disorder characterized by facial dysmorphism, growth and cognitive impairment, limb malformations and multiple organ involvement. 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. Cohesin complex participates in chromosome segregation, DNA repair mechanisms, gene expression and chromosome conformation. Turner syndrome (TS) affects about one in 2000 live born females and results from complete or partial absence of one of the X chromosomes, frequently accompanied by cell-line mosaicism. Here, we describe a patient with CdLS due to a mutation in the NIPBL gene (c.1445_1448delGAGA, p.(Arg482Asnfs*20)) and mosaic TS (mos 45,X/46,XX karyotype). The patient showed multiple clinical features related to CdLS: craniofacial dysmorphism, pre- and post-natal growth delay, minor musculoskeletal anomalies, congenital heart defects and hirsutism. She also presented severe neurological involvement, including slight hypertonia, learning disabilities, verbal and motor development delay, intellectual impairment and (autistic-like features, aggression, self-injurious behaviour). In addition, the proband was clinically diagnosed with TS because of two typical recognizable features: the peripheral lymphedema and the webbed neck. Molecular characterization showed that the NIPBL mutation was present in the two tissues analyzed from different embryonic origins (peripheral blood lymphocytes from mesoderm and oral mucosa epithelial cells from ectoderm). However, FISH analyses revealed that the percentage of cells with monosomy X was low and tissue-specific. These findings indicate that, ontogenically, the NIPBL mutation may have appeared before the mosaic monosomy X. The coexistence in a patient of two rare disorders raises the issue of whether there is indeed a cause-effect association. In addition, we are forced to investigate the correlation between the genotype (a frameshift NIPBL mutation) and karyotype (mosaic X chromosome aneuploidy), with the patient’s phenotype. Therefore, we compare the clinical signs of each organ system described in our case to the typical clinical features of Cornelia de Lange and Turner syndromes. We conclude that our case seems to show a predominant CdLS phenotype, although additional TS manifestations might appear in adolescence. Besides, the significant neurological involvement reinforces the idea that the brain is the organ most sensitive to cohesin disruption.

Abstract: Cornelia de Lange Syndrome (CdLS) is an autosomal dominant (NIPBL, SMC3 and RAD21) or X-linked (SMC1A and HDAC8) disorder, characterized by distinctive craniofacial appearance, growth retardation, intellectual disability and limb anomalies. Its clinical presentation can be extremely variable. Here we report on a girl with classical CdLS phenotype, growth retardation, intellectual disability and gastroesophageal reflux disease, who is mosaic for the c.6647A>C mutation in the NIPBL gene. While this mutation was undetected by standard Sanger sequencing, it was identified by subsequent exome and panel sequencing approaches. Allele quantification by pyrosequencing showed the presence of the mutation in about 10%, 23.5% and 46.5% of DNA samples from peripheral blood leukocytes, buccal epithelial cells and fibroblasts, respectively. NIPBL mutations in a mosaic state are a frequent cause of CdLS, but clinical diagnosis of these patients can be challenging. In our case, the panel enriched sequencing as well as the exome sequencing clearly demonstrated to be very sensitive tools for mosaic mutation detection.

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.