Abstract: Background: Deep brain stimulation (DBS) surgery is a treatment in the advanced stage of Parkinson's disease (PD). Despite close follow-up, multiple evaluations, and several months of timeconsuming programming sessions, the clinical response may not be optimal in some cases. Imageguided programming (I-GP) could help optimize programming sessions with better clinical outcomes. Objective: To evaluate clinical and quality of life (QoL) outcomes with I-GP in PD patients with DBS of the subthalamic nucleus (STN) and suboptimal clinical improvement and refractory symptoms to conventional clinical programming. Methods: A prospective study in 16 patients with a diagnosis of PD with STN-DBS and remaining adverse effects or symptoms despite a clinical programming adjustment. We simulate potentially effective stimulation based on volume tissue activated (VTA) using commercially available software tools. Clinical outcomes were assessed with motor and quality of life scales. Results: The most frequent suboptimal symptom was gait disorder 33.3% (n=9), residual motor symptoms 25.9%(n=7), and speech 25.9%(n=7). Statistically significant results (p=0.001) were found after I-GP with change in the global Deep Brain Stimulation – Impairment score (41%), The 8- item version of the Parkinson's Disease Questionnaire (47%), EuroQol visual analogue scale (62%), and motor scale (24%). Conclusions: In suboptimal cases of patients with PD and STN-DBS, especially with ongoing and residual motor symptoms, I-GP could be useful to optimize the programming of DBS and improve patients' QoL.

Abstract: Spiking neural networks (SNNs) using time-to-first-spike (TTFS) codes, in which neurons fire at most once, are appealing for rapid and low power processing. In this theoretical paper, we focus on information coding and decoding in those networks, and introduce a new unifying mathematical framework that allows the comparison of various coding schemes. In an early proposal, called rankorder coding (ROC), neurons are maximally activated when inputs arrive in the order of their synaptic weights, thanks to a shunting inhibition mechanism that progressively desensitizes the neurons as spikes arrive. In another proposal, called NoM coding, only the first N spikes of M input neurons are propagated, and these ``first spike patterns'' can be readout by downstream neurons with homogeneous weights and no desensitization: as a result, the exact order between the first spikes does not matter. This paper also introduces a third option - ""Ranked-NoM"" (R-NoM), which combines features from both ROC and NoM coding schemes: only the first N input spikes are propagated, but their order is readout by downstream neurons thanks to inhomogeneous weights and linear desensitization. The unifying mathematical framework allows the three codes to be compared in terms of discriminability, which measures to what extent a neuron responds more strongly to its preferred input spike pattern than to random patterns. This discriminability turns out to be much higher for RNoM than for the other codes, especially in the early phase of the responses. We also argue that RNoM is much more hardware-friendly than the original ROC proposal, although NoM remains the easiest to implement in hardware because it only requires binary synapses. Resumen: Las redes neuronales de picos o potenciales de acciôn (SNN) que utilizan códigos de tiempo hasta el primer pico (TTFS), en los que las neuronas se disparan una vez como máximo, son atractivas para un procesamiento rápido y de baja potencia. En este artículo teórico, nos enfocamos en la codificación y decodificación de información en esas redes, e introducimos un nuevo marco matemático unificador que permite la comparación de varios esquemas de codificación. En una propuesta inicial, llamada codificación por orden de rango (ROC), las neuronas se activan al máximo cuando las entradas llegan en el orden de sus pesos sinápticos, gracias a un mecanismo de inhibición de derivación que insensibiliza progresivamente las neuronas a medida que llegan los picos. En otra propuesta, denominada codificación NoM, solo se propagan los primeros N picos de las M neuronas de entrada, y estos ""primeros patrones de picos"" pueden ser leídos por las ""downstream neurons"" con pesos homogéneos y sin desensibilización: como resultado, el orden exacto entre los primeros picos no importa. Este documento también presenta una tercera opción: ""Ranked-NoM"" (R-NoM), que combina características de los esquemas de codificación ROC y NoM: solo se propagan los primeros picos de entrada N, pero las neuronas posteriores leen su orden gracias a pesos no homogéneos y desensibilización lineal. El marco matemático unificador permite comparar los tres códigos en términos de discriminabilidad, que mide en qué medida una neurona responde con más fuerza a su patrón de picos de entrada preferido que a patrones aleatorios. Esta discriminabilidad resulta ser mucho mayor para R-NoM que para los otros códigos, especialmente en la fase temprana de las respuestas. También argumentamos que R-NoM es mucho más compatible con el hardware que la propuesta ROC original, aunque NoM sigue siendo el más fácil de implementar en hardware porque solo requiere sinapsis binarias.

Resumen: PREGUNTA DE ESTUDIO: ¿Cuáles son las opiniones de las mujeres sobre tener hijos, incluida la edad a la que quieren tenerlos y otras influencias como como la pandemia de la enfermedad por coronavirus 2019 (COVID-19)? RESPUESTA RESUMIDA: Las opiniones de las mujeres sobre tener hijos, a su edad preferida de 30 años, incluían su impulso maternal y sus preocupaciones. sobre su reloj biológico y estabilidad, mientras que el 19% dijo que COVID-19 había afectado sus puntos de vista. DISEÑO DEL ESTUDIO, TAMAÑO, DURACIÓN: Realizamos una encuesta anónima en línea de preguntas abiertas y de opción múltiple. los La encuesta estuvo activa durante 32 días, desde el 15 de mayo de 2020 hasta el 16 de junio de 2020, y se promocionó a través de las redes sociales. PARTICIPANTES/MATERIALES, ESCENARIO, MÉTODOS: Un total de 887 mujeres de 44 países participaron en la encuesta. Después de filtrar de las mujeres que no dieron su consentimiento, dieron respuestas en blanco o incompletas, y aquellas que no estaban en el Reino Unido, quedaron 411 respuestas. Desde los datos, se analizaron tres áreas de cuestionamiento: sus opiniones sobre tener hijos, la edad ideal a la que quieren tener hijos y los efectos de la pandemia de COVID-19. Los datos cualitativos fueron analizados por análisis temático. PRINCIPALES RESULTADOS Y EL PAPEL DEL AZAR: La edad media (§SD) de las mujeres que completaron la encuesta fue de 32,2 años. (§5.9), siendo mayoritariamente heterosexuales (90,8%) y 84,8% con estudios universitarios. Un tercio de las mujeres estaban casadas/en matrimonio pareja (37,7%) y 36,0% convivían. En relación a sus visiones sobre tener hijos, los principales temas identificados fueron: la urgencia, el tictac del reloj biológico, ¿por qué nadie nos enseñó esto?, la necesidad de estabilidad y equilibrio en su vida, presión para comenzar una familia y considerando otras maneras de tener una familia. Ante la pregunta 'En un mundo ideal, ¿a qué edad aproximadamente te gustaría tener tuvo o tiene hijos?’ se observó una distribución normal con una edad media de 29,9 (§3.3) años. Cuando se le preguntó ""¿Qué factores le han llevado decidir sobre esa edad en particular?’, la elección más frecuente fue ‘Estoy desarrollando mi carrera’. Tres temas surgieron de la cualitativa pregunta sobre por qué eligieron esa edad: la necesidad de estabilidad y equilibrio en su vida, la importancia de encontrar el momento adecuado y las experiencias de vida. La mayoría de las mujeres sintieron que la pandemia de COVID-19 no había afectado su decisión de tener hijos (72,3%), pero el 19,1% dijo tenía. Los comentarios cualitativos mostraron que tenían preocupaciones sobre la inestabilidad en su vida, como finanzas y carreras, y retrasos en la fertilidad. Tratamiento.

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.

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.