Engineered Graphene Material Improves the Performance of Intraneural Peripheral Nerve Electrodes.

Limb neuroprostheses aim to restore motor and sensory functions in amputated or severely nerve-injured patients. These devices use neural interfaces to record and stimulate nerve action potentials, creating a bidirectional connection with the nervous system. Most neural interfaces are based on standard metal microelectrodes. In this work, a new generation of neural interfaces which replaces metals with engineered graphene, called EGNITE, is tested. In vitro and in vivo experiments are conducted to assess EGNITE biocompatibility. In vitro tests show that EGNITE does not impact cell viability. In vivo, no significant functional decrease or harmful effects are observed. Furthermore, the foreign body reaction to the intraneural implant is similar compared to other materials previously used in neural interfaces. Regarding functionality, EGNITE devices are able to stimulate nerve fascicles, during two months of implant, producing selective muscle activation with about three times less current compared to larger microelectrodes of standard materials. CNAP elicited by electrical stimuli and ENG evoked by mechanical stimuli are recorded with high resolution but are more affected by decreased functionality over time. This work constitutes further proof that graphene-derived materials, and specifically EGNITE, is a promising conductive material of neural electrodes for advanced neuroprostheses.

Nanoporous graphene-based thin-film microelectrodes for in vivo high-resolution neural recording and stimulation.

One of the critical factors determining the performance of neural interfaces is the electrode material used to establish electrical communication with the neural tissue, which needs to meet strict electrical, electrochemical, mechanical, biological and microfabrication compatibility requirements. This work presents a nanoporous graphene-based thin-film technology and its engineering to form flexible neural interfaces. The developed technology allows the fabrication of small microelectrodes (25 µm diameter) while achieving low impedance (∼25 kΩ) and high charge injection (3-5 mC cm-2). In vivo brain recording performance assessed in rodents reveals high-fidelity recordings (signal-to-noise ratio >10 dB for local field potentials), while stimulation performance assessed with an intrafascicular implant demonstrates low current thresholds (<100 µA) and high selectivity (>0.8) for activating subsets of axons within the rat sciatic nerve innervating tibialis anterior and plantar interosseous muscles. Furthermore, the tissue biocompatibility of the devices was validated by chronic epicortical (12 week) and intraneural (8 week) implantation. This work describes a graphene-based thin-film microelectrode technology and demonstrates its potential for high-precision and high-resolution neural interfacing.

Calcium Imaging In Electrically Stimulated Flat-Mounted Retinas.

Retinal dystrophies are a leading cause of blindness worldwide. Extensive efforts are underway to develop advanced retinal prostheses that can bypass the impaired light-sensing photoreceptor cells in the degenerated retina, aiming to partially restore vision by inducing visual percepts. One common avenue of investigation involves the design and production of implantable devices with a flexible physical structure, housing a high number of electrodes. This enables the efficient and precise generation of visual percepts. However, with each technological advancement, there arises a need for a reliable and manageable ex vivo method to verify the functionality of the device before progressing to in vivo experiments, where factors beyond the device's performance come into play. This article presents a comprehensive protocol for studying calcium activity in the retinal ganglion cell layer (GCL) following electrical stimulation. Specifically, the following steps are outlined: (1) fluorescently labeling the rat retina using genetically encoded calcium indicators, (2) capturing the fluorescence signal using an inverted fluorescence microscope while applying distinct patterns of electrical stimulation, and (3) extracting and analyzing the calcium traces from individual cells within the GCL. By following this procedure, researchers can efficiently test new stimulation protocols prior to conducting in vivo experiments.

Prevalencia de obesidad posCovid-19 en jóvenes universitarios de Tabasco.

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Development of a telematic pharmaceutical care app (Haemoassist) for multidisciplinary follow-up of patients with congenital coagulopathies.

BACKGROUND: Guidelines for congenital coagulopathies recommend that patients record treatment administrations and bleeding episodes to help healthcare professionals monitor the disease. RESEARCH DESIGN AND METHODS: We studied over two years which patient profiles (age, treatment regimen, treatment compliance) were most likely to accept the use of an app to collect this information. We validated the quality of patient-reported data by comparing it with data obtained from hospital electronic records, pharmacy dispensing records and patient interview, collected in an access database used as a reference. Patient and professional opinions were solicited through open-ended interviews. RESULTS: The app was used by 52% of 315 patients studied. Younger patients were the most frequent users. Patients with better treatment compliance used the app more, although data collection was incomplete for most patients. The best rated by patients were the reminders of days of administration and the minimum stock alerts at home. Healthcare professionals rated the app positively. CONCLUSIONS: Healthcare professionals valued the app as useful for managing treatment of congenital coagulopathies. Patients need support and time to use the app and improve the quality of the data entered. Patients who used the app rated it positively. The treatment compliance improved.

Comorbidities and laboratory parameters associated with SARS-CoV-2 infection severity in patients from the southeast of Mexico: a cross-sectional study.

Background. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic. Among the risk factors associated with the severity of this disease is the presence of several metabolic disorders. For this reason, the aim of this research was to identify the comorbidities and laboratory parameters among COVID-19 patients admitted to the intensive care unit (ICU), comparing the patients who required invasive mechanical ventilation (IMV) with those who did not require IMV, in order to determine the clinical characteristics associated with the COVID-19 severity. Methods. We carried out a cross-sectional study among 152 patients who were admitted to the ICU from April 1 st to July 31 st, 2021, in whom the comorbidities and laboratory parameters associated with the SARS-CoV-2 infection severity were identified. The data of these patients was grouped into two main groups: "patients who required IMV" and "patients who did not require IMV". The nonparametric Mann-Whitney U test for continuous data and the χ2 test for categorical data were used to compare the variables between both groups. Results. Of the 152 COVID-19 patients who were admitted to the ICU, 66 required IMV and 86 did not require IMV. Regarding the comorbidities found in these patients, a higher prevalence of type 2 diabetes mellitus (T2DM), hypertension and obesity was observed among patients who required IMV vs. those who did not require IMV ( p<0.05). Concerning laboratory parameters, only glucose, Interleukin 6 (IL-6), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were significantly higher among patients who required IMV than in those who did not require IMV ( p<0.05). Conclusion. This study performed in a Mexican population indicates that comorbidities such as: T2DM, hypertension and obesity, as well as elevated levels of glucose, IL-6, LDH and CRP are associated with the COVID-19 severity.

Full-bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene microtransistor depth neural probes.

Mapping the entire frequency bandwidth of brain electrophysiological signals is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously DC-shifts, infraslow oscillations (<0.1 Hz), typical local field potentials (0.1-80 Hz) and higher frequencies (80-600 Hz) using the same recording site would particularly benefit preclinical epilepsy research and could provide clinical biomarkers for improved seizure onset zone delineation. However, commonly used metal microelectrode technology suffers from instabilities that hamper the high fidelity of DC-coupled recordings, which are needed to access signals of very low frequency. In this study we used flexible graphene depth neural probes (gDNPs), consisting of a linear array of graphene microtransistors, to concurrently record DC-shifts and high-frequency neuronal activity in awake rodents. We show here that gDNPs can reliably record and map with high spatial resolution seizures, pre-ictal DC-shifts and seizure-associated spreading depolarizations together with higher frequencies through the cortical laminae to the hippocampus in a mouse model of chemically induced seizures. Moreover, we demonstrate the functionality of chronically implanted devices over 10 weeks by recording with high fidelity spontaneous spike-wave discharges and associated infraslow oscillations in a rat model of absence epilepsy. Altogether, our work highlights the suitability of this technology for in vivo electrophysiology research, and in particular epilepsy research, by allowing stable and chronic DC-coupled recordings.

Novel transducers for high-channel-count neuroelectronic recording interfaces.

Neuroelectronic interfaces with the nervous system are an essential technology in state-of-the-art neuroscience research aiming to uncover the fundamental working mechanisms of the brain. Progress towards increased spatio-temporal resolution has been tightly linked to the advance of microelectronics technology and novel materials. Translation of these technologies to neuroscience has resulted in multichannel neural probes and acquisition systems enabling the recording of brain signals using thousands of channels. This review provides an overview of state-of-the-art neuroelectronic technologies, with emphasis on recording site architectures which enable the implementation of addressable arrays for high-channel-count neural interfaces. In this field, active transduction mechanisms are gaining importance fueled by novel materials, as they facilitate the implementation of high density addressable arrays.

A 1024-Channel 10-Bit 36- µW/ch CMOS ROIC for Multiplexed GFET-Only Sensor Arrays in Brain Mapping.

This paper presents a 1024-channel neural read-out integrated circuit (ROIC) for solution-gated GFET sensing probes in massive µECoG brain mapping. The proposed time-domain multiplexing of GFET-only arrays enables low-cost and scalable hybrid headstages. Low-power CMOS circuits are presented for the GFET analog frontend, including a CDS mechanism to improve preamplifier noise figures and 10-bit 10-kS/s A/D conversion. The 1024-channel ROIC has been fabricated in a standard 1.8-V 0.18- µm CMOS technology with 0.012 mm 2 and 36 µ W per channel. An automated methodology for the in-situ calibration of each GFET sensor is also proposed. Experimental ROIC tests are reported using a custom FPGA-based µECoG headstage with 16×32 and 32×32 GFET probes in saline solution and agar substrate. Compared to state-of-art neural ROICs, this work achieves the largest scalability in hybrid platforms and it allows the recording of infra-slow neural signals.

Characterization of optogenetically-induced cortical spreading depression in awake mice using graphene micro-transistor arrays.

Objective.The development of experimental methodology utilizing graphene micro-transistor arrays to facilitate and advance translational research into cortical spreading depression (CSD) in the awake brain.Approach.CSDs were reliably induced in awake nontransgenic mice using optogenetic methods. High-fidelity DC-coupled electrophysiological mapping of propagating CSDs was obtained using flexible arrays of graphene soultion-gated field-effect transistors (gSGFETs).Main results.Viral vectors targetted channelrhopsin expression in neurons of the motor cortex resulting in a transduction volume ⩾1 mm3. 5-10 s of continous blue light stimulation induced CSD that propagated across the cortex at a velocity of 3.0 ± 0.1 mm min-1. Graphene micro-transistor arrays enabled high-density mapping of infraslow activity correlated with neuronal activity suppression across multiple frequency bands during both CSD initiation and propagation. Localized differences in the CSD waveform could be detected and categorized into distinct clusters demonstrating the spatial resolution advantages of DC-coupled recordings. We exploited the reliable and repeatable induction of CSDs using this preparation to perform proof-of-principle pharmacological interrogation studies using NMDA antagonists. MK801 (3 mg kg-1) suppressed CSD induction and propagation, an effect mirrored, albeit transiently, by ketamine (15 mg kg-1), thus demonstrating this models' applicability as a preclinical drug screening platform. Finally, we report that CSDs could be detected through the skull using graphene micro-transistors, highlighting additional advantages and future applications of this technology.Significance.CSD is thought to contribute to the pathophysiology of several neurological diseases. CSD research will benefit from technological advances that permit high density electrophysiological mapping of the CSD waveform and propagation across the cortex. We report anin vivoassay that permits minimally invasive optogenetic induction, combined with multichannel DC-coupled recordings enabled by gSGFETs in the awake brain. Adoption of this technological approach could facilitate and transform preclinical investigations of CSD in disease relevant models.

Novel Graphene Electrode for Retinal Implants: An in vivo Biocompatibility Study.

Evaluating biocompatibility is a core essential step to introducing a new material as a candidate for brain-machine interfaces. Foreign body reactions often result in glial scars that can impede the performance of the interface. Having a high conductivity and large electrochemical window, graphene is a candidate material for electrical stimulation with retinal prosthesis. In this study, non-functional devices consisting of chemical vapor deposition (CVD) graphene embedded onto polyimide/SU-8 substrates were fabricated for a biocompatibility study. The devices were implanted beneath the retina of blind P23H rats. Implants were monitored by optical coherence tomography (OCT) and eye fundus which indicated a high stability in vivo up to 3 months before histology studies were done. Microglial reconstruction through confocal imaging illustrates that the presence of graphene on polyimide reduced the number of microglial cells in the retina compared to polyimide alone, thereby indicating a high biocompatibility. This study highlights an interesting approach to assess material biocompatibility in a tissue model of central nervous system, the retina, which is easily accessed optically and surgically.

Niveles de procalcitonina y ferritina predicen la gravedad de Covid-19 en pacientes ingresados a la unidad de cuidados intensivos.

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Registry of patients with congenital bleeding disorders and COVID-19 in Madrid.

INTRODUCTION: We present the first registry of patients with congenital bleeding disorders and COVID-19. The study has been carried out in the Community of Madrid, which has the highest number of cases in Spain. The objective is to understand the incidence of COVID-19, the course of the disease if it occurs and the psychosocial and occupational impact on this population. METHODS: We included 345 patients (246 of haemophilia, 69 of von Willebrand Disease, two rare bleeding disorders and 28 carriers of haemophilia). A telephone survey was used to collect the data. RESULTS: Forty-two patients presented symptoms suggestive of infection by COVID-19, and in six cases, the disease was confirmed by RT-PCR. The cumulative incidence of our series was 1.73%. It is worth noting the complexity of the management of COVID-19 in two patients on prophylaxis with non-factor replacement therapy. Adherence to the prescribed treatment was maintained by 95.5% of patients. Although 94% were independent for daily living activities, 42.4% had a recognized disability and 58% required assistance, provided by the Madrid Haemophilia Association (Ashemadrid) in 75% of cases. Only 4.4% of consultations were held in person. CONCLUSIONS: Patients with congenital bleeding disorders infected with SARS-CoV-2 presented a mild course of the disease that did not require admission. Their identification and treatment by a specialist team from a Haemophilia Treatment Center are essential to make a correct assessment of the risk of haemorrhage/thrombosis. COVID-19 had a major impact on the psychosocial aspects of these patients which must be remedied with recovery plans.

Switchless Multiplexing of Graphene Active Sensor Arrays for Brain Mapping.

Sensor arrays used to detect electrophysiological signals from the brain are paramount in neuroscience. However, the number of sensors that can be interfaced with macroscopic data acquisition systems currently limits their bandwidth. This bottleneck originates in the fact that, typically, sensors are addressed individually, requiring a connection for each of them. Herein, we present the concept of frequency-division multiplexing (FDM) of neural signals by graphene sensors. We demonstrate the high performance of graphene transistors as mixers to perform amplitude modulation (AM) of neural signals in situ, which is used to transmit multiple signals through a shared metal line. This technology eliminates the need for switches, remarkably simplifying the technical complexity of state-of-the-art multiplexed neural probes. Besides, the scalability of FDM graphene neural probes has been thoroughly evaluated and their sensitivity demonstrated in vivo. Using this technology, we envision a new generation of high-count conformal neural probes for high bandwidth brain machine interfaces.

Distortion-Free Sensing of Neural Activity Using Graphene Transistors.

Graphene solution-gated field-effect transistors (g-SGFETs) are promising sensing devices to transduce electrochemical potential signals in an electrolyte bath. However, distortion mechanisms in g-SGFET, which can affect signals of large amplitude or high frequency, have not been evaluated. Here, a detailed characterization and modeling of the harmonic distortion and non-ideal frequency response in g-SGFETs is presented. This accurate description of the input-output relation of the g-SGFETs allows to define the voltage- and frequency-dependent transfer functions, which can be used to correct distortions in the transduced signals. The effect of signal distortion and its subsequent calibration are shown for different types of electrophysiological signals, spanning from large amplitude and low frequency cortical spreading depression events to low amplitude and high frequency action potentials. The thorough description of the distortion mechanisms presented in this article demonstrates that g-SGFETs can be used as distortion-free signal transducers not only for neural sensing, but also for a broader range of applications in which g-SGFET sensors are used.

Bias dependent variability of low-frequency noise in single-layer graphene FETs.

Low-frequency noise (LFN) variability in graphene transistors (GFETs) is for the first time researched in this work under both experimental and theoretical aspects. LFN from an adequate statistical sample of long-channel solution-gated single-layer GFETs is measured in a wide range of operating conditions while a physics-based analytical model is derived that accounts for the bias dependence of LFN variance with remarkable performance. LFN deviations in GFETs stem from the variations of the parameters of the physical mechanisms that generate LFN, which are the number of traps (N tr) for the carrier number fluctuation effect (ΔN) due to trapping/detrapping process and the Hooge parameter (α H) for the mobility fluctuations effect (Δµ). ΔN accounts for an M-shape of normalized LFN variance versus gate bias with a minimum at the charge neutrality point (CNP) as it was the case for normalized LFN mean value while Δµ contributes only near the CNP for both variance and mean value. Trap statistical nature of the devices under test is experimentally shown to differ from classical Poisson distribution noticed at silicon-oxide devices, and this might be caused both by the electrolyte interface in GFETs under study and by the premature stage of the GFET technology development which could permit external factors to influence the performance. This not fully advanced GFET process growth might also cause pivotal inconsistencies affecting the scaling laws in GFETs of the same process.

Subsidized pharmacological treatment for smoking cessation by the Spanish public health system: A randomized, pragmatic, clinical trial by clusters.

INTRODUCTION: Research has shown that financing drug therapy increases smoking abstinence rates, although most of these studies have been carried out in the private healthcare setting. The aim of this work is to assess the effect of subsidized pharmacological treatment on smoking cessation rates by the Spanish public healthcare system. METHODS: A pragmatic, randomized, clinical trial was performed by clusters. Randomization unit was the primary healthcare center and the analysis unit was the patient. Smokers consuming ≥10 cigarettes/day were randomly assigned to an intervention group that received financed pharmacological treatment or to a control group that followed usual care. The main outcome was self-reported or CO-confirmed continuous abstinence at 12 months. The main outcome, continuous abstinence rates (%), were compared between groups at 12 months post-intervention. A model was adjusted using mixed-effect logistic regression. RESULTS: A total of 1154 patients were included from 23 healthcare centers. In the intention-to-treat analysis, self-reported abstinence after 12 months in the control and intervention groups, respectively, was 9.6% (37/387) and 15.4% (118/767) (gender-adjusted OR=1.75; 95% CI: 1.1-2.8); for CO-confirmed abstinence the corresponding values were 3.1% (12/387) and 6.4% (49/767) (gender-adjusted OR=1.72; 95% CI: 0.7-4.0). Pharmacological treatment use was 35.1% (136/387) in the control group, and 58.3% (447/767) in the intervention group (adjusted OR=4.25; 95% CI: 1.8-9.9). CONCLUSIONS: Subsidizing pharmacological treatment for smoking cessation increases self-reported or CO-confirmed abstinence rates under realistic conditions in the primary care setting of the Spanish public health system.