The mechanisms of febrile seizure (FS) induction are unresolved; however, there is evidence of a strong genetic component, based on analysis of families, twin studies, and genome-wide analyses. Notably, FS are common and generally benign; in some children, they can be a central clinical feature of genetic epilepsy. In particular, FS are strongly associated with epilepsy-linked ion-channel genes, namely SCN1A, SCN1B, HCN1, and some GABAA-receptors. Additionally, recent genome-wide association studies have identified SCN1A, SCN2A, and GABRG2 as significant contributors to FS risk. Subsets of ion channel genes where FS are present but not a central clinical feature have also been identified. We discuss these genes, their associated clinical phenotypes, and insights into the molecular, cellular, and network mechanisms. A discussion on potential febrile-mediated mechanisms is presented aiming to identify converging principles. Association of FS with SCN1A, which encodes the major GABAergic neuron sodium channel, and certain GABAA-receptors, may implicate disinhibition as a common cause. However, association with other ion channel genes, where channel dysfunction is not immediately linked to disinhibition, suggests that mechanisms underlying FS are likely to be multifactorial.
Objective This meta-analysis of randomized controlled trials (RCTs) evaluates if treating sleep disturbances improves cognitive function over at least 12 weeks. Methods Multiple data sources were searched until November 1, 2021. RCTs were included if they examined the effect of an intervention (behavioral or medical) on sleep and cognition in an adult sample with sleep disturbances and had an intervention duration and follow-up of at least 12 weeks. Two independent reviewers located 3784 studies; 16 satisfied the inclusion criteria. Primary outcomes included the broad cognitive domains of visual processing, short-term memory, long-term storage and retrieval, processing speed, and reaction time. Results Most trials were conducted in participants with obstructive sleep apnea (OSA; N = 13); the most studied intervention was continuous positive airway pressure (CPAP; N = 10). All RCTs were 12 months in duration or less. The estimates of mean pooled effects were not indicative of significant treatment effect for any primary outcome. Although the interventions reduced daytime sleepiness (Hedge's g, 0.51; 95% confidence interval, 0.29–0.74; p < 0.01), this did not lead to cognitive enhancement. Conclusions Overall, there was insufficient evidence to suggest that treating sleep dysfunction can improve cognition. Further studies with longer follow-up duration and supporting biomarkers are needed.
Objectives People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from ‘First Seizure Clinics’ (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. Methods We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. Results The median age at FSC presentation was 37 years (IQR 26–53, range 18–94). Pre-existing conditions were reported by 40 %; from 32 % in the youngest group (18–30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3–6 %, most often amongst those older than 65 years (p < 0.01). Eight percent (n = 112) reported disorders in >1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. Conclusions Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.
Objectives To assess the effects of a non-admitted management pathway following emergency department (ED) presentation with suspected TIA on: 90-day stroke and ED re-presentations, overnight admission, length of stay (LOS) and costs. Methods We implemented a management pathway across an Australian regional health service (4 hospitals; 2 rural, 10,000 km²) including ED protocols followed by urgent outpatient review or telemedicine consultation to one rural hospital. Interrupted time series analysis was conducted on linked hospital administrative datasets for all ED TIA diagnoses 5 years before and 2 years after intervention (2015). We assessed whether pathway introduction was associated with immediate change (level) or subsequent rate of change (slope) in outcomes. Results There were 2031 presentations: 1,467 before, 564 after implementation. Against background declining trends, overnight admissions decreased by 12.4% (95%CI 5.0, 19.7) and total LOS decreased 6 hours (95%CI 1.5, 10.4). Hospital costs reduced by AUD683 per patient with implementation. Outpatient review occurred for 36% at median 5 days (IQR 3, 9), including 19/87 (22%) telemedicine reviews. Pathway adherence was incomplete: 29% had no specialist review. Recurrent stroke increased by 1.3/100 presentations (95%CI 0.6, 2.1) with implementation, then returned to baseline of 0.9/100. ED re-presentations rose at a significant rate after implementation (extra 1.69/100 patients re-presenting/quarter; 95%CI 0.8, 2.6) reaching 32/100. Conclusions An ED TIA management pathway designed to avoid hospital admission resulted in decreased hospital use and costs; but an initial increase in recurrent stroke and sustained rise in ED re-presentation, possibly related to delayed and incomplete follow-up.
Metal dyshomeostasis is a well-established consequence of neurodegenerative diseases and traumatic brain injury. While the significance of metals continues to be uncovered in many neurological disorders, their implication in repetitive mild traumatic brain injury remains uncharted. To address this gap, we characterised the spatial distribution of metal levels (iron, zinc and copper) using laser ablation-inductively coupled plasma-mass spectrometry, the profile of metal-binding proteins via size exclusion chromatography-inductively coupled plasma-mass spectrometry and the expression of the major iron storing protein ferritin via western blotting. Using a mouse model of repetitive mild traumatic brain injury, 3-month-old male and female C57Bl6 mice received one or five impacts (48 h apart). At 1-month following 5x TBI, iron and ferritin levels were significantly elevated in the contralateral cortex. There was a trend towards increased iron levels in the entire contralateral hemisphere and a reduction in contralateral cortical iron-binding proteins following 1x TBI. No major changes in zinc levels were seen in both hemispheres following 5x or 1x TBI, although there was a reduction in ipsilateral zinc-binding proteins following 5x TBI and a contralateral increase in zinc-binding proteins following 1x TBI. Copper levels were significantly increased in both hemispheres following 5x TBI, without changes in copper-binding proteins. This study shows for the first time that r-mTBI leads to metal dyshomeostasis, highlighting its potential involvement in promoting neurodegeneration which provides a rationale for examining the benefit of metal-targeting drugs, which have shown promising results in neurodegenerative conditions and single TBI, but have yet to be tested following r-mTBI.
The relationship between pain and depression is thought to be bidirectional and the underlying neurobiology ‘shared’ between the two conditions. However, these claims are often based on qualitative comparisons of brain regions implicated in pain or depression, while focused quantitative studies of the neurobiology of pain-depression comorbidity are lacking. Particularly, the direction of comorbidity, i.e., pain with depression vs. depression with pain, is rarely addressed. In this systematic review (PROSPERO registration CRD42020219876), we aimed to delineate brain correlates associated with primary pain with concomitant depression, primary depression with concurrent pain, and equal pain and depression comorbidity, using activation likelihood estimation (ALE) meta-analysis. Neuroimaging studies published in English until the 28th of September 2021 were evaluated using PRISMA guidelines. A total of 70 studies were included, of which 26 reported stereotactic coordinates and were analysed with ALE. All studies were assessed for quality by two authors, using the National Institute of Health Quality Assessment Tool. Our results revealed paucity of studies that directly investigated the neurobiology of pain-depression comorbidity. The ALE analysis indicated that pain with concomitant depression was associated with the right amygdala, while depression with concomitant pain was related primarily to the left dorsolateral prefrontal cortex (DLPFC). We provide evidence that pain and depression have a cumulative negative effect on a specific set of brain regions, distinct for primary diagnosis of depression vs. pain.
Background Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD. This might be because these CBD-dominant hemp products contain other bioactive compounds, including phytocannabinoids and terpenes, which may exert unique effects on epilepsy-relevant drug targets. Voltage-gated sodium (Na V ) channels are vital for initiation of neuronal action potential propagation and genetic mutations in these channels result in epilepsy phenotypes. Recent studies suggest that Na V channels are inhibited by purified CBD. However, the effect of cannabis-based products on the function of Na V channels is unknown. Methods Using automated-planar patch-clamp technology, we profile a hemp-derived nutraceutical product (NP) against human Na V 1.1–Na V 1.8 expressed in mammalian cells to examine effects on the biophysical properties of channel conductance, steady-state fast inactivation and recovery from fast inactivation. Results NP modifies peak current amplitude of the Na V 1.1–Na V 1.7 subtypes and has variable effects on the biophysical properties for all channel subtypes tested. NP potently inhibits Na V channels revealing half-maximal inhibitory concentration (IC 50 ) values of between 1.6 and 4.2 μg NP/mL. Purified CBD inhibits Na V 1.1, Na V 1.2, Na V 1.6 and Na V 1.7 to reveal IC 50 values in the micromolar range. The CBD content of the product equates to IC 50 values (93–245 nM), which are at least an order of magnitude lower than purified CBD. Unlike NP, hemp seed oil vehicle alone did not inhibit Na V channels, suggesting that the inhibitory effects of NP are independent of hemp seed oil. Conclusions This CBD-dominant NP potently inhibits Na V channels. Future study of the individual elements of NP, including phytocannabinoids and terpenes, may reveal a potent individual component or that its components interact to modulate Na V channels.
We aimed to determine whether SNP-microarray genomic testing of saliva had a greater diagnostic yield than blood for pathogenic copy number variants (CNVs). We selected patients who underwent CMA testing of both blood and saliva from 23,289 blood and 21,857 saliva samples. Our cohort comprised 370 individuals who had testing of both, 224 with syndromic intellectual disability (ID) and 146 with isolated ID. Mosaic pathogenic CNVs or aneuploidy were detected in saliva but not in blood in 20/370 (4.4%). All 20 individuals had syndromic ID, accounting for 9.1% of the syndromic ID sub-cohort. Pathogenic CNVs were large in size (median of 46 Mb), and terminal in nature, with median mosaicism of 27.5% (not exceeding 40%). By contrast, non-mosaic pathogenic CNVs were 100% concordant between blood and saliva, considerably smaller in size (median of 0.65 Mb), and predominantly interstitial in location. Given that salivary microarray testing has increased diagnostic utility over blood in individuals with syndromic ID, we recommend it as a first-tier testing in this group.
This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.
Background and Objectives While chronological age is one of the most influential determinants of post-stroke outcomes, little is known of the impact of neuroimaging-derived biological “brain age”. We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of stroke patients will be associated with cardiovascular risk factors and worse functional outcomes. Methods We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison to chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs, and a logistic regression model of favorable functional outcomes taking RBA as input. Results We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age=62.8 years, 42.0% females). T2-FLAIR radiomics predicted chronological ages (mean absolute error=6.9 years, r=0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted Odds-Ratios: 0.58, 0.76, 0.48, 0.55; all p-values<0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes. Discussion T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.
Background: In Alzheimer's disease (AD), plasma amyloid beta (Aβ)1-42 and phosphorylated tau (p-tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown. Methods: Prototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Results: The p-tau181/Aβ1-42 ratio showed the best prediction of Aβ-PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86-0.95) and in CN (AUC = 0.873; 0.80-0.94), and symptomatic (AUC = 0.908; 0.82-1.00) adults. Plasma p-tau181/Aβ1-42 ratio correlated with cerebrospinal fluid (CSF) p-tau181 (Elecsys, Spearman's ρ = 0.74, P < 0.0001) and predicted abnormal CSF Aβ (AUC = 0.816; 0.74-0.89). The p-tau181/Aβ1-42 ratio also predicted future rates of cognitive decline assessed by AIBL Preclinical Alzheimer Cognitive Composite or Clinical Dementia Rating Sum of Boxes (P < 0.0001). Discussion: Plasma p-tau181/Aβ1-42 ratio predicted both Aβ-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical AD trials.
Background: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. Methods: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). Results: There were 131 patients; the median age was 64 [53-74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12-22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1-3] versus 3 [1-6] in the patients selected with noncontrast CT+CT angiography, P=0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01-0.19]; P<0.01). Conclusions: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.
We investigated the effect of low-intensity focused ultrasound (LIFU) on gene expression related to alcohol dependence and histological effects on brain tissue. We also aimed at determining the miRNA-mRNA relationship and their pathways in alcohol dependence-induced expression changes after focused ultrasound therapy. We designed a case–control study for 100 days of observation to investigate differences in gene expression in the short-term stimulation group (STS) and long-term stimulation group (LTS) compared with the control sham group (SG). The study was performed in our Experimental Research Laboratory. 24 male high alcohol-preferring rats 63 to 79 days old, weighing 270 to 300 g, were included in the experiment. LTS received 50-day LIFU and STS received 10-day LIFU and 40-day sham stimulation, while the SG received 50-day sham stimulation. In miRNA expression analysis, it was found that LIFU caused gene expression differences in NAc. Significant differences were found between the groups for gene expression. Compared to the SG, the expression of 454 genes in the NAc region was changed in the STS while the expression of 382 genes was changed in the LTS. In the LTS, the expression of 32 genes was changed in total compared to STS. Our data suggest that LIFU targeted on NAc may assist in the treatment of alcohol dependence, especially in the long term possibly through altering gene expression. Our immunohistochemical studies verified that LIFU does not cause any tissue damage. These findings may lead to new studies in investigating the efficacy of LIFU for the treatment of alcohol dependence and also for other psychiatric disorders.
Huntington’s disease is a fatal autosomal dominant neurodegenerative disorder, characterized by neuronal cell loss, primarily in the striatum, cortex, and hippocampus, causing motor, cognitive, and psychiatric impairments. Unfortunately, no treatments are yet available to modify the progression of the disease. Recent evidence from Huntington’s disease mouse models suggests that protein phosphorylation (catalysed by kinases and hydrolysed by phosphatases) might be dysregulated, making this major posttranslational modification a potential area of interest to find novel therapeutic targets. Furthermore, environmental enrichment, used to model an active lifestyle in preclinical models, has been shown to alleviate Huntington’s disease-related motor and cognitive symptoms. However, the molecular mechanisms leading to these therapeutic effects are still largely unknown. In this study, we applied a phosphoproteomics approach combined with proteomic analyses on brain samples from pre-motor symptomatic R6/1 Huntington’s disease male mice and their wild-type littermates, after being housed either in environmental enrichment conditions, or in standard housing conditions from 4 to 8 weeks of age (n = 6 per group). We hypothesised that protein-phosphorylation dysregulations occur prior to motor onset in this mouse model, in two highly affected brain regions, the striatum and hippocampus. Furthermore, we hypothesised that these phosphoproteome alterations are rescued by environmental enrichment. When comparing 8-week-old Huntington’s disease mice and wild-type mice in standard housing conditions, our analysis revealed 229 differentially phosphorylated peptides in the striatum, compared to only 15 differentially phosphorylated peptides in the hippocampus (statistical thresholds fold discovery rate 0.05, fold change 1.5). At the same disease stage, minor differences were found in protein levels, with 24 and 22 proteins dysregulated in the striatum and hippocampus, respectively. Notably, we found no differences in striatal protein phosphorylation and protein expression when comparing Huntington’s disease mice and their wild-type littermates in enriched conditions. In the hippocampus, only four peptides were differentially phosphorylated between the two genotypes under enriched conditions, and 22 proteins were differentially expressed. Together, our data indicates that protein phosphorylation dysregulations occur in the striatum of Huntington’s disease mice, prior to motor symptoms, and that the kinases and phosphatases leading to these changes in protein phosphorylation might be viable drug targets to consider for this disorder. Furthermore, we show that an early environmental intervention was able to rescue the changes observed in protein expression and phosphorylation in the striatum of Huntington’s disease mice and might underlie the beneficial effects of environmental enrichment, thus identifying novel therapeutic targets.
Rationale The evidence base for acute post-stroke rehabilitation is inadequate and global guideline recommendations vary. Aim To define optimal early mobility intervention regimens for ischaemic stroke patients of mild and moderate severity. Hypotheses Compared to a pre-specified reference arm, the optimal dose regimen(s) will result in: more participants experiencing little or no disability (mRS 0-2) at 3 months post stroke (primary), fewer deaths at 3 months, fewer and less severe complications during the intervention period, faster recovery of unassisted walking and better quality of life at 3 months (secondary). We also hypothesise these regimens will be more cost-effective. Sample size estimates For the primary outcome, recruitment of 1300 mild and 1400 moderate participants will yield 80% power to detect a 10% risk difference. Methods and design Multi-Arm Multi-Stage Covariate-Adjusted Response-Adaptive randomised trial of mobility training commenced within 48 hours of stroke in mild (NIHSS<7) and moderate (NIHSS 8-16) stroke patient strata, with analysis of blinded outcomes at 3 (primary) and 6 months. Eligibility criteria are broad, while excluding those with severe premorbid disability (mRS >2) and haemorrhagic stroke. With four arms per stratum (reference arm retained throughout), only the single treatment arm demonstrating the highest proportion of favourable outcomes at the first stage will proceed to second stage in each stratum, resulting in a final comparison with the reference arm. Three prognostic covariates of age, geographic region and reperfusion interventions, as well as previously observed mRS0-2 responses inform the adaptive randomisation procedure. Participants randomised receive prespecified mobility training regimens (functional task-specific), provided by physiotherapists/nurses until discharge or 14 days. Interventions replace usual mobility training. Fifty hospitals in seven countries (Australia, Malaysia, United Kingdom, Ireland, India, Brazil, Singapore) are expected to participate. Summary Our novel adaptive trial design will evaluate a wider variety of mobility regimes than a traditional two arm design. The data-driven adaptions during the trial will enable a more efficient evaluation to determine the optimal early mobility intervention for patients with mild and moderate ischaemic stroke.
The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-terminal peptide residues with the receptor core. MD of VIP modelled into PAC1R predicts more transient VIP-PAC1R interactions in the receptor core, compared to VIP-VPAC1R, which may underlie the selectivity of VIP for VPAC1R over PAC1R. Collectively, our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists.
Introduction Ayahuasca is a plant-based decoction native to Amazonia, where it has a long history of use in traditional medicine. Contemporary ritual use of ayahuasca has been expanding throughout the world for mental health purposes, and for spiritual and personal growth. Although researchers have been conducting clinical trials and observational studies reporting medical and psychological benefits, most of these do not report ayahuasca’s immediate or medium-term adverse effects, so these are underrepresented in the literature. With the expansion of ayahuasca ceremonies from their traditional contexts to countries around the world, there is an important public health question regarding the risk/benefit balance of its use. Methods We used data from an online Global Ayahuasca Survey (n = 10,836) collected between 2017 and 2019 involving participants from more than 50 countries. Principal component analysis was performed to assess group effects. Logistic regression analysis was performed to test for adverse effects associated with history of ayahuasca use, clinical, context of use and spiritual effect variables. Results Acute physical health adverse effects (primarily vomiting) were reported by 69.9% of the sample, with 2.3% reporting the need for subsequent medical attention. Adverse mental health effects in the weeks or months following consumption were reported by 55.9% of the sample, however, around 88% considered such mental health effects as part of a positive process of growth or integration. Around 12% sought professional support for these effects. Physical adverse effects were related to older age at initial use of ayahuasca, having a physical health condition, higher lifetime and last year ayahuasca use, having a previous substance use disorder diagnosis, and taking ayahuasca in a non-supervised context. Mental health adverse effects were positively associated with anxiety disorders; physical health conditions; and the strength of the acute spiritual experience; and negatively associated with consumption in religious settings. Conclusions While there is a high rate of adverse physical effects and challenging psychological effects from using ayahuasca, they are not generally severe, and most ayahuasca ceremony attendees continue to attend ceremonies, suggesting they perceive the benefits as outweighing any adverse effects. Knowing what variables might predict eventual adverse effects may serve in screening of, or providing additional support for, vulnerable subjects. Improved understanding of the ayahuasca risk/benefit balance can also assist policy makers in decisions regarding potential regulation and public health responses.
Olive oil (OO) polyphenols have been shown to improve high density lipoprotein (HDL) anti-atherogenic function, thus demonstrating beneficial effects against cardiovascular risk factors. The aim of the present study was to investigate the effect of extra-virgin high polyphenol olive oil (HPOO) vs. low polyphenol olive oil (LPOO) on the capacity of HDL to promote cholesterol efflux in healthy adults. In a double blind, randomized cross-over trial, 50 participants (aged 38.5±13.9 years, 66% females) were supplemented with a daily dose (60 mL) of HPOO (320 mg/kg polyphenols) or LPOO (86 mg/kg polyphenols) for 3-weeks. Following a 2-week wash-out period, participants crossed-over to the alternate treatment. Serum HDL cholesterol efflux capacity, circulating lipids (i.e., total cholesterol (TC), triglycerides (TG), HDL, low density lipoprotein (LDL)) and anthropometrics were measured at baseline and follow-up. No significant between-group differences were observed. Furthermore, no significant changes in HDL cholesterol efflux were found within either the LPOO and HPOO treatment arms; mean changes were 0.54% (95% CI -0.29 to 1.37) and 0.10% (95% CI -0.74 to 0.94), respectively. Serum HDL increased significantly after LPOO and HPOO intake, by 0.13 mmol/L (95% CI 0.04 to 0.22) and 0.10 mmol/L (95% CI 0.02 to 0.19), respectively. A small but significant increase in LDL of 0.14 mmol/L (95% CI 0.001 to 0.28) was observed following the HPOO intervention. Our results suggest that additional research is warranted to further understand the effect of OO with different phenolic content on mechanisms of cholesterol efflux via different pathways in multi-ethnic populations with diverse diets.
Planning motor actions can improve behavioral performance; however, it can also lead to premature actions. Although the anterior lateral motor cortex (ALM) is known to be important for correct motor planning, it is currently unknown how it contributes to premature impulsive motor output. This was addressed using whole-cell voltage recordings from layer 2/3 pyramidal neurons within the ALM while mice performed a cued sensory association task. Here, a robust voltage response was evoked during the auditory cue, which was greater during incorrect premature behavior than during correct performance in the task. Optogenetically suppressing ALM during the cued sensory association task led to enhanced behavior, with fewer, and more delayed, premature responses and faster correct responses. Taken together, our findings extend the current known roles of the ALM, illustrating that ALM plays an important role in impulsive behavior by encoding and influencing premature motor output.
Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10–5; rs12211604: HR 1.16, P = 3.2 × 10–7; rs55858457: HR 0.93, P = 3.7 × 10–7; rs10271373: HR 0.90, P = 1.1 × 10–7; rs11256593: HR 1.13, P = 5.1 × 10–57; rs12588969: HR = 1.10, P = 2.1 × 10–10; rs1465697: HR 1.09, P = 1.7 × 10–128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.
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