APOE3 Christchurch modulates ß-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated ß-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.

Molecular identification and lipolytic potential of filamentous fungi isolated from residual cooking oil.

Filamentous fungi, microorganisms that develop and are located in different habitats, are considered important producers of enzymes and metabolites with potential for the biotechnology industry. The objective of this work was to isolate and identify filamentous fungi that grow in used oil. Two fungal species were characterised through their morphology and molecular identification. The DNA of each extracted strain was amplified by PCR using primers ITS1 and ITS4, obtaining sequences that were later in GenBank (NCBI). A white coloured strain (HB) with a cottony, white, hyaline morphology and irregular borders was observed; so too, a brown colony (HC) with a sandy surface, a well-defined border of beige colour in early growth until it became a dark brown colour. The identity result by homology of the sequences in the BLASTn database was 100% and 99.55%, indicating that they correspond to Cladosporiumtenuissimum and Fomitopsismeliae, respectively. Finally, the results in lipolytic activity show greater potential for Fomitopsismeliae with 0.61 U/l in residual oil. Thus, it is important to highlight the potential of this type of waste to favour the prospection of microorganisms for a sustainable alternative for future studies of biological conversion.

Are the Steps on Likert Scales Equidistant? Responses on Visual Analog Scales Allow Estimating Their Distances.

A recurring question regarding Likert items is whether the discrete steps that this response format allows represent constant increments along the underlying continuum. This question appears unsolvable because Likert responses carry no direct information to this effect. Yet, any item administered in Likert format can identically be administered with a continuous response format such as a visual analog scale (VAS) in which respondents mark a position along a continuous line. Then, the operating characteristics of the item would manifest under both VAS and Likert formats, although perhaps differently as captured by the continuous response model (CRM) and the graded response model (GRM) in item response theory. This article shows that CRM and GRM item parameters hold a formal relation that is mediated by the form in which the continuous dimension is partitioned into intervals to render the discrete Likert responses. Then, CRM and GRM characterizations of the items in a test administered with VAS and Likert formats allow estimating the boundaries of the partition that renders Likert responses for each item and, thus, the distance between consecutive steps. The validity of this approach is first documented via simulation studies. Subsequently, the same approach is used on public data from three personality scales with 12, eight, and six items, respectively. The results indicate the expected correspondence between VAS and Likert responses and reveal unequal distances between successive pairs of Likert steps that also vary greatly across items. Implications for the scoring of Likert items are discussed.

Immunoglobulin-resistant Kawasaki disease.

BACKGROUND: Kawasaki disease is a systemic vasculitis that affects small and medium-sized vessels, primarily the coronary arteries. First-line treatment includes intravenous immunoglobulin (IVIG) and acetylsalicylic acid; however, 20% do not respond adequately despite treatment. We describe a case treated with etanercept after initial IVIG failure, showing a good response. CASE REPORT: A 5-year-old female was diagnosed with classic Kawasaki disease. Echocardiography and angiotomography revealed giant and fusiform aneurysms in the coronary arteries. A first dose of IVIG therapy was administered without improvement; after the second dose, the fever persisted, so etanercept was administered, and the fever subsided. There were no new lesions in medium-caliber vessels and the previously identified coronary lesions did not progress. CONCLUSIONS: The use of etanercept in Kawasaki disease has demonstrated a clinically favorable response. Controlled clinical trials of this drug are needed to establish it as a formal therapy in cases of initial IVIG failure.

INTRODUCCIÓN: La enfermedad de Kawasaki es una vasculitis sistémica que afecta los vasos de pequeño y mediano calibre con predominio de las arterias coronarias. El tratamiento de primera línea incluye inmunoglobulina intravenosa (IGIV) y ácido acetilsalicílico; a pesar del tratamiento, el 20% de los pacientes no responden adecuadamente. Se presenta un caso tratado con etanercept debido a la falla inicial a IGIV, con buena respuesta. CASO CLÍNICO: Se trata de una paciente de 5 años de edad, a quien se diagnosticó con enfermedad de Kawasaki clásica. En ecocardiografía y angiotomografía se evidenciaron aneurismas gigantes y fusiformes en las coronarias. Se administró una primera dosis con IGIV, sin mejoría; después de la segunda dosis, la paciente persistió con fiebre, por lo que se administró etanercept, tras lo cual esta cesó. No aparecieron nuevas lesiones en vasos de mediano calibre y las lesiones coronarias previas no progresaron. CONCLUSIONES: Con el uso de etanercept se presentó una respuesta favorable clínicamente en la enfermedad de Kawasaki. Se requieren ensayos clínicos controlados con este fármaco para establecerlo como terapia formal en los casos de falla inicial a IGIV.

Evaluation of the effectiveness of non-contact respiration rate detection for post-crash care application.

The ability of emergency medical services (EMS) personnel to understand the mortality and morbidity risks associated with different injuries is critical for effective motor vehicle collision (MVC) post-crash care. Interwoven with this ability is the practice of accurate and efficient patient triage. Triage allows EMS to gain a better understanding of the physiological and physical status of a patient and their injuries, with the intention of identifying additional resources needed, potential treatment options, and the most appropriate care destination. An interactive, in-vehicle triage system, based on the Simple Triage and Rapid Treatment protocol, under development could lead to improved MVC triage accuracy and efficiency. As a component of that system, this study examines the effectiveness of using non-contact respiration rate detection technologies integrated into a vehicle cabin. The selected technologies included ultrasonic respiration detection, thermal respiration detection, and pressurebased detection which were all compared against data collected from a respiration belt. All technologies were integrated into a 2015 Ford Taurus. Testing took place inside the running vehicle and considered occupant weight, cabin temperature, occupant clothing weight, and environmental sound as experimental factors. Respiration rate was then calculated using a 30-second sliding window where the means and standard deviations were used to compare the accuracy and precision of the sensor systems across the experimental factors. The sensor type, temperature level, and sound level main effects significantly influenced the mean respiration rate. For the standard deviation of respiration rate, significant effects were found for the sensor type, sound level, and clothing weight main effects. Among the tested sensor systems, the pressure sensor was found to best match the accuracy and precision of the respiration belt. Future work should address limitations in the approach used for this proof-of-concept work.

Both reduced ovarian reserve and severe semen alterations are overrepresented in couples seeking assisted reproductive technology treatment for the first time: a cross-sectional study.

BACKGROUND: Once a mate choice decision has been made, couples that fail to reach a live birth in natural and/or intrauterine insemination (IUI) cycles will likely visit fertility clinics seeking assisted reproductive technology (ART) treatment. During the more or less prolonged period of infertility experienced, those couples with mild/moderate reproductive anomalies would have advantage over couples displaying more severe reproductive alterations in achieving a natural or IUI conception. Thus, we can expect to find a progressive increase in the proportion of couples with more severe reproductive anomalies as duration of infertility rises. In this study, we aim to ascertain whether there is an association between male and female infertility diagnoses and duration of infertility in couples seeking ART treatment for the first time. METHODS: A cross-sectional analysis of 1383 infertile couples that sought ART treatment for the first time. Forward-stepwise binary logistic regression analyses were applied to calculate exponentiated regression coefficients. RESULTS: Men suffering from any combination of oligo-, astheno-, and teratozoospermia (ACOAT) exhibited higher odds of having a duration of infertility > 2 years compared with non-ACOAT men [odds ratio (95% confidence interval): 1.340 (1.030-1.744)]. Women from ACOAT couples displaying a duration of infertility > 2 years presented shorter menstrual cycles (P ≤ 0.047) and lower antral follicular count (AFC) values (P ≤ 0.008) and serum anti-Müllerian hormone (AMH) levels (P ≤ 0.007) than women from non-ACOAT couples exhibiting > 2 years of infertility. Likewise, AFC values (P ≤ 0.013) and serum AMH levels (P ≤ 0.001) were decreased when compared with women from ACOAT couples displaying ≤ 2 years of infertility. A relative low but significant percentage of ACOAT couples displaying > 2 years of infertility stood out for their smoking habits. CONCLUSIONS: Couples consisting of ACOAT men and women with a relative low ovarian reserve are overrepresented in couples seeking ART treatment for the first time after experiencing > 2 years of infertility. This outcome leads us to develop a general hypothesis proposing that the origin of couple's infertility is a consequence of a process of positive assortative mating shaped by sexual selection forces.

Immunoglobulin-resistant Kawasaki disease / Enfermedad de Kawasaki refractaria a tratamiento con inmunoglobulina

Abstract Background: Kawasaki disease is a systemic vasculitis that affects small and medium-sized vessels, primarily the coronary arteries. First-line treatment includes intravenous immunoglobulin (IVIG) and acetylsalicylic acid; however, 20% do not respond adequately despite treatment. We describe a case treated with etanercept after initial IVIG failure, showing a good response. Case report: A 5-year-old female was diagnosed with classic Kawasaki disease. Echocardiography and angiotomography revealed giant and fusiform aneurysms in the coronary arteries. A first dose of IVIG therapy was administered without improvement; after the second dose, the fever persisted, so etanercept was administered, and the fever subsided. There were no new lesions in medium-caliber vessels and the previously identified coronary lesions did not progress. Conclusions: The use of etanercept in Kawasaki disease has demonstrated a clinically favorable response. Controlled clinical trials of this drug are needed to establish it as a formal therapy in cases of initial IVIG failure.

Resumen Introducción: La enfermedad de Kawasaki es una vasculitis sistémica que afecta los vasos de pequeño y mediano calibre con predominio de las arterias coronarias. El tratamiento de primera línea incluye inmunoglobulina intravenosa (IGIV) y ácido acetilsalicílico; a pesar del tratamiento, el 20% de los pacientes no responden adecuadamente. Se presenta un caso tratado con etanercept debido a la falla inicial a IGIV, con buena respuesta. Caso clínico: Se trata de una paciente de 5 años de edad, a quien se diagnosticó con enfermedad de Kawasaki clásica. En ecocardiografía y angiotomografía se evidenciaron aneurismas gigantes y fusiformes en las coronarias. Se administró una primera dosis con IGIV, sin mejoría; después de la segunda dosis, la paciente persistió con fiebre, por lo que se administró etanercept, tras lo cual esta cesó. No aparecieron nuevas lesiones en vasos de mediano calibre y las lesiones coronarias previas no progresaron. Conclusiones: Con el uso de etanercept se presentó una respuesta favorable clínicamente en la enfermedad de Kawasaki. Se requieren ensayos clínicos controlados con este fármaco para establecerlo como terapia formal en los casos de falla inicial a IGIV.

Pathogenic Leptospira Species Are Present in Urban Rats in Sydney, Australia.

Leptospirosis is an emerging disease among people and dogs in Sydney, Australia. However, the routes of Leptospira transmission in these cases, and in particular the possible role of rats as reservoirs of infection in Sydney, are unknown. Rats were collected within the City of Sydney Council area and their kidneys were tested for pathogenic Leptospira DNA by real-time (q)PCR. A subset of rats also had qPCR testing performed on whole blood and urine, and Microscopic Agglutination Testing (MAT) that included a panel of 10 Leptospira serovars from nine different Leptospira serogroups was performed on a subset of serum samples. Based on qPCR testing, the proportion of rats with Leptospira DNA in their kidneys was 9/111 (8.1%). qPCR testing of blood samples (n = 9) and urine (n = 4) was negative. None of the 10 serum samples tested MAT positive. A primary cluster of qPCR-positive locations was detected based on six infected rats, which partially overlapped with a previously identified cluster of canine leptospirosis cases in Sydney. These findings suggest that rats in Sydney might play a role in the transmission of leptospirosis to dogs and people. Further testing of rats in Sydney and investigation into other possible wildlife reservoirs of infection and environmental sources of leptospires are needed.

Medicinal cannabis for psychiatry-related conditions: an overview of current Australian prescribing.

Objective: Evidence is accumulating that components of the Cannabis sativa plant may have therapeutic potential in treating psychiatric disorders. Medicinal cannabis (MC) products are legally available for prescription in Australia, primarily through the Therapeutic Goods Administration (TGA) Special Access Scheme B (SAS-B). Here we investigated recent prescribing practices for psychiatric indications under SAS-B by Australian doctors. Methods: The dataset, obtained from the TGA, included information on MC applications made by doctors through the SAS-B process between 1st November 2016 and 30th September 2022 inclusive. Details included the primary conditions treated, patient demographics, prescriber location, product type (e.g., oil, flower or capsule) and the general cannabinoid content of products. The conditions treated were categorized according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR). Trends in prescribing for conditions over time were analyzed via polynomial regression, and relationships between categorical variables determined via correspondence analyses. Results: Approximately 300,000 SAS-B approvals to prescribe MC had been issued in the time period under investigation. This included approvals for 38 different DSM-5-TR defined psychiatric conditions (33.9% of total approvals). The majority of approvals were for anxiety disorders (66.7% of psychiatry-related prescribing), sleep-wake disorders (18.2%), trauma- and stressor-related disorders (5.8%), and neurodevelopmental disorders (4.4%). Oil products were most prescribed (53.0%), followed by flower (31.2%) and other inhaled products (12.4%). CBD-dominant products comprised around 20% of total prescribing and were particularly prevalent in the treatment of autism spectrum disorder. The largest proportion of approvals was for patients aged 25-39 years (46.2% of approvals). Recent dramatic increases in prescribing for attention deficit hyperactivity disorder were identified. Conclusion: A significant proportion of MC prescribing in Australia is for psychiatry-related indications. This prescribing often appears somewhat "experimental", given it involves conditions (e.g., ADHD, depression) for which definitive clinical evidence of MC efficacy is lacking. The high prevalence of THC-containing products being prescribed is of possible concern given the psychiatric problems associated with this drug. Evidence-based clinical guidance around the use of MC products in psychiatry is lacking and would clearly be of benefit to prescribers.

A Comparative Study Regarding the Impact of Covid-19 on Latin American College Students

COVID-19 has changed educational opportunities for students around the world, and, in the process, affected their lifestyle, happiness, and engagement. The present research is part of a project from six universities in different countries across Latin America to examine the impact of COVID-19 on university students. Objectives: The purpose of this study was to assess and compare the impact of COVID-19 on lifestyle changes, orientations to happiness, and student engagement among a sample of college students in Mexico, El Salvador, Colombia, the Dominican Republic, Peru, and the US. Methods: Participants were 1764 students from the six previously identified countries. Data were collected using the Student Health Behavior Inventory, the Orientations to Happiness Scale, and the University Student Engagement Inventory. Results: Student respondents were mostly female, with a median age of 22. Most reported no changes in academic performance and statistically significant changes in some lifestyle behaviors such as nutrition and physical activity. Conclusions: The global pandemic led to behavioral changes among college students in Latin America, and it affected their orientations to happiness and engagement. Institutions of higher learning are called to create opportunities for their students to reintegrate into an in-person learning environment to facilitate positive lifestyle changes for their students.

El COVID-19 ha cambiado las oportunidades educativas para los estudiantes de todo el mundo y en el proceso afectó su estilo de vida, felicidad y compromiso. La presente investigación es parte de un proyecto de seis universidades en diferentes países de América Latina para determinar el impacto de COVID-19 en estudiantes universitarios. Objetivos: El propósito de este estudio fue evaluar y comparar el impacto del COVID-19 en los cambios de estilo de vida, las orientaciones hacia la felicidad y el compromiso de los estudiantes entre una muestra de estudiantes universitarios en México, El Salvador, Colombia, República Dominicana, Perú y Estados Unidos. Métodos: Los participantes fueron 1764 estudiantes de los seis países previamente identificados. Los datos se recolectaron utilizando el Inventario de Conducta de Salud del Estudiante, la Escala de Orientaciones a la Felicidad y el Inventario de Participación de los Estudiantes Universitarios. Resultados. Los estudiantes encuestados eran en su mayoría mujeres con una edad promedio de 22 años. La mayoría informó que no hubo cambios en el rendimiento académico y cambios estadísticamente significativos en algunos comportamientos de estilo de vida, como la nutrición y la actividad física. Conclusiones: La pandemia global provocó cambios de comportamiento entre los estudiantes universitarios de América Latina y afectó sus orientaciones hacia la felicidad y su compromiso. Las instituciones de educación superior están llamadas a crear oportunidades para que sus estudiantes se reintegren en un entorno de aprendizaje en persona para facilitar cambios positivos en el estilo de vida de sus estudiantes.

Sleep disorders in university students during COVID-19: United States of America, Mexico and El Salvador / Trastornos del sueño en universitarios durante el COVID-19: Estados Unidos, México y El Salvador

Abstract Objective: The purpose of this cross-sectional study was to measure students' sleep disorders 12 months after the start of the COVID-19 pandemic. Materials and Methods: Data were collected from 693 students from three universities in El Salvador, Mexico, and the United States using the Student Health Behavior Inventory. Results: Sleep disorders were identified in the sample with those in the US reporting higher levels of sleep disorders and those in El Salvador reported the least. Differences were also observed by gender with females reporting more sleep disorders one year into the pandemic than males. Conclusions: The global pandemic related to COVID-19 has had a profound impact on the mental and physical wellbeing of students. Sudden changes in learning modalities, modifications to work schedules, and potential loss of loved ones have contributed to sleep disorders in this population group. Universities need to take steps to address the evolving needs of college students as they cope with this pandemic.

Resumen Objetivo: El propósito de este estudio transversal fue medir los trastornos de sueño de los estudiantes, 12 meses después del principio de la pandemia de COVID. Materiales y Métodos: Se recolectaron datos de 693 estudiantes de tres universidades en El Salvador, México y los Estados Unidos, utilizando el Inventario de Conducta de Salud del Estudiante. Resultados: Se identificaron síntomas de trastornos del sueño; los universitarios de EUA informaron niveles más altos de trastornos del sueño y los de El Salvador menos. También, se observaron diferencias por género, ya que las mujeres reportaron más trastornos del sueño un año después de la pandemia que los hombres. Conclusiones: La pandemia relacionada con COVID-19 ha tenido un profundo impacto en el bienestar mental y físico de los estudiantes. Los cambios repentinos en las modalidades de aprendizaje, las modificaciones en los horarios de trabajo y la posible pérdida de seres queridos han contribuido a los trastornos del sueño en este grupo poblacional. Las universidades deben tomar medidas para abordar las necesidades cambiantes de los estudiantes universitarios a raíz de la pandemia.

How long does a single oral dose of cannabidiol persist in plasma? Findings from three clinical trials.

A growing number of clinical trials (CTs) are investigating the therapeutic potential of cannabidiol (CBD), a non-intoxicating phytocannabinoid found in Cannabis sativa. These CTs often use crossover experimental designs requiring 'washout' (clearance) periods. However, the length of time CBD persists in plasma (its 'window of detection') is unclear and could be significant. Indeed, the structurally related phytocannabinoid, Δ9 -tetrahydrocannabinol (THC), has a long window of detection in plasma. We investigated the extent to which CBD and its major metabolites persist in plasma. Data from three CTs that measured plasma cannabinoid concentrations ≥7 days after administering a single oral dose of CBD were pooled. The CBD doses were as follows: CT #1: 300 mg; CT #2: 200 mg (and 10 mg THC); and CT #3: 15, 300 and 1500 mg (one per treatment session). Thirty-two participants were included in the analysis, 17 of whom (from CT #3) provided repeated measures. Overall, 0% (15 mg), 60% (200 mg), 28% (300 mg) and 100% (1500 mg) of participants had detectable concentrations (i.e., >0.25 ng·ml-1 ) of CBD in plasma ≥7 days post-treatment (some, several weeks post-treatment). A zero-inflated negative binomial mixed-effects regression analysis (R2 m = 0.44; R2 c = 0.73) predicted that, on average, a 13 day washout period would reduce plasma CBD concentrations to 'zero' (i.e., <0.25 ng·ml-1 ) if a single oral dose of 300 mg was consumed. Higher doses require longer washout periods; concomitant medications may also affect clearance. In conclusion, CBD has a long window of detection in plasma. Crossover studies involving CBD should, therefore, be conducted with caution, particularly when higher doses and/or chronic dosing regimens are used.

Differences in frequency of occurrence, event characteristics, and pre-impact vehicle kinematics between crashes, near-crashes, and single vehicle conflicts in a large-scale naturalistic driving study.

Objective: Motor vehicle crashes result in egregious personal injury, mortality, and economic cost but are relatively rare in naturalistic observations. There is, however, evidence of strong relationships between crashes and less severe (but more common) "surrogate" events (e.g., near-crashes). Despite this strong relationship, there can still be some important differences in findings when these surrogate events are investigated in lieu of, or combined with, crashes. Therefore, it is relevant to describe and quantify differences between crashes and crash-surrogate events. Consequently, the focus of this investigation was to establish how crashes and crash surrogate events in a large-scale naturalistic driving study compare in terms of frequency of occurrence, event characteristics, and pre-impact vehicle kinematics.Methods: Crashes, near-crashes, and single-vehicle conflicts (SVCs) derived from the Second Strategic Highway Research Program Naturalistic Driving Study were coded to summarize the environmental and contributing variables involved. The original coding for these events was downsized to the variables of interest, and those variables underwent recoding to simplify the coded options. Additional variables based on the kinematic characteristics for each event were also derived and analyzed. Multinomial logistic regression was used to assess the contributions of these different variables toward classification of an event as a crash, near-crash, or SVC.Results: The regression model comparing crashes with near-crashes and SVCs identified several variables that allowed differentiation between crashes and these surrogates, primarily the pre-incident maneuver of the subject vehicle and the evasive maneuver that was executed by the driver. Kinematic variables prior to event onset, however, were not predictive of event outcome.Conclusions: The results suggest that important differences exist between crashes and their near-crash surrogates, and between crashes and SVCs. These results, however, should not discourage the analysis of surrogate events, which still provide useful information in prevention and mitigation of crash circumstances. This investigation highlights how crashes are different from two types of surrogate events and provides information that may allow for more precise analysis of these surrogate events in the future.

Accuracy and precision of responses to visual analog scales: Inter- and intra-individual variability.

Visual analog scales (VASs) are gaining popularity for collecting responses in computer administration of psychometric tests and surveys. The VAS format consists of a line marked at its endpoints with the minimum and maximum positions that it covers for respondents to place a mark at their selected location. Creating the line with intermediate marks along its length was discouraged, but no empirical evidence has ever been produced to show that their absence does any good. We report a study that asked respondents to place marks at pre-selected locations on a 100-unit VAS line, first when it only had numerical labels (0 and 100) at its endpoints and then when intermediate locations (from 0 to 100 in steps of 20) were also labeled. The results show that settings are more accurate and more precise when the VAS line has intermediate tick marks: The average absolute error decreased from 3.02 units without intermediate marks to 0.82 units with them. Provision of intermediate tick marks also reduced substantially inter- and intra-individual variability in accuracy and precision: The standard deviation of absolute error decreased from 0.87 units without tick marks to 0.25 units with them and the standard deviation of signed distance to target decreased from 1.16 units without tick marks to 0.24 units with them. These results prompt the recommendation that the design of VASs includes intermediate tick marks along the length of the line.

The Long-Term Pannexin 1 Ablation Produces Structural and Functional Modifications in Hippocampal Neurons.

Enhanced activity and overexpression of Pannexin 1 (Panx1) channels contribute to neuronal pathologies such as epilepsy and Alzheimer's disease (AD). The Panx1 channel ablation alters the hippocampus's glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, Panx1-knockout (Panx1-KO) mice still retain the ability to learn, suggesting that compensatory mechanisms stabilize their neuronal activity. Here, we show that the absence of Panx1 in the adult brain promotes a series of structural and functional modifications in the Panx1-KO hippocampal synapses, preserving spontaneous activity. Compared to the wild-type (WT) condition, the adult hippocampal neurons of Panx1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and an increased proportion of multiple synaptic contacts. These modifications seem to rely on the actin-cytoskeleton dynamics as an increase in the actin polymerization and an imbalance between the Rac1 and the RhoA GTPase activities were observed in Panx1-KO brain tissues. Our findings highlight a novel interaction between Panx1 channels, actin, and Rho GTPases, which appear to be relevant for synapse stability.

Patient-Reported Symptoms in the Global Multiple System Atrophy Registry.

Background: The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver. Objectives: To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire. Methods: Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence. Results: At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%). Conclusions: Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice.

Expert-Agreed Practical Recommendations on the Use of Cladribine.

Cladribine is a disease-modifying selective immune reconstitution oral therapy for adult patients with highly active relapsing multiple sclerosis (RMS). It was approved in the USA in 2019 and in Europe in 2017, thus there are still gaps in existing guidelines for using cladribine tablets in clinical practice. Nine experts with extensive experience in managing patients with multiple sclerosis in Spain identified some of the unanswered questions related to the real-life use of cladribine tablets. They reviewed the available clinical trial data and real-world evidence, including their own experiences of using cladribine, over the course of three virtual meetings held between November 2020 and January 2021. This article gathers their practical recommendations to aid treatment decision-making and optimise the use of cladribine tablets in patients with RMS. The consensus recommendations cover the following areas: candidate patient profiles, switching strategies (to and from cladribine), managing response to cladribine and safety considerations.