New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN.

Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels. Unique complements of coexpressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intracellular concentrations of ions, mainly Na+, K+, and Cl-, and their passive permeation across the cell membrane through leak ion channels. Indeed, dysregulation of RMP causes significant effects on cellular excitability. This review describes the molecular and physiological properties of the Na+ leak channel NALCN, which associates with its accessory subunits UNC-79, UNC-80, and NLF-1/FAM155 to conduct depolarizing background Na+ currents in various excitable cell types, especially neurons. Studies of animal models clearly demonstrate that NALCN contributes to fundamental physiological processes in the nervous system including the control of respiratory rhythm, circadian rhythm, sleep, and locomotor behavior. Furthermore, dysfunction of NALCN and its subunits is associated with severe pathological states in humans. The critical involvement of NALCN in physiology is now well established, but its study has been hampered by the lack of specific drugs that can block or agonize NALCN currents in vitro and in vivo. Molecular tools and animal models are now available to accelerate our understanding of how NALCN contributes to key physiological functions and the development of novel therapies for NALCN channelopathies.

Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study.

PURPOSE: To determine the effectiveness and safety outcomes of cenobamate in a cohort of patients with highly refractory focal epilepsy in routine clinical practice. METHODS: Observational, retrospective, phase 4 study on subjects receiving cenobamate in three Spanish centers. The primary endpoint was the retention rate at the last follow-up. The main secondary endpoints were the 50%-responder  and seizure-free rates at three months and the last follow-up. Other secondary endpoints were Global Clinical Impressions-Improvement (CGI-I) scores and treatment-emergent adverse events (TEAEs). RESULTS: Fifty-one patients with highly refractory focal epilepsy with 24.7 years of disease evolution, ten previously tried ASM, and a 23.5% of previous epilepsy surgery were included. The retention rate at the last follow-up was 80.4%. The 50% responder rate in focal seizures at three months was 56.5% (median reduction per month 51%, 0-74.6; p < 0.0001) and in focal to bilateral tonic-clonic seizures was 63.6% (median reduction per month 89%, 0-100; p = 0.022). A total of 54.3% of subjects reported a reduction in the intensity of focal seizures, and 66% manifested clinically significant satisfaction. Cenobamate allowed a significant decrease in concomitant ASM, especially sodium channel blockers. TEAEs were reported in 43.1% of individuals, 85% of whom resolved or improved, with no new safety findings. CONCLUSION: In this analysis of patients with highly refractory focal epilepsy treated with cenobamate according to standard clinical practice, there was evidence of a high reduction in both seizure frequency and intensity, with a manageable safety profile.

Reliability and agreement of the timed up and go test in children and teenagers with autism spectrum disorder.

ASD patients include a variety of motor deficits; however, these issues have received less scientific attention than other ASD symptoms. Due to understanding and behavioral difficulties, it might be difficult to administer motor assessment measures to children and adolescents with ASD. To evaluate motor challenges in this population, including gait and dynamic balance issues, the timed up and go test (TUG) may be a simple, easy to apply, quick, and inexpensive tool. This test measures in seconds the time it takes for an individual to get up from a standard chair walk 3 m, turn around, walk back to the chair, and sit down again. The study purpose was to evaluate the inter- and intra-rater reliability of TUG test in children and teenagers with ASD. A total of 50 children and teenagers with ASD (43 boys and 7 girls) between 6 and 18 years were included. Reliability was verified by the intraclass correlation coefficient, standard error of measurement, and minimum detectable change. The agreement was analyzed by the Bland-Altman method. A good intra-rater reliability (ICC = 0.88; 95% CI = 0.79-0.93) and an excellent inter-rater reliability (ICC = 0,99; 95% CI = 0.98 to 0.99) were observed. Additionally, Bland-Altman plots demonstrated that there was no evidence of bias in either the replicates or between examiners. Furthermore, the limits of agreement (LOAs) between the testers and test replicates were close, indicating that there was little variation between measurements.       Conclusions: The test TUG showed strong intra- and inter-rater reliability values, low proportion of measurement errors, and lack of significant bias based on by test repetition in children and teenagers with ASD. These results could be clinically useful for assessing balance and the risk of falls in children and teenagers with ASD. However, the present study is not free of limitations, such as the use of a non-probabilistic sampling. What is Known: • People with ASD have a variety of motor deficits that have a prevalence rate almost as common as intellectual disability. In our knowledge, there are no studies that provide data on the reliability of the use of scales or assessment tests in children and adolescents with ASD to measure motor difficulties, such as gait and dynamic balance, in children and teenagers with ASD. • Timed up and go test (TUG) could be a possible tool to measure this motor skills. What is New: • The reliability and agreement of the Timed up and go test in 50 children and teenagers with autism spectrum disorder showed strong intra- and inter-rater reliability values, low proportion of measurement errors, and lack of significant bias based on by test repetition.

Nintendo Switch Joy-Cons' Infrared Motion Camera Sensor for Training Manual Dexterity in People with Multiple Sclerosis: A Randomized Controlled Trial.

BACKGROUND: The Nintendo Switch® (NS) is the ninth video game console developed by Nintendo®. Joy-Cons® are the primary game controllers for the NS® video game console, and they have an infrared motion camera sensor that allows capturing the patient's hands without the need to place sensors or devices on the body. The primary aim of the present study was to evaluate the effects of the NS®, combined with a conventional intervention, for improving upper limb (UL) grip muscle strength, coordination, speed of movements, fine and gross dexterity, functionality, quality of life, and executive function in multiple sclerosis (MS) patients. Furthermore, we sought to assess satisfaction and compliance levels. METHODS: A single-blinded, randomized clinical trial was conducted. The sample was randomized into two groups: an experimental group who received treatment based on Dr Kawashima's Brain Training® for the NS® (20 min) plus conventional rehabilitation (40 min), and a control group who received the same conventional rehabilitation (60 min) for the ULs. Both groups received two 60 min sessions per week over an eight-week period. Grip strength, the Box and Blocks Test (BBT), the Nine Hole Peg Test (NHPT), the QuickDASH, the Multiple Sclerosis Impact Scale (MSIS-29), the Trail Making Test (TMT), and the Stroop Color and Word Test (SCWT) were used pre- and post-treatment. Side effects and attendance rates were also recorded. RESULTS: Intragroup analysis showed significant improvements for the experimental group in the post-treatment assessments for grip strength in the more affected side (p = 0.033), the BBT for the more (p = 0.030) and the less affected side (p = 0.022), the TMT (A section) (p = 0.012), and the QuickDASH (p = 0.017). No differences were observed for the control group in intragroup analysis, but they were observed in the NHPT for the more affected side (p = 0.012). The intergroup analysis did not show differences between both groups. CONCLUSIONS: Our results show that an eight-week experimental protocol, after using Dr Kawashima's Brain Training® and the right-side Joy-Con controller for the NS®, combined with a conventional intervention, showed improvements in grip strength, coordination, fine and gross motor function, executive functions, and upper limb functionality in the experimental group. However, no differences were observed when both groups were compared in the intergroup analysis. The addition of Brain Training® for the NS® for the upper limb rehabilitation did not show side effects and was rated with a high satisfaction and excellent compliance in people with MS. TRIAL REGISTRATION: This randomized controlled trial has been registered at ClinicalTrials Identifier: NCT04171908, November 2019.

2D Nanosheets-A New Class of Therapeutic Formulations against Cancer.

Researchers in cancer nanomedicine are exploring a revolutionary multifaceted carrier for treatment and diagnosis, resulting in the proposal of various drug cargos or "magic bullets" in this past decade. Even though different nano-based complexes are registered for clinical trials, very few products enter the final stages each year because of various issues. This prevents the formulations from entering the market and being accessible to patients. In the search for novel materials, the exploitation of 2D nanosheets, including but not limited to the highly acclaimed graphene, has created extensive interest for biomedical applications. A unique set of properties often characterize 2D materials, including semiconductivity, high surface area, and their chemical nature, which allow simple decoration and functionalization procedures, structures with high stability and targeting properties, vectors for controlled and sustained release of drugs, and materials for thermal-based therapies. This review discusses the challenges and opportunities of recently discovered 2D nanosheets for cancer therapeutics, with special attention paid to the most promising design technologies and their potential for clinical translation in the future.

Does the Country Make a Difference in Impulse Control Disorders? A Systematic Review.

BACKGROUND: Impulse control disorders (ICDs) have an increased frequency in patients with Parkinson's disease (PD), mainly because of treatment with dopamine agonists (DA). Factors related with the country of origin (culture, economy, healthcare politics) may impact phenomenology. OBJECTIVES: To explore phenomenology of ICDs depending on the country. METHODS: A systematic review following PRISMA guidelines was performed using Pubmed database. Articles published up to 2018 in which the prevalence of ICDs was analyzed were selected. RESULTS: Thirty-two studies from 22 countries worldwide were included. The highest prevalence of ICDs in each continent was found in UK (59%), USA (39.1%) and India (31.6%). Frequency of ICDs was higher in those studies with lower mean age, higher proportion of males, whenever a screening instrument was used and whenever prescription of DAs was more common. Prevalence of ICDs was higher in Western countries compared to Asian countries (20.8% vs. 12.8%, P < 0.001) as it was the proportion of patients treated with DAs (66% vs. 48.2%, P < 0.001). Hypersexuality was the most common ICD overall (up to 23.8%). The highest frequencies of compulsive buying and eating were found in Western countries. Gambling was less commonly diagnosed, but prevalence was relevant Japan (14%). CONCLUSION: We observed a tendency towards a different ICD profile in different geographical areas, which may be attributable to socio-economical, cultural or political influences in the phenomenology of these disorders. Acknowledging these differences could help their early detection, which is critical for prognosis.

Malignant Left Atrial Appendage Morphology: Current Classification vs H-L System.

INTRODUCTION: In previous studies the risk of stroke recurrence has been associated with the left atrial appendage (LAA) morphology (non-chicken wing (NCW)), knowing those with a greater risk as malignant LAA. Recently, a simpler morphological classification has been suggested with two categories: Low-risk (LAA-L) and High-risk (LAA-H); which could be easier to apply and may correlate better with the risk of embolic stroke. METHODS: Retrospective analysis from a registry of patients with recurrent cardioembolic strokes despite appropriate anticoagulant therapy, in which LAA morphology was studied with cardiac CT scan. LAA morphology was classified according to the four current categories and H-L morphology by the same cardiologist. Other variables associated with a high risk of stroke were also assessed, such as CHA2DS2-VASc score and left atrial (LA) size. RESULTS: Twenty-six cases were included in the analysis. We identified 22 (84.6%) chicken wing (CW), 1 (3.8%) windsock and 3 (11.5%) cactus by the current classification system, while 15 (57.7%) were classified as LAA-H and 11 (42.3%) as LAA-L by the new system. Half of the 22 cases with CW morphology were considered LAA-H, whereas all NCW were also classified as LAA-H. LA diameter and area were significantly higher in cases with LAA-H morphology (p=0.03 and 0.014), and also in those CW and LAA-H, compared to those CW with LAA-L (p=0.035). CONCLUSIONS: With this new classification system more than half of the cases of our malignant LAAs were classified as high-risk morphology. This morphology was also associated with an increased LA size.

Antifungal biomaterial for reducing infections caused by Candida albicans in edentulous patients.

INTRODUCTION: Polymethylmethacrylate (PMMA) acrylic resins are used to make dentures for edentulous patients. OBJECTIVE: To find out the prevalence of Candida species in patients with and without removable prostheses from a dental clinic in León, Guanajuato, as well as to assess the antifungal effect and biological behavior of an experimental PMMA with silver nanoparticles for its possible application in prostheses. METHOD: To identify Candida species, smear samples were obtained from the palatal mucosa of 140 patients aged ≥ 60 years. The experimental PMMA with silver nnoparticles was placed in Candida albicans cultures, which were stained with the Live/Dead® kit for analysis under confocal microscopy; subsequently, it was implanted in Wistar rats in order to know its behavior in the surrounding tissues. RESULTS: Candida albicans was the most prevalent species in the evaluated patients, followed by Candida tropicalis and Candida krusei. The acrylic resin with silver nanoparticles significantly decreased the presence of Candida albicans. In the animal model, a discrete and controlled inflammatory reaction was found, which indicated biocompatibility of the acrylic resin that was used. CONCLUSIONS: It is possible for the nanostructured material with antifungal effect to be used in order to promote the reduction of oral Candida infections in edentulous patients.

INTRODUCCIÓN: Las resinas acrílicas de polimetilmetacrilato (PMMA) son utilizadas para elaborar dentaduras para pacientes edéntulos. OBJETIVO: Conocer la prevalencia de las especies de Candida en pacientes con y sin prótesis removibles de una clínica de odontología en León, Guanajuato; así como valorar el efecto antifúngico y el comportamiento biológico de un PMMA experimental con nanopartículas de plata para su posible aplicación en prótesis. MÉTODO: Para identificar las especies de Candida se obtuvieron muestras para frotis de la mucosa palatina de 140 pacientes con edad ≥ 60 años. El PMMA experimental con nanopartículas de plata fue colocado en cultivos de Candida albicans, los cuales fueron teñidos con el kit Live/Dead® para su análisis bajo microscopia confocal; posteriormente, se implantó en ratas Wistar para conocer su comportamiento en los tejidos circundantes. RESULTADOS: Candida albicans fue la especie más prevalente en los pacientes valorados, seguida de Candida tropicalis y Candida krusei. La resina acrílica con nanopartículas de plata disminuyó significativamente la presencia de Candida albicans. En el modelo animal se encontró reacción inflamatoria discreta y controlada, lo cual indicó la biocompatibilidad de la resina acrílica utilizada. CONCLUSIONES: Es posible utilizar el material nanoestructurado con efecto antifúngico para promover la reducción de infecciones orales por Candida en pacientes edéntulos.

Toxicity and antimicrobial effect of silver nanoparticles in swine sperms.

Bacterial contamination in swine semen affects the quality and longevity of sperm and consequently fertility is reduced. Antibiotics have been used to prevent bacterial growth, but the frequency of bacterial resistance to various antibiotics are increasing. Silver nanoparticles (AgNPs) of 10-20 nm in size have shown a biocide effect in bacteria and fungi microorganisms without toxicity to certain mammalian cells. The goal of this study was to analyze both, antimicrobial activity against Staphylococcus aureus and toxicity in swine sperms after 10-20 nm AgNPs treatment. S. aureus proliferation decreased when concentrations from 0.4 to 10 mM AgNPs were assayed. Also, sperm viability measured by mitochondrial metabolism after AgNPs treatment up to a concentration of 10 mM, was viable. In addition, viability determined by membrane integrity of sperms showed that AgNPs treatment up to a concentration of 10 mM was safe. Sperm morphology was evaluated by automated quantification of proximal and distal drops and whiptails. Data indicated that AgNPs treatment up to a concentration of 4 mM were harmless. Finally, sperm capacitation and acrosome reactions were determined by (chlortetracycline) CTC assay. Data showed that no changes in sperm capacitation were observed when sperms were treated with 2 mM of AgNPs, but data showed increased calcium mobilization when treated with 10 mM AgNPs, which suggested sperm capacitation. Finally, there were no significant changes encountered on sperm acrosome reaction for any of the treatments after AgNPs treatment. Taken together, these results show the potential of AgNPs as an alternative to conventional antimicrobial agents that are currently used in extenders to preserve semen required for storage. ABBREVIATIONS: AgNPs: silver nanoparticles; AMK: amikacin; AMP: adenosine monophosphate; AR: acrosome reaction; C: capacitation; CF: cefallotin; CFU: colony-forming unit; CTC: chlortetracycline; CXM: cefuroxime; DMSO: dimethyl sulfoxide; NC: non-capacitation; NOM: Norma Oficial Mexicana; PBS: phosphate buffered saline; RLUs: relative light units; ROS: reactive oxygen species; SQS: Seminal Quality System.

Cardioembolic acute cerebral micro-infarcts in the context of atrial fibrillation after low-dose intravenous infusion of lacosamide.

Lacosamide (LCM) is a well-tolerated and increasingly used second-generation AED, and side effects such as atrial fibrillation are rare and poorly characterized. Supported by a literature review, we share our experience of the management of the first reported case of cardioembolic cerebral infarcts in the context of de novo atrial fibrillation, which appeared following a 200-mg intravenous infusion of LCM for the treatment of non-convulsive status epilepticus. Case report and literature review using search items including "atrial fibrillation OR atrial flutter AND LCM" in the thesaurus of Medline. We found three cases of atrial fibrillation/atrial flutter secondary to LCM, one following a 200-mg intravenous infusion. In one patient, previous risk factors for atrial fibrillation were reported and another was started on warfarin; all required suspension of LCM for cessation of atrial fibrillation. Previous risk factors for atrial fibrillation in our patient were older age, male gender, obesity, hypertension, valvular disease, first-degree atrioventricular block and left anterior fascicle block. Atrial fibrillation appeared at the end of the infusion and ceased after a loading dose of amiodarone and suspension of LCM. Apixaban was initiated indefinitely five days later, and MRI showed four acute silent infarctions. The appearance of atrial fibrillation has severe therapeutic and clinical implications and the use of LCM might be reconsidered within a context of increased predisposition to developing atrial fibrillation. If atrial fibrillation appears, the drug should be discontinued and anticoagulation should be considered according to embolic risk. Further investigation is needed in order to better categorize the risk profile of lacosamide regarding atrial fibrillation.

Economic consequences of over-diagnosis of threatened preterm labor.

OBJECTIVE: To investigate whether adherence to a cervical length-based protocol can reduce both unnecessary admissions and the socioeconomic costs associated with inappropriately admitted patients. METHODS: The present retrospective observational study included women admitted for threatened preterm labor (TPL) at 24-34 weeks of pregnancy to a tertiary hospital in the Canary Islands, 2009-2014. Data were reviewed from all patients admitted for TPL. Those with a long cervix (>25 mm) were classified as "inappropriate admissions", and both the economic burden based on diagnosis-related group (DRG) and the social costs associated with sick leave for these women were calculated. RESULTS: During the 6-year study period, 430 women were admitted for TPL. The rate of inappropriate hospital admissions was 45% in the first year, but was reduced to 23% in the final year (P<0.001); the premature delivery rates in these years did not differ (P=0.224). The mean DRG-based cost of the admission per patient with a long cervix was EU euros €2099. The total annual costs from inappropriate admission (both social security sick leave costs and hospital costs) were estimated to be up to €571 047.37 during the 6-year study period, and reduced from €60 420.76 in 2009 to €29 998.04 in 2014. CONCLUSION: Reductions in inappropriate admissions from applying cervical length-based management protocol could reduce healthcare costs without increasing the incidence of premature delivery.

ECCE Toolkit: Prototyping Sensor-Based Interaction.

Building and exploring physical user interfaces requires high technical skills and hours of specialized work. The behavior of multiple devices with heterogeneous input/output channels and connectivity has to be programmed in a context where not only the software interface matters, but also the hardware components are critical (e.g., sensors and actuators). Prototyping physical interaction is hindered by the challenges of: (1) programming interactions among physical sensors/actuators and digital interfaces; (2) implementing functionality for different platforms in different programming languages; and (3) building custom electronic-incorporated objects. We present ECCE (Entities, Components, Couplings and Ecosystems), a toolkit for non-programmers that copes with these issues by abstracting from low-level implementations, thus lowering the complexity of prototyping small-scale, sensor-based physical interfaces to support the design process. A user evaluation provides insights and use cases of the kind of applications that can be developed with the toolkit.

Giving meaning to tweets in emergency situations: a semantic approach for filtering and visualizing social data.

In this paper, we propose a semantic approach for monitoring information published on social networks about a specific event. In the era of Big Data, when an emergency occurs information posted on social networks becomes more and more helpful for emergency operators. As direct witnesses of the situation, people share photos, videos or text messages about events that call their attention. In the emergency operation center, these data can be collected and integrated within the management process to improve the overall understanding of the situation and in particular of the citizen reactions. To support the tracking and analyzing of social network activities, there are already monitoring tools that combine visualization techniques with geographical maps. However, tweets are written from the perspective of citizens and the information they provide might be inaccurate, irrelevant or false. Our approach tries to deal with data relevance proposing an innovative ontology-based method for filtering tweets and extracting meaningful topics depending on their semantic content. In this way data become relevant for the operators to make decisions. Two real cases used to test its applicability showed that different visualization techniques might be needed to support situation awareness. This ontology-based approach can be generalized for analyzing the information flow about other domains of application changing the underlying knowledge base.

Designing Mobile Applications for Emergency Response: Citizens Acting as Human Sensors.

When an emergency occurs, citizens can be a helpful support for the operation centers involved in the response activities. As witnesses to a crisis, they initially can share updated and detailed information about what is going on. Moreover, thanks to the current technological evolution people are able to quickly and easily gather rich information and transmit it through different communication channels. Indeed, modern mobile devices embed several sensors such as GPS receivers, Wi-Fi, accelerometers or cameras that can transform users into well-equipped human sensors. For these reasons, emergency organizations and small and medium enterprises have demonstrated a growing interest in developing smart applications for reporting any exceptional circumstances. In this paper, we present a practical study about this kind of applications for identifying both limitations and common features. Based on a study of relevant existent contributions in this area and our personal direct experience in developing and evaluating emergency management solutions, our aim is to propose several findings about how to design effective and efficient mobile emergency notification applications. For this purpose we have exploited the basic sensors of modern mobile devices and the users' aptitude for using them. The evaluation consists of a practical and a theoretical part. In the practical part, we have simulated a traffic accident as closely as possible to a real scenario, with a victim lying on the ground near a car in the middle of a street. For the theoretical part, we have interviewed some emergency experts for collecting their opinions about the utility of the proposed solution. Results from this evaluation phase confirm the positive impact that EN application have for both operators' and citizens' perspective. Moreover, we collected several findings useful for future design challenges in the same area, as shown in the final redesign of the proposed application.

Personalized alert notifications and evacuation routes in indoor environments.

The preparedness phase is crucial in the emergency management process for reaching an adequate level of readiness to react to potential threats and hazards. During this phase, emergency plans are developed to establish, among other procedures, evacuation and emergency escape routes. Information and Communication Technologies (ICT) can support and improve these procedures providing appropriate, updated and accessible information to all people in the affected zone. Current emergency management and evacuation systems do not adapt information to the context and the profile of each person, so messages received in the emergency might be useless. In this paper, we propose a set of criteria that ICT-based systems could achieve in order to avoid this problem adapting emergency alerts and evacuation routes to different situations and people. Moreover, in order to prove the applicability of such criteria, we define a mechanism that can be used as a complement of traditional evacuation systems to provide personalized alerts and evacuation routes to all kinds of people during emergency situations in working places. This mechanism is composed by three main components: CAP-ONES for notifying emergency alerts, NERES for defining emergency plans and generating personalized evacuation routes, and iNeres as the interface to receive and visualize these routes on smartphones. The usability and understandability of proposed interface has been assessed through a user study performed in a fire simulation in an indoor environment. This evaluation demonstrated that users considered iNeres easy to understand, to learn and to use, and they also found very innovative the idea to use smartphones as a support for escaping instead of static signals on walls and doors.

Novel nucleotide triphosphates as potent P2Y2 agonists with enhanced stability over UTP.

The synthesis of a series of novel C-linked nucleotide triphosphates is reported. These exhibit excellent agonist potency and selectivity for the P2Y2 receptor with a number of examples having EC50 values below 10 nM. Representative compounds from the N-linked and C-linked series showed enhanced metabolic stability compared with that of the natural ligand UTP.

Truffle aroma analysis by headspace solid phase microextraction.

An experimental design has been used to optimize the extraction of volatile compounds from summer truffle aroma (Tuber aestivum) by using headspace solid phase microextraction. The extracted compounds have been analyzed by gas chromatography with a flame ionization detector and by gas chromatography-mass spectrometry (GC-MS). In an attempt to develop an objective method to fully characterize truffle aroma, a fiber of medium polarity (for flavors) was used to avoid discrimination toward very nonpolar and polar volatile compounds. To optimize the extraction conditions, a response surface experimental design was applied considering three factors such as extraction temperature, equilibrium time, and extraction time. From the statistical analysis of the experimental design, it was possible to determine that the most important factor influencing the abundance of aroma compounds was the extraction temperature. Optimal extraction temperature was established at approximately 50 degrees C. By using GC-MS, it was possible to identify 37 compounds, most of them previously described as responsible for truffle aroma.