Bioinspired robotic rehabilitation tool for lower limb motor learning after stroke

Mención Internacional en el título de doctorEsta tesis doctoral presenta, tras repasar la marcha humana, las principales patologíıas y condiciones que la afectan, y los distintos enfoques de rehabilitación con la correspondiente implicación neurofisiológica, el camino de investigación que desemboca en la herramienta robótica de rehabilitación y las terapias que se han desarrollado en el marco de los proyectos europeos BioMot: Smart Wearable Robots with Bioinspired Sensory-Motor Skills y HANK: European advanced exoskeleton for rehabilitation of Acquired Brain Damage (ABD) and/or spinal cord injury’s patients, y probado bajo el paraguas del proyecto europeo ASTONISH: Advancing Smart Optical Imaging and Sensing for Health y el proyecto nacional ASSOCIATE: A comprehensive and wearable robotics based approach to the rehabilitation and assistance to people with stroke and spinal cord injury.This doctoral thesis presents, after reviewing human gait, the main pathologies and conditions that affect it, and the different rehabilitation approaches with the corresponding neurophysiological implications, the research journey that leads to the development of the rehabilitation robotic tool, and the therapies that have been designed, within the framework of the European projects BioMot: Smart Wearable Robots with Bioinspired Sensory-Motor Skills and HANK: European advanced exoskeleton for rehabilitation of Acquired Brain Damage (ABD) and/or spinal cord injury’s patients and tested under the umbrella of the European project ASTONISH: Advancing Smart Optical Imaging and Sensing for Health and the national project ASSOCIATE: A comprehensive and wearable robotics based approach to the rehabilitation and assistance to people with stroke and spinal cord injury.This work has been carried out at the Neural Rehabilitation Group (NRG), Cajal Institute, Spanish National Research Council (CSIC). The research presented in this thesis has been funded by the Commission of the European Union under the BioMot project - Smart Wearable Robots with Bioinspired Sensory-Motor Skills (Grant Agreement number IFP7-ICT - 611695); under HANK Project - European advanced exoskeleton for rehabilitation of Acquired Brain Damage (ABD) and/or spinal cord injury’s patients (Grant Agreements number H2020-EU.2. - PRIORITY ’Industrial leadership’ and H2020-EU.3. - PRIORITY ’Societal challenges’ - 699796); also under the ASTONISH Project - Advancing Smart Optical Imaging and Sensing for Health (Grant Agreement number H2020-EU.2.1.1.7. - ECSEL - 692470); with financial support of Spanish Ministry of Economy and Competitiveness (MINECO) under the ASSOCIATE project - A comprehensive and wearable robotics based approach to the rehabilitation and assistance to people with stroke and spinal cord injury (Grant Agreement number 799158449-58449-45-514); and with grant RYC-2014-16613, also by Spanish Ministry of Economy and Competitiveness.Programa de Doctorado en Ingeniería Eléctrica, Electrónica y Automática por la Universidad Carlos III de MadridPresidente: Fernando Javier Brunetti Fernández.- Secretario: Dorin Sabin Copaci.- Vocal: Antonio Olivier

Hipoplasia del esmalte dental y su uso en Prehistoria: marcador de períodos críticos en la vida del individuo

27 p. : il. -- Bibliogr.: p. 25-27Son numerosos los llamados marcadores de estrés que se usan dentro de la osteoarqueología para poder llegar a conclusiones sobre los modos y la calidad de vida de las poblaciones del pasado. Uno de estos marcadores es la hipoplasia del esmalte dental, que consiste en una disminución del grosor del esmalte que puede presentarse en diferentes formas: oquedades, opacidades, bandas, etc. Se atribuyen, principalmente, a deficiencias nutricionales y a enfermedades infecciosas, relacionadas por numerosos autores con el momento del destete. En el estudio de las poblaciones prehistóricas este marcador se ha usado en numerosos trabajos de diferentes yacimientos a nivel mundial. Las causas atribuidas a este marcador son múltiples e inespecíficas en muchos casos. Esto provoca un debate sobre el significado que puede tener para la interpretación de las poblaciones del pasado y sobre la importancia del propio marcador en este tipo de estudios antropológicos. El objetivo de este trabajo es explicar lo que se sabe hasta el momento de la hipoplasia del esmalte dental, los métodos usados para su estudio y las limitaciones con las que los mismos cuentan; relacionado todo ello con su importancia y valía como indicador del estado de salud general y de los modos de vida de las poblaciones prehistóricas. Para ello, haremos una recopilación de varios trabajos sobre prehistoria en la península ibérica que contengan alusiones a la hipoplasia del esmalte dental y analizaremos en qué medida se ahonda en este tema y las causas que se le atribuyen. De este modo, queremos estudiar hasta qué punto se está utilizando este marcador como reflejo del estado de salud de las poblaciones del pasado. Como fin último, queremos poner de manifiesto la importancia de este biomarcador y de la necesidad de un análisis más exhaustivo del mismo para proporcionar información valiosa que nos permita ser capaces de reconstruir los modos de vida de nuestros antepasados

Hipoplasia del esmalte dental y su uso en Prehistoria: marcador de períodos críticos en la vida del individuo

27 p. : il. -- Bibliogr.: p. 25-27Son numerosos los llamados marcadores de estrés que se usan dentro de la osteoarqueología para poder llegar a conclusiones sobre los modos y la calidad de vida de las poblaciones del pasado. Uno de estos marcadores es la hipoplasia del esmalte dental, que consiste en una disminución del grosor del esmalte que puede presentarse en diferentes formas: oquedades, opacidades, bandas, etc. Se atribuyen, principalmente, a deficiencias nutricionales y a enfermedades infecciosas, relacionadas por numerosos autores con el momento del destete. En el estudio de las poblaciones prehistóricas este marcador se ha usado en numerosos trabajos de diferentes yacimientos a nivel mundial. Las causas atribuidas a este marcador son múltiples e inespecíficas en muchos casos. Esto provoca un debate sobre el significado que puede tener para la interpretación de las poblaciones del pasado y sobre la importancia del propio marcador en este tipo de estudios antropológicos. El objetivo de este trabajo es explicar lo que se sabe hasta el momento de la hipoplasia del esmalte dental, los métodos usados para su estudio y las limitaciones con las que los mismos cuentan; relacionado todo ello con su importancia y valía como indicador del estado de salud general y de los modos de vida de las poblaciones prehistóricas. Para ello, haremos una recopilación de varios trabajos sobre prehistoria en la península ibérica que contengan alusiones a la hipoplasia del esmalte dental y analizaremos en qué medida se ahonda en este tema y las causas que se le atribuyen. De este modo, queremos estudiar hasta qué punto se está utilizando este marcador como reflejo del estado de salud de las poblaciones del pasado. Como fin último, queremos poner de manifiesto la importancia de este biomarcador y de la necesidad de un análisis más exhaustivo del mismo para proporcionar información valiosa que nos permita ser capaces de reconstruir los modos de vida de nuestros antepasados

Voluntary control of wearable robotic exoskeletons by patients with paresis via neuromechanical modeling.

BACKGROUND: Research efforts in neurorehabilitation technologies have been directed towards creating robotic exoskeletons to restore motor function in impaired individuals. However, despite advances in mechatronics and bioelectrical signal processing, current robotic exoskeletons have had only modest clinical impact. A major limitation is the inability to enable exoskeleton voluntary control in neurologically impaired individuals. This hinders the possibility of optimally inducing the activity-driven neuroplastic changes that are required for recovery. METHODS: We have developed a patient-specific computational model of the human musculoskeletal system controlled via neural surrogates, i.e., electromyography-derived neural activations to muscles. The electromyography-driven musculoskeletal model was synthesized into a human-machine interface (HMI) that enabled poststroke and incomplete spinal cord injury patients to voluntarily control multiple joints in a multifunctional robotic exoskeleton in real time. RESULTS: We demonstrated patients' control accuracy across a wide range of lower-extremity motor tasks. Remarkably, an increased level of exoskeleton assistance always resulted in a reduction in both amplitude and variability in muscle activations as well as in the mechanical moments required to perform a motor task. Since small discrepancies in onset time between human limb movement and that of the parallel exoskeleton would potentially increase human neuromuscular effort, these results demonstrate that the developed HMI precisely synchronizes the device actuation with residual voluntary muscle contraction capacity in neurologically impaired patients. CONCLUSIONS: Continuous voluntary control of robotic exoskeletons (i.e. event-free and task-independent) has never been demonstrated before in populations with paretic and spastic-like muscle activity, such as those investigated in this study. Our proposed methodology may open new avenues for harnessing residual neuromuscular function in neurologically impaired individuals via symbiotic wearable robots

Population pharmacokinetics of daptomycin in critically ill patients

Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC24/MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cminss) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560-840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient.This study was supported by the University of the Basque Country UPV/EHU (PPG17/65)

Optimization of levetiracetam dosing regimen in critically ill patients with augmented renal clearance: a Monte Carlo simulation study

[EN] Background Levetiracetam pharmacokinetics is extensively altered in critically ill patients with augmented renal clearance (ARC). Consequently, the dosage regimens commonly used in clinical practice may not be sufficient to achieve target plasma concentrations. The aim of this study is to propose alternative dosage regimens able to achieve target concentrations in this population. Furthermore, the feasibility of the proposed dosing regimens will be discussed from a clinical point of view. Methods Different dosage regimens for levetiracetam were evaluated in critically ill patients with ARC. Monte Carlo simulations were conducted with extended or continuous infusions and/or high drug doses using a previously developed population pharmacokinetic model. To assess the clinical feasibility of the proposed dosages, we carried out a literature search to evaluate the information on toxicity and efficacy of continuous administration or high doses, as well as the post-dilution stability of levetiracetam. Results According to the simulations, target concentrations in patients with CrCl of 160 or 200 mL/min can be achieved with the 3000 mg daily dose by prolonging the infusion time of levetiracetam. For patients with CrCl of 240 mL/min, it would be necessary to administer doses higher than the maximum recommended. Available evidence suggests that levetiracetam administration in continuous infusion or at higher doses than those approved seems to be safe. It would be desirable to re-examinate the current recommendations about drug stability and to achieve a consensus in this issue. Conclusions Conventional dosage regimens of levetiracetam (500-1500 mg twice daily in a short infusion) do not allow obtaining drug plasma concentrations among the defined target in critically ill patients with ARC. Therefore, new dosing guidelines with specific recommendations for patients in this subpopulation are needed. This study proposes new dosages for levetiracetam, including extended (4 or 6 h) infusions, continuous infusions or the administration of doses higher than the recommended in the summary of product characteristics (> 3000 mg). These new dosage recommendations take into account biopharmaceutical and pharmacokinetic aspects and meet feasibility criteria, which allow them to be transferred to the clinical environment with safety and efficacy. Nevertheless, further clinical studies are needed to confirm these results.This research was funded by Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU20/048)

Novel population pharmacokinetic model for Linezolid in critically Ill patients and evaluation of the adequacy of the current dosing recommendation

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved

Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.This research was funded by Department of Education of the Basque Government, grant number PIBA 2019-57; and by the University of the Basque Country UPV/EHU, grant number GIU20/048. A.A.-L. thanks the University of the Basque Country UPV/EHU for her research grant, number PIFG19/23

Colo-Pro: a pilot randomised controlled trial to compare standard bolus-dosed cefuroxime prophylaxis to bolus-continuous infusion–dosed cefuroxime prophylaxis for the prevention of infections after colorectal surgery

Standard bolus-dosed antibiotic prophylaxis may not inhibit growth of antibiotic resistant colonic bacteria, a cause of SSIs after colorectal surgery. An alternative strategy is continuous administration of antibiotic throughout surgery, maintaining concentrations of antibiotics that inhibit growth of resistant bacteria. This study is a pilot comparing bolus-continuous infusion with bolus-dosed cefuroxime prophylaxis in colorectal surgery. This is a pilot randomised controlled trial in which participants received cefuroxime bolus-infusion (intervention arm) targeting free serum cefuroxime concentrations of 64 mg/L, or 1.5 g cefuroxime as a bolus dose four-hourly (standard arm). Patients in both arms received metronidazole (500 mg intravenously). Eligible participants were adults undergoing colorectal surgery expected to last for over 2 h. Results were analysed on an intention-to-treat basis. The study was successfully piloted, with 46% (90/196) of eligible patients recruited and 89% (80/90) of participants completing all components of the protocol. A trialled bolus-continuous dosing regimen was successful in maintaining free serum cefuroxime concentrations of 64 mg/L. No serious adverse reactions were identified. Rates of SSIs (superficial and deep SSIs) were lower in the intervention arm than the standard treatment arm (24% (10/42) vs. 30% (13/43)), as were infection within 30 days of operation (41% (17/43) vs 51% (22/43)) and urinary tract infections (2% (1/42) vs. 9% (4/43)). These infection rates can be used to power future clinical trials. This study demonstrates the feasibility of cefuroxime bolus-continuous infusion of antibiotic prophylaxis trials, and provides safety data for infusions targeting free serum cefuroxime concentrations of 64 mg/L. Trial registration: NCT02445859

Control of an ambulatory exoskeleton with a brain-machine interface for spinal cord injury gait rehabilitation

The closed-loop control of rehabilitative technologies by neural commands has shown a great potential to improve motor recovery in patients suffering from paralysis. Brain-machine interfaces (BMI) can be used as a natural control method for such technologies. BMI provides a continuous association between the brain activity and peripheral stimulation, with the potential to induce plastic changes in the nervous system. Paraplegic patients, and especially the ones with incomplete injuries, constitute a potential target population to be rehabilitated with brain-controlled robotic systems, as they may improve their gait function after the reinforcement of their spared intact neural pathways. This paper proposes a closed-loop BMI system to control an ambulatory exoskeleton-without any weight or balance support-for gait rehabilitation of incomplete spinal cord injury (SCI) patients. The integrated system was validated with three healthy subjects, and its viability in a clinical scenario was tested with four SCI patients. Using a cue-guided paradigm, the electroencephalographic signals of the subjects were used to decode their gait intention and to trigger the movements of the exoskeleton. We designed a protocol with a special emphasis on safety, as patients with poor balance were required to stand and walk. We continuously monitored their fatigue and exertion level, and conducted usability and user-satisfaction tests after the experiments. The results show that, for the three healthy subjects, 84.44 ± 14.56% of the trials were correctly decoded. Three out of four patients performed at least one successful BMI session, with an average performance of 77.6 1 ± 14.72%. The shared control strategy implemented (i.e., the exoskeleton could only move during specific periods of time) was effective in preventing unexpected movements during periods in which patients were asked to relax. On average, 55.22 ± 16.69% and 40.45 ± 16.98% of the trials (for healthy subjects and patients, respectively) would have suffered from unexpected activations (i.e., false positives) without the proposed control strategy. All the patients showed low exertion and fatigue levels during the performance of the experiments. This paper constitutes a proof-of-concept study to validate the feasibility of a BMI to control an ambulatory exoskeleton by patients with incomplete paraplegia (i.e., patients with good prognosis for gait rehabilitation)