Navigating through the complexities of synucleinopathies: Insights into pathogenesis, heterogeneity, and future perspectives.

The aggregation of alpha-synuclein (aSyn) represents a neuropathological hallmark observed in a group of neurodegenerative disorders collectively known as synucleinopathies. Despite their shared characteristics, these disorders manifest diverse clinical and pathological phenotypes. The mechanism underlying this heterogeneity is thought to be due to the diversity in the aSyn strains present across the diseases. In this perspective, we will explore recent findings on aSyn strains and discuss recent discoveries about Lewy bodies' composition. We further discuss the current hypothesis for aSyn spreading and emphasize the emerging biomarker field demonstrating promising results. A comprehension of these mechanisms holds substantial promise for future clinical applications. This understanding can pave the way for the development of personalized medicine strategies, specifically targeting the unique underlying causes of each synucleinopathy. Such advancements can revolutionize therapeutic approaches and significantly contribute to more effective interventions in the intricate landscape of neurodegenerative disorders.

Arsenic modifies the effect of folic acid in spina bifida prevention, a large hospital-based case-control study in Bangladesh.

BACKGROUND: Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies have been successful in reducing rates of spina bifida, some areas continue to be at higher risk because of chemical exposures. Bangladesh has high arsenic exposures through contaminated drinking water and high rates of spina bifida. This study examines the relationships between mother's arsenic exposure, folic acid, and spina bifida risk in Bangladesh. METHODS: We conducted a hospital-based case-control study at the National Institute of Neurosciences & Hospital (NINS&H) in Dhaka, Bangladesh, between December 2016 and December 2022. Cases were infants under age one year with spina bifida and further classified by a neurosurgeon and imaging. Controls were drawn from children seen at NINS&H and nearby Dhaka Shishu Hospital. Mothers reported folic acid use during pregnancy, and we assessed folate status with serum assays. Arsenic exposure was estimated in drinking water using graphite furnace atomic absorption spectrophotometry (GF-AAS) and in toenails using inductively coupled plasma mass spectrometry (ICP-MS). We used logistic regression to examine the associations between arsenic and spina bifida. We used stratified models to examine the associations between folic acid and spina bifida at different levels of arsenic exposure. RESULTS: We evaluated data from 294 cases of spina bifida and 163 controls. We did not find a main effect of mother's arsenic exposure on spina bifida risk. However, in stratified analyses, folic acid use was associated with lower odds of spina bifida (adjusted odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.25-1.00, p = 0.05) among women with toenail arsenic concentrations below the median value of 0.46 µg/g, and no association was seen among mothers with toenail arsenic concentrations higher than 0.46 µg/g (adjusted OR: 1.09, 95% CI: 0.52-2.29, p = 0.82). CONCLUSIONS: Mother's arsenic exposure modified the protective association of folic acid with spina bifida. Increased surveillance and additional preventive strategies, such as folic acid fortification and reduction of arsenic, are needed in areas of high arsenic exposure.

Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Plasma water T2 detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation.

Cerebral cavernous malformations (CCMs) are abnormal clusters of capillaries in the nervous system. This pilot study analyzed the cardiometabolic health status of individuals with familial CCMs caused by a rare mutation in the CCM1 gene (fCCM1). The aim was to compare plasma water T2 values from individuals with fCCM1 with values from metabolically unhealthy and healthy individuals with no known CCM mutations. This observational, cross-sectional study included 75 participants: 11 fCCM1 patients, 24 metabolically unhealthy and 40 metabolically healthy individuals. Plasma water T2, an early, global and practical marker of cardiometabolic health, was measured in the time domain using benchtop magnetic resonance relaxometry. The results were stratified by age (equal to or less than 45 vs. older than 45 years). Group means were compared using Welch's one-way ANOVA and post hoc Tukey-Kramer tests. Multivariable linear regression, with T2 as the outcome variable, was used to explore associations with age, gender, Hispanic ethnicity and fCCM1 status. In the younger age stratum, the fCCM1 group had a mean plasma water T2 value comparable to the metabolically healthy group (p = 0.6388), but higher than the unhealthy group (p < 0.0001). By contrast, in the older stratum, the mean plasma water T2 value for the fCCM1 group was comparable to the metabolically unhealthy group (p = 0.7819) and lower than the healthy group (p = 0.0005). Multivariable linear regression revealed that age and the interaction between age and fCCM1 status were significant predictors of T2, even after adjusting for gender and Hispanic ethnicity. Plasma water T2 shows potential as a biomarker for assessing the health status of individuals with fCCM1. Further research is needed to validate these preliminary observations and elucidate the association between CCMs and cardiometabolic health.

Composite Injection Technique With a Digital Workflow: A Pragmatic Approach for a Protruding Central Incisor Restoration.

Esthetic concerns frequently drive individuals to seek dental treatment, leading to a rising demand for minimally invasive and time-efficient procedures. The Minimal Intervention Dentistry (MID) concept, which employs dental adhesive and resin composites, offers an effective approach for enhancing esthetics while preserving natural tooth structure. This case report outlines the esthetic enhancement of a protruding maxillary right central incisor through a direct composite restoration approach, utilizing a composite injection technique with a digital workflow. A 42-year-old male patient presented with a discolored and protruding maxillary right central incisor. After declining orthodontic treatment due to time and cost constraints, the patient opted for an alternative approach. A digital wax-up was 3D printed to create a clear silicone index, enabling precise resin composite injection to achieve the desired esthetic outcome. After internal bleaching and minimal labial surface reduction, a flowable resin composite was applied freehand to the mesial-proximal surface using a curved plastic matrix manufactured universally. The composite injection technique was subsequently employed through the incisal opening of the clear silicone index to shape the labial surface and incisal edge. In order to address insufficient tooth reduction, an additional partial labial resin composite cutback was performed, ensuring minimal reduction while enhancing esthetics. This direct composite veneer restoration, combining conventional proximal surface creation with a composite injection technique utilizing a custom-made clear silicone index prepared via a digital workflow, emerged as a pragmatic solution in a case where orthodontic treatment was not preferred. Moreover, in situations of insufficient dentin preparation, additional cutback preparation and composite placement can enhance color matching with minimal reduction. The direct composite restoration, facilitated by the composite injection technique and digital workflow, effectively rectified the inclination of the protruding maxillary central incisor, highlighting the potential of this approach in addressing esthetic dental concerns. The research and clinical technique presented in this case report hold clinical importance by offering a minimally invasive and practical alternative to orthodontic treatment and conventional restorations for patients with esthetic concerns. The composite injection technique with a digital workflow preserves natural tooth structure, reduces chair time, and enhances esthetic outcomes. This approach is particularly relevant to esthetic dentistry as it addresses anterior dental malalignment and discolored teeth while prioritizing patient satisfaction and individualized care, aligning with the principles of pragmatic esthetics and MID. The potential for long-term durability and patient satisfaction makes it a valuable addition to esthetic dental practice.

Antagonistic interactions of the dinoflagellate Alexandrium catenella under simultaneous warming and acidification.

There is a concern that harmful algal bloom (HAB) species may increase under climate change. Yet, we lack understanding of how ecological interactions will be affected under ocean warming and acidification (OWA) conditions. We tested the antagonistic effects of three strains of the dinoflagellate HAB species Alexandrium catenella on three target species (the chlorophyte Tetraselmis sp., the cryptomonad Rhodomonas salina, and the diatom Thalassiosira weissflogii) at various biomass ratios between species, at ambient (16 °C and 400 µatm CO2) and OWA (20 °C and 2000 µatm CO2) conditions. In these experiments the Alexandrium strains had been raised under OWA conditions for ∼100 generations. All three non-HAB species increased their growth rate under OWA relative to ambient conditions. Growth rate inhibition was evident for R. salina and Tetraselmis sp. under OWA conditions, but not under ambient conditions. These negative effects were exacerbated at higher concentrations of Alexandrium relative to non-HAB species. By contrast, T. weissflogii showed positive growth in the presence of two strains of Alexandrium under ambient conditions, whereas growth was unaffected under OWA. Contrary to our expectations, A. catenella had a slight negative response in the presence of the diatom. These results demonstrate that Alexandrium exerts higher antagonistic effects under OWA compared to ambient conditions, and these effects are species-specific and density dependent. These negative effects may shift phytoplankton community composition under OWA conditions.

Arsenic modifies the effect of folic acid in spina bifida prevention, a large hospital-based case-control study in Bangladesh.

Background: Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies have been successful in reducing rates of spina bifida, some areas continue to be at higher risk because of chemical exposures. Bangladesh has high arsenic exposures through contaminated drinking water and high rates of spina bifida. Methods: We conducted a hospital-based case-control study at the National Institute of Neurosciences & Hospital (NINS&H) in Dhaka, Bangladesh, between December 2016 and December 2022. Cases were infants under age one year with spina bifida and further classified using data from observations by neurosurgeons and available imaging. Controls were drawn from children who presented to NINS&H or Dhaka Shishu Hospital (DSH) during the same study period. Mothers reported folic acid use during pregnancy, and we assessed folate status with serum assays. Arsenic exposure was estimated in drinking water using graphite furnace atomic absorption spectrophotometry (GF-AAS) and in toenails using inductively coupled plasma mass spectrometry (ICP-MS). Results: We evaluated data from 294 cases of spina bifida and 163 controls. We did not find a main effect of mother's arsenic exposure on spina bifida risk. However, in stratified analyses, folic acid use was associated with lower odds of spina bifida (adjusted odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.25-1.00, p = 0.05) among women with toenail arsenic concentrations below the median, and no association was seen among mothers with toenail arsenic concentrations higher than median (adjusted OR: 1.09, 95% CI: 0.52-2.29, p = 0.82). Conclusions: Mother's arsenic exposure modified the protective association of folic acid with spina bifida. Increased surveillance and additional preventive strategies, such as folic acid fortification and reduction of arsenic, are needed in areas of high arsenic exposure.

Analysing environmental opinion using highly customisable visualisation tools to understand citizens' attitudes and barriers.

Knowledge of public opinion is key to understanding citizens' attitudes towards environmental policies. However, large polls and surveys generate complex datasets from which it is not always easy to draw conclusions. In addition, tailor-made solutions for analysing public opinion face the challenge of handling too many layers of information, which can easily lead to an overwhelming user experience and impair decision-making. Service design methodologies can support the design of ad hoc visualisation tools focused on user needs. We present Op-e-nion, a case study of a visualisation tool for the analysis of public opinion regarding environmental issues, aimed at administrations and public institutions. The involvement of experts from different fields allowed for the identification of the main metrics necessary to target the least engaged socio-demographic groups as well as the barriers that limited their environmental actions. Experts also highlighted useful aspects of the design process and the final prototype to help them define more effective campaigns and policies to address social challenges and promote citizen action. An innovative step was introduced in the methodology by involving non-state actors in the evaluation of the tool, ensuring problem detection and enhancing the sustainability of the final product. Important aspects for the visualisation of multi-categorical data included simplifying the interaction with the tool while prioritising relevant information, and using highly customizable visualisations to answer specific user requirements and changing needs (i.e. analytical vs. managerial tasks). Improved visualisations of public opinion data will, in turn, better support the development of policies shaped by citizens' concerns.

Intracellular microbial rhodopsin-based optogenetics to control metabolism and cell signaling.

Microbial rhodopsin (MRs) ion channels and pumps have become invaluable optogenetic tools for neuroscience as well as biomedical applications. Recently, MR-optogenetics expanded towards subcellular organelles opening principally new opportunities in optogenetic control of intracellular metabolism and signaling via precise manipulations of organelle ion gradients using light. This new optogenetic field expands the opportunities for basic and medical studies of cancer, cardiovascular, and metabolic disorders, providing more detailed and accurate control of cell physiology. This review summarizes recent advances in studies of the cellular metabolic processes and signaling mediated by optogenetic tools targeting mitochondria, endoplasmic reticulum (ER), lysosomes, and synaptic vesicles. Finally, we discuss perspectives of such an optogenetic approach in both fundamental and applied research.

Microfluidic 3D hepatic cultures integrated with a droplet-based bioanalysis unit.

A common challenge in microfluidic cell cultures has to do with analysis of cell function without replacing a significant fraction of the culture volume and disturbing local concentration gradients of signals. To address this challenge, we developed a microfluidic cell culture device with an integrated bioanalysis unit to enable on-chip analysis of picoliter volumes of cell-conditioned media. The culture module consisted of an array of 140 microwells with a diameter of 300 m which were made low-binding to promote organization of cells into 3D spheroids. The bioanalysis module contained a droplet generator unit, 15 micromechanical valves and reservoirs loaded with reagents. Each 0.8 nL droplet contained an aliquot of conditioned media mixed with assay reagents. The use of microvalves allowed us to load enzymatic assay and immunoassay into sequentially generated droplets for detection of glucose and albumin, respectively. As a biological application of the microfluidic device, we evaluated hormonal stimulation and glucose consumption of hepatic spheroids. To mimic physiological processes occurring during feeding and fasting, hepatic spheroids were exposed to pancreatic hormones, insulin or glucagon. The droplet-based bioanalysis module was used to measure uptake or release of glucose upon hormonal stimulation. In the future, we intend to use this microfluidic device to mimic and measure pathophysiological processes associated with hepatic insulin resistance and diabetes in the context of metabolic syndrome.

Utility of a clinical risk scale to predict the requirement of advanced airway management in patients with a diagnosis of deep neck abscess.

OBJECTIVES: To analyze the clinical utility of a clinical risk scale to predict the need for advanced airway management in patients with deep neck abscess. METHODS: Observational, analytical, cross-sectional study. Patients over 18 years old, both genders, with surgical management of a deep neck abscess, between January 1st, 2015 to December 31th, 2021, who were applied the clinical risk scale (https://7-414-5-19.shinyapps.io/ClinicalRiskScore/). The sensitivity, specificity, and predictive values of the scale were calculated based on the identified clinical outcomes. A p<0.05 was considered significant. RESULTS: A sample of 213 patients was obtained, 121 (56.8%) men, of whom 50 (23.5%) required advanced airway management. Dyspnea was the variable with the most statistical weight in our study, (p=0.001) as well as the multiple spaces involvement, (p=0.001) the presence of air corpuscles, (p=0.001) compromise of the retropharyngeal space (p=0.001) and age greater than 55 years (p=0.001). Taking these data into account, were found for the clinical risk scale a sensitivity of 97% and a specificity of 65% (p=0.001, 95% CI 0.856-0.984). CONCLUSIONS: The clinical risk scale developed to predict advanced airway management in patients with a diagnosis of deep neck abscess may be applicable in our environment with high sensitivity and specificity. LEVEL OF EVIDENCE: IV.

Utility of a clinical risk scale to predict the requirement of advanced airway management in patients with a diagnosis of deep neck abscess,

Abstract Objectives To analyze the clinical utility of a clinical risk scale to predict the need for advanced airway management in patients with deep neck abscess. Methods Observational, analytical, cross-sectional study. Patients over 18 years old, both genders, with surgical management of a deep neck abscess, between January 1st, 2015 to December 31th, 2021, who were applied the clinical risk scale (https://7-414-5-19.shinyapps.io/ClinicalRiskScore/). The sensitivity, specificity, and predictive values of the scale were calculated based on the identified clinical outcomes. A p < 0.05 was considered significant. Results A sample of 213 patients was obtained, 121 (56.8%) men, of whom 50 (23.5%) required advanced airway management. Dyspnea was the variable with the most statistical weight in our study, (p = 0.001) as well as the multiple spaces involvement, (p = 0.001) the presence of air corpuscles, (p = 0.001) compromise of the retropharyngeal space (p = 0.001) and age greater than 55 years (p = 0.001). Taking these data into account, were found for the clinical risk scale a sensitivity of 97% and a specificity of 65% (p = 0.001, 95% CI 0.856-0.984). Conclusions The clinical risk scale developed to predict advanced airway management in patients with a diagnosis of deep neck abscess may be applicable in our environment with high sensitivity and specificity. Level of evidence: IV.

Atopy and Response to Omalizumab Treatment in Chronic Spontaneous Urticaria.

INTRODUCTION: The possible influence of sensitization to aeroallergens on omalizumab response in chronic spontaneous urticaria (CSU) has been insufficiently investigated. This study's aim was to investigate atopy's influence on omalizumab response in CSU patients. METHOD: Retrospective study of CSU patients followed at a Portuguese Urticaria Center of Reference and Excellence (UCARE), treated with omalizumab for at least 6 months, between 2015 and 2022. At T0, all patients underwent quantification of specific immunoglobulin E (IgE) for total extract of most prevalent aeroallergens (ImmunoCAP Thermo Fisher Scientific®) and were divided in 2 groups, according to their response to omalizumab during the first 16 weeks of treatment: responders (R) (UAS7 <7) versus partial (PR) (UAS7 = 7-15) and nonresponders (UAS7 >15). R were further classified as fast (FR) (4-6 weeks) and slow responders (SR) (12-16 weeks). Total serum IgE, circulating eosinophil, and basophil counts were compared between groups at T0. p < 0.05 was considered statistically significant (SPSS® v25.0). RESULTS: Ninety-six patients (80% female) were studied, mean age 49 ± 14 years. Median CSU duration pre-omalizumab was 3 (0.6-20) years and mean omalizumab treatment duration was 3.7 ± 2.3 years. 38 (40%) had concomitant chronic inducible urticaria and 72 (75%) angioedema. Based on positive results of the specific IgE assay, 35 patients (36%) were considered atopic. Most patients (n = 30; 86%) were sensitized to house dust mites (HDM) (Dermatophagoides farinae = 28, Dermatophagoides pteronyssinus = 27, Blomia tropicalis = 19, Lepidoglyphus destructor = 17), followed by pollens (n = 12; 34%) (mixture of grasses = 10, Olea europaea = 7, Parietaria officinalis = 6), epithelia (n = 9; 26%) (dog = 8, cat = 7), and fungi (Alternaria alternata = 4; 11%). Eight patients (23%) were monosensitized to HDM and 4 (11%) to pollens. No significant association was found between aeroallergen sensitization and CSU duration, concomitant chronic inducible urticaria, or angioedema. Atopic patients featured significantly higher levels of baseline total serum IgE than nonatopic (469 vs. 94 U/mL, respectively; p = 0.0009). Mean baseline counts of eosinophils and basophils were not significantly different between atopic and non-atopic, respectively: eosinophils (128 vs. 121/mm3) and basophils (26 vs. 28/mm3). Regarding response to omalizumab, most patients (58; 60%) were responders: FR - 46 (79%); SR - 12 (21%). There was no significant association between aeroallergen sensitization and omalizumab response or speed of response. CONCLUSIONS: As far as we know, this is the first study exploring the influence of atopy sensitization pattern on omalizumab response in CSU. According to our results, presence of atopy/sensitization pattern does not influence omalizumab response in CSU patients.

Clark's nutcracker forest community visitation: Whitebark pine maintains a keystone seed disperser.

Clark's nutcrackers (Nucifraga columbiana) are obligate seed dispersers for whitebark pine (Pinus albicaulis), but they frequently use other conifer seed resources because of annual variability in cone production or geographic variation in whitebark pine availability. Whitebark pine is declining from several threats including white pine blister rust, leading to potential population declines in the nutcracker and the pine. We hypothesize that where there are few additional seed resources, whitebark pine becomes the key and limiting resource supporting nutcracker populations. We investigated how nutcrackers use coniferous forest community types within Yellowstone National Park to determine potential seed resources and the importance of whitebark pine. We established sites representing five forest community types, including whitebark pine, lodgepole pine (P. contorta), Engelmann spruce (Picea engelmannii), limber pine (P. flexilis), and Douglas-fir (Pseudotsuga menziesii). Each transect annually generated nutcracker point counts, conifer cone production indices, community composition data, and seed resource use observations. We compared hierarchical distance sampling models, estimating nutcracker density and its relationship to forest community type, seed harvesting time-period, year, study site, and cone seed energy. We found cone production varied across years indicating annual variability in energy availability. Nutcracker density was best predicted by forest community type and survey time-period and was highest in whitebark pine stands during the mid-harvesting season. Nutcracker density was comparatively low for all other forest community types. This finding underscores the importance of whitebark pine as a key seed resource for Clark's nutcracker in Yellowstone National Park. The decline of whitebark pine potentially leads to a downward spiral in nutcrackers and whitebark pine, arguing for continued monitoring of nutcrackers and implementation of restoration treatments for whitebark pine.

Testing Geology with Biology: Plate Tectonics and the Diversification of Microhylid Frogs in the Papuan Region.

Studies of the Papuan region have provided fundamental insights into the evolutionary processes generating its exceptional biodiversity, but the influence of geological processes merits further study. Lying at the junction of five tectonic plates, this region has experienced a turbulent geological history that has not only produced towering mountains allowing elevational specialization and island archipelagos with varying degrees of isolation promoting vicariance, but also active margins where land masses have collided and been subsequently rifted apart creating a mosaic of intermixed terranes with vastly different geological histories. Asterophryine frogs are a hyperdiverse clade representing half the world's microhylid diversity (over 360 species) centered on New Guinea and its satellite islands. We show that vicariance facilitated by geological history explains this far and wide distribution of a clade that should have poor dispersal abilities. We recovered a mainland tectonic unit, the East Papua Composite Terrane (EPCT), as the center of origin for Asterophryinae and no fewer than 71 instances of what appear to be long-distance dispersal events, 29 of which are between mainland regions, with 42 from the mainland to the islands, some presently as far as 200 km away from source populations over open ocean. Furthermore, we find strong support for a "Slow and Steady" hypothesis for the formation of the northern margin of New Guinea by many separate accretion events during the Miocene, over other major geological alternatives, consistent with the 20 M year age of the clade and arrival via the EPCT. In addition, the historical biogeography of our frogs strongly supports an affiliation of the Louisiade Archipelago and Woodlark Island with the Owen Stanley Range on the EPCT, and the recent proximity of the large New Britain Island. Our results show that Asterophryinae did not have to repeatedly and independently disperse across large ocean barriers to the offshore islands, against the predictions of island biogeography theory, but that the current distribution can be explained through vicariance and short-distance oceanic dispersal as historical land connections disappeared and islands slowly became separated from each other. We show that islands have a life history, changing in distance from other land masses, with consequent opportunities for dispersal, isolation, and cladogenesis of their biotas. More broadly, we can begin to see how the geological history of the Papuan region can result in the rapid accumulation and staggering number of extant species.

Plasma water T2 detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation.

Introduction: Cerebral cavernous malformations (CCMs) are abnormal clusters of capillaries in the nervous system. This pilot study analyzed the cardiometabolic health status of individuals with familial CCMs caused by a rare mutation in the CCM1 gene (fCCM1). The aim was to compare plasma water T2 values from individuals with fCCM1 with values from metabolically unhealthy and healthy individuals with no known CCM mutations. Design: This observational, cross-sectional study included 75 participants: 11 fCCM1 patients, 24 metabolically unhealthy and 40 metabolically healthy individuals. Plasma water T2, an early, global and practical marker of cardiometabolic health, was measured in the time domain using benchtop magnetic resonance relaxometry. The results were stratified by age (equal to or less than 45 vs. older than 45 years). Group means were compared using Welch's one-way ANOVA and post hoc Tukey-Kramer tests. Multivariable linear regression, with T2 as the outcome variable, was used to explore associations with age, gender, Hispanic ethnicity and fCCM1 status. Results: In the younger age stratum, the fCCM1 group had a mean plasma water T2 value comparable to the metabolically healthy group (p=0.6388), but higher than the unhealthy group (p<0.0001). By contrast, in the older stratum, the mean plasma water T2 value for the fCCM1 group was comparable to the metabolically unhealthy group (p=0.7819) and lower than the healthy group (p=0.0005). Multivariable linear regression revealed that age and the interaction between age and fCCM1 status were significant predictors of T2, even after adjusting for gender and Hispanic ethnicity. Conclusion: Plasma water T2 shows potential as a biomarker for assessing the health status of individuals with fCCM1. Further research is needed to validate these preliminary observations and elucidate the association between CCMs and cardiometabolic health.

Millifluidic valves and pumps made of tape and plastic.

There is growing interest in producing micro- and milli-fluidic technologies made of thermoplastic with integrated fluidic control elements that are easy to assemble and suitable for mass production. Here, we developed millifluidic valves and pumps made of acrylic layers bonded with double-sided tape that are simple and fast to assemble. We demonstrate that a layer of pressure-sensitive adhesive (PSA) is flexible enough to be deformed at relatively low pressures. A chemical treatment deposited on specific regions of the PSA prevents it from sticking to the thermoplastic, which enabled us to create three different types of valves in normally open or closed configurations. We characterized different aspects of their performance, their operating pressures, the cut-off pressure values to open or close the valves (for different configurations and sizes), and the flow rate and volume pumped by seven different micropumps. As an application, we implemented a glucose assay with integrated pumps and valves, automatically generating glucose dilutions and reagent mixing. The ability to create polymeric microfluidic control units made with tape paves the way for their mass manufacturing.

Plasma water T2 detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation.

Introduction: Cerebral cavernous malformations (CCMs) are abnormal clusters of capillaries in the nervous system. This pilot study analyzed the cardiometabolic health status of individuals with familial CCMs caused by a rare mutation in the CCM1 gene (fCCM1). The aim was to compare plasma water T2 values from individuals with fCCM1 with values from metabolically unhealthy and healthy individuals with no known CCM mutations. Design: This observational, cross-sectional study included 75 participants: 11 fCCM1 patients, 24 metabolically unhealthy and 40 metabolically healthy individuals. Plasma water T2, an early, global and practical marker of cardiometabolic health, was measured in the time domain using benchtop magnetic resonance relaxometry. The results were stratified by age (≤ 45 vs. >45 years). Group means were compared using Welch's one-way ANOVA and post hoc Tukey-Kramer tests. Multivariable linear regression, with T2 as the outcome variable, was used to explore associations with age, gender, Hispanic ethnicity and fCCM1 status. Results: In the younger age stratum, the fCCM1 group had a mean plasma water T2 value comparable to the metabolically healthy group (p=0.6388), but higher than the unhealthy group (p<0.0001). By contrast, in the older stratum, the mean plasma water T2 value for the fCCM1 group was comparable to the metabolically unhealthy group (p=0.7819) and lower than the healthy group (p=0.0005). Multivariable linear regression revealed that age and the interaction between age and fCCM1 status were significant predictors of T2, even after adjusting for gender and Hispanic ethnicity. Conclusion: Plasma water T2 shows potential as a biomarker for assessing the health status of individuals with fCCM1. Further research is needed to validate these preliminary observations and elucidate the association between CCMs and cardiometabolic health.

Patient experiences of virtual care across specialist neuroscience and psychiatry clinics related to the second wave of the COVID-19 pandemic in Calgary, Alberta.

Purpose: The emergence of the COVID-19 (SARS-CoV-2) pandemic has led to public health restrictions and a shift towards virtual care and telehealth. The aim of this study was to explore barriers and facilitators of virtual care from the perspective of neurological and psychiatric patients. Methods: One-on-one interviews were conducted remotely using telephone and online video teleconferencing. There was a total of 57 participants, and a thematic content analysis was conducted using NVivo software. Results: The two main themes were (1) virtual health service delivery and (2) virtual physician/patient interaction, with subthemes around how virtual care improved accessibility of care for patients and improved patient-centered care; how privacy and technical issues impact patients using virtual care; and the need for relationality and connection between health care providers and patients while using virtual care. Conclusions: This study showed that virtual care can increase accessibility and efficiency for patients and providers, indicating its potential for ongoing use in the delivery of clinical care. Virtual care was found to be an acceptable mode of healthcare delivery from the perspective of patients; however, there is a continued need for relationship-building between care providers and patients.

Intestinal infection triggers mitochondria-mediated α-synuclein pathology: relevance to Parkinson's disease.

Parkinson's disease (PD) is a multifactorial neurodegenerative disease characterized by the loss of dopaminergic neurons in the midbrain. In the prodromal phase several autonomic symptoms including orthostatic hypotension and constipation are correlated with increased α-synuclein pathology in peripheral tissues. It is currently accepted that some idiopathic PD cases may start in the gut (body-first PD) with accumulation of pathological α-synuclein in enteric neurons that may subsequently propagate caudo-rostrally to the central nervous system. In addition to the already-established regulation of synaptic vesicle trafficking, α-synuclein also seems to play a role in neuronal innate immunity after infection. Our goal was to understand if seeding the gut with the foodborne pathogen Listeria monocytogenes by oral gavage would impact gut immunity and eventually the central nervous system. Our results demonstrate that L. monocytogenes infection induced oligomerization of α-synuclein in the ileum, along with a pronounced pro-inflammatory local and systemic response that ultimately culminated in neuronal mitochondria dysfunction. We propose that, having evolved from ancestral endosymbiotic bacteria, mitochondria may be directly targeted by virulence factors of intracellular pathogens, and that mitochondrial dysfunction and fragmentation resulting also from the activation of the innate immune system at the gut level, trigger innate immune responses in midbrain neurons, which include α-synuclein oligomerization and neuroinflammation, all of which hallmarks of PD.