Early vs late anticoagulation in acute ischemic stroke with indications outside atrial fibrillation.

BACKGROUND: Current literature lacks guidance on the safety of administering anticoagulation in acute ischemic stroke with emergent indications that require anticoagulation other than atrial fibrillation. Therefore, we tend to rely on studies investigating acute ischemic stroke in atrial fibrillation for anticoagulation recommendations. METHODS: We retrospectively reviewed data for patients with acute ischemic stroke who had a non-atrial fibrillation emergent indication for anticoagulation (e.g., intra-arterial thrombus, intracardiac thrombus, acute coronary syndrome, acute limb ischemia, deep vein thrombosis and pulmonary embolism) diagnosed within 3 days of acute ischemic stroke. Patients who received anticoagulation ≤ 3 days of stroke onset (Group A) were compared to those who either received it afterwards or did not receive it at all (Group B). RESULTS: Out of the 558 patients, only 88 patients met our inclusion criteria. Of the total cohort, 55.7 % patients were males, and basic demographics were similar in both groups except for milder strokes in Group A (national institute of health stroke scale 6 vs. 12.5, p = 0.03). Only 2 patients in Group A and 1 patient in Group B developed intracranial hemorrhage, which was not statistically significant. Group A patients had a lower incidence of both new diagnosis (2 % vs. 34.2 % %, p < 0.001) and propagation of an established venous thromboembolism. They also had a lower rate of any thromboembolic complication (2 % vs. 42 %, p < 0.001). CONCLUSION: Early anticoagulation (i.e., ≤ 3 days) in non-atrial fibrillation ischemic stroke patients with an emergent indication may be safe and carry a lower risk of thromboembolic complications than later anticoagulation.

New-onset as opposed to established atrial fibrillation as a risk factor for incident stroke.

BACKGROUND: Atrial fibrillation (AF) is an established risk factor for acute ischemic stroke (AIS). It remains unclear if new-onset AF confers a higher risk of AIS than longer-standing AF. METHODS: We retrospectively analyzed all stroke-free patients who underwent transthoracic echocardiography (TTE) in the Henry Ford Health System between March 6 and September 6, 2016. Incident AIS and new-onset AF were ascertained by the presence of new diagnostic codes in the electronic medical record over a follow-up period of up to 5 years. Cox proportional hazards regression was used to identify risk factors for new-onset AF or AIS. RESULTS: Of 7310 patients who underwent baseline TTE the mean age was 65 years, 54% were female, 51% were Caucasian, and 46% had left atrial enlargement (LAE). Of at-risk patients, 10.9% developed new-onset AF and 2.9% experienced incident AIS. The risk of new-onset AF among at-risk patients was 3.1 times higher among patients with any degree of LAE compared to those with normal LA size (95% CI 2.6-3.6, P < 0.0001). New-onset AF, more than established AF, in turn had a powerful association with incident AIS. The cumulative 5-year risk of AIS was 3.5% in those without AF, 5.9% in those with established AF prior to TTE, and 20.1% in those with new-onset AF (P < 0.0001). In multivariable analysis new-onset AF had the strongest association with incident AIS (P < 0.0001), followed by increasing age (P = 0.0025), black race (P = 0.0032), and smoking (P = 0.0063). CONCLUSIONS: New-onset AF has a strong relationship with incident AIS. LAE was present in nearly half of stroke-free patients undergoing TTE, and was associated with a significantly higher likelihood of new-onset AF during follow-up. Vigilant cardiac monitoring for AF in individuals with LAE, coupled with the timely initiation of anticoagulation, may be an important strategy for the primary prevention of AF-related stroke.

An exposure-based implementation strategy to decrease clinician anxiety about implementing suicide prevention evidence-based practices: protocol for development and pilot testing (Project CALMER).

BACKGROUND: Clinicians often report that their own anxiety and low self-efficacy inhibit their use of evidence-based suicide prevention practices, including gold-standard screening and brief interventions. Exposure therapy to reduce clinician maladaptive anxiety and bolster self-efficacy use is a compelling but untested approach to improving the implementation of suicide prevention evidence-based practices (EBPs). This project brings together an interdisciplinary team to leverage decades of research on behavior change from exposure theory to design and pilot test an exposure-based implementation strategy (EBIS) to target clinician anxiety to improve suicide prevention EBP implementation. METHODS: We will develop, iteratively refine, and pilot test an EBIS paired with implementation as usual (IAU; didactic training and consultation) in preparation for a larger study of the effect of this strategy on reducing clinician anxiety, improving self-efficacy, and increasing use of the Columbia Suicide Severity Rating Scale and the Safety Planning Intervention in outpatient mental health settings. Aim 1 of this study is to use participatory design methods to develop and refine the EBIS in collaboration with a stakeholder advisory board. Aim 2 is to iteratively refine the EBIS with up to 15 clinicians in a pilot field test using rapid cycle prototyping. Aim 3 is to test the refined EBIS in a pilot implementation trial. Forty community mental health clinicians will be randomized 1:1 to receive either IAU or IAU + EBIS for 12 weeks. Our primary outcomes are EBIS acceptability and feasibility, measured through questionnaires, interviews, and recruitment and retention statistics. Secondary outcomes are the engagement of target implementation mechanisms (clinician anxiety and self-efficacy related to implementation) and preliminary effectiveness of EBIS on implementation outcomes (adoption and fidelity) assessed via mixed methods (questionnaires, chart-stimulated recall, observer-coded role plays, and interviews). DISCUSSION: Outcomes from this study will yield insight into the feasibility and utility of directly targeting clinician anxiety and self-efficacy as mechanistic processes informing the implementation of suicide prevention EBPs. Results will inform a fully powered hybrid effectiveness-implementation trial to test EBIS' effect on implementation and patient outcomes. TRIAL REGISTRATION: Clinical Trials Registration Number: NCT05172609 . Registered on 12/29/2021.

Freely Available Training Videos for Suicide Prevention: Scoping Review.

BACKGROUND: Freely available and asynchronous implementation supports can reduce the resource burden of evidence-based practice training to facilitate uptake. Freely available web-based training videos have proliferated, yet there have been no efforts to quantify their breadth, depth, and content for suicide prevention. OBJECTIVE: This study presents results from a scoping review of freely available training videos for suicide prevention and describes a methodological framework for reviewing such videos. METHODS: A scoping review of freely available training videos (≥2 minutes) for suicide prevention practices was conducted using 4 large video-sharing platforms: YouTube, Vimeo, Bing Video, and Google Video. Identified suicide prevention training videos (N=506) were reviewed and coded. RESULTS: Most content was targeted toward gatekeepers or other lay providers (n=370) versus clinical providers (n=136). Videos most commonly provided content related to suicidal thoughts or behaviors (n=420). Many videos (n=274, 54.2%) included content designed for certain communities or organizations. Less than half (n=232, 45.8%) of training videos included formal clinical content pertaining to assessment or intervention for suicide prevention. CONCLUSIONS: Results suggested an abundance of videos providing broad informational content (eg, "signs and symptoms of someone at risk for suicide") and a limited portion of videos with instructional content aimed at clinical providers delivering formal evidence-based assessments or interventions for suicide prevention. Development of resources to address identified gaps may be needed. Future work may leverage machine learning techniques to expedite the review process.

Gender differences in transdiagnostic domains and function of adults measured by DSM-5 assessment scales at the first clinical visit: a cohort study.

BACKGROUND: Measurement-based care has been called for as best practice in psychiatric care and learning health systems and use of transdiagnostic measures was suggested as part of the DSM-5. Our objective is to examine gender differences in first visit socioeconomic, transdiagnostic, and functional characteristics of a dynamic, real-world measurement-based care cohort. METHODS: Transdiagnostic, functional, and clinical measures were collected from 3,556 patients at first visit in an ambulatory psychiatric clinic. All patients were evaluated at the first visit by board-certified psychiatrists or licensed clinical psychologists. Demographic variables and clinical diagnoses were collected from the Electronic Medical Record. Self-report measures were collected that assessed transdiagnostic symptoms (DSM-5 Level 1 Cross-cutting Measure and Level 2 symptom scales), disability, alcohol use, attention deficit hyperactivity disorder (ADHD) symptoms, depression, anxiety, mania, suicidal thoughts and behaviors, and trauma exposure. RESULTS: Men and women did not differ in age, BMI, household income, high school graduation rate, race, or ethnicity, but women were more likely to be formerly married and less likely to have commercial insurance. Compared to men, women reported significantly higher overall psychopathology on the transdiagnostic Level 1 Cross-cutting measure and had higher depression, anxiety, sleep, anger, ADHD combined presentation, and suicidality severity. Women also had higher disability scores than men. However, men reported higher alcohol, tobacco and substance use, and more risky behavior than women. Trauma exposure differed significantly by gender; men reported more exposure to accidents, war-related trauma, serious accidents, and major disasters and women reported more unwanted sexual contact. CONCLUSIONS: This cross-sectional study of a transdiagnostic, ecologically-valid real-word measurement-based care cohort demonstrates gender differences in socioeconomic factors, trauma exposure, transdiagnostic symptoms, and functioning.

Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain.

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABAARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAAR subunit composition, there was a redistribution of extrasynaptic GABAARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABAARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca2+/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.

Non-stenosing carotid artery plaques in embolic stroke of undetermined source: a retrospective analysis.

BACKGROUND: We aim to identify the association between high-risk carotid plaques and their laterality to stroke in ESUS patient population. We also discuss recurrent stroke events and their laterality to the index stroke. METHODS: This was a retrospective study. We reviewed data for patients with ESUS between June 20, 2016, and June 20, 2021. Using computed tomography angiography, we analyzed plaque features that are associated with ESUS, and then, we identified the recurrent stroke events and characterized lateralization to the index stroke. RESULTS: Out of 1779 patients with cryptogenic ischemic stroke, we included 152 patients who met the criteria for ESUS. High-risk plaque features were found more often ipsilateral to the stroke side when compared contralaterally: plaque ulceration (19.08% vs 5.26%, p < .0001), plaque thickness > 3 mm (19.08% vs 7.24%, p = 0.001), and plaque length > 1 cm (13.16% vs 5.92%, p = 0.0218). There was also a significant difference in plaque component in which both components (soft and calcified) and only soft plaques were more prevalent ipsilaterally (42.76% vs 23.68% and 17.76% vs 9.21%, respectively, p < .0001). Of the 152 patients, 17 patients were found to have a recurrent stroke event, and 47% (n = 8) had an ipsilateral stroke to the index event. Moreover, stroke was bilateral in 41% of the patients (n = 7), and contralateral in 12% (n = 2). CONCLUSION: High-risk plaque features studied here were more prevalent ipsilaterally to the stroke side in ESUS than contralaterally. Multicenter studies are needed to form precise prediction models and scoring systems to help guide treatment, i.e., choice of medical therapy and/or revascularization.

Clinician Maladaptive Anxious Avoidance in the Context of Implementation of Evidence-Based Interventions: A Commentary.

This paper posits that a clinician's own anxious reaction to delivering specific evidence-based interventions (EBIs) should be better accounted for within implementation science frameworks. A key next step for implementation science is to delineate the causal processes most likely to influence successful implementation of evidence-based interventions (EBIs). This is critical for being able to develop tailored implementation strategies that specifically target mechanisms by which implementation succeeds or fails. First, we review the literature on specific EBIs that may act as negatively valenced stimuli for clinicians, leading to a process of clinician maladaptive anxious avoidance that can negatively impact EBI delivery. In the following sections, we argue that there are certain EBIs that can cause emotional distress or discomfort in a clinician, related to either: (1) a clinicians' fear of the real or predicted short-term distress the EBI can cause patients, or (2) fears that the clinician will inadvertently cause the patient harm and/or face liability. This distress experienced by the clinician can perpetuate a cycle of maladaptive anxious avoidance by the clinician, contributing to lack of or suboptimal EBI implementation. We illustrate how this cycle of maladaptive anxious avoidance can influence implementation by providing several examples from leading EBIs in the psychosocial literature. To conclude, we discuss how leveraging decades of treatment literature aimed at mitigating maladaptive anxious avoidance can inform the design of more tailored and effective implementation strategies for EBIs that are negatively valenced.

Assessing Causal Pathways and Targets of Implementation Variability for EBP use (Project ACTIVE): a study protocol.

BACKGROUND: Advancing causal implementation theory is critical for designing tailored implementation strategies that target specific mechanisms associated with evidence-based practice (EBP) use. This study will test the generalizability of a conceptual model that integrates organizational constructs and behavioral theory to predict clinician use of cognitive-behavioral therapy (CBT) techniques in community mental health centers. CBT is a leading psychosocial EBP for psychiatric disorders that remains underused despite substantial efforts to increase its implementation. METHODS: We will leverage ongoing CBT implementation efforts in two large public health systems (Philadelphia and Texas) to recruit 300 mental health clinicians and 600 of their clients across 40 organizations. Our primary implementation outcomes of interest are clinician intentions to use CBT and direct observation of clinician use of CBT. As CBT comprises discrete components that vary in complexity and acceptability, we will measure clinician use of six discrete components of CBT. After finishing their CBT training, participating clinicians will complete measures of organizational and behavior change constructs delineated in the model. Clinicians also will be observed twice via audio recording delivering CBT with a client. Within 48 h of each observation, theorized moderators of the intention-behavior gap will be collected via survey. A subset of clinicians who report high intentions to use CBT but demonstrate low use will be purposively recruited to complete semi-structured interviews assessing reasons for the intention-behavior gap. Multilevel path analysis will test the extent to which intentions and determinants of intention predict the use of each discrete CBT component. We also will test the extent to which theorized determinants of intention that include psychological, organizational, and contextual factors explain variation in intention and moderate the association between intentions and CBT use. DISCUSSION: Project ACTIVE will advance implementation theory, currently in its infancy, by testing the generalizability of a promising causal model of implementation. These results will inform the development of implementation strategies targeting modifiable factors that explain substantial variance in intention and implementation that can be applied broadly across EBPs.

Genomic time-series data show that gene flow maintains high genetic diversity despite substantial genetic drift in a butterfly species.

Effective population size affects the efficacy of selection, rate of evolution by drift and neutral diversity levels. When species are subdivided into multiple populations connected by gene flow, evolutionary processes can depend on global or local effective population sizes. Theory predicts that high levels of diversity might be maintained by gene flow, even very low levels of gene flow, consistent with species long-term effective population size, but tests of this idea are mostly lacking. Here, we show that Lycaeides butterfly populations maintain low contemporary (variance) effective population sizes (e.g. ~200 individuals) and thus evolve rapidly by genetic drift. However, populations harboured high levels of genetic diversity consistent with an effective population size several orders of magnitude larger. We hypothesized that the differences in the magnitude and variability of contemporary versus long-term effective population sizes were caused by gene flow of sufficient magnitude to maintain diversity but only subtly affect evolution on generational timescales. Consistent with this hypothesis, we detected low but nontrivial gene flow among populations. Furthermore, using short-term population-genomic time-series data, we documented patterns consistent with predictions from this hypothesis, including a weak but detectable excess of evolutionary change in the direction of the mean (migrant gene pool) allele frequencies across populations and consistency in the direction of allele frequency change over time. The documented decoupling of diversity levels and short-term change by drift in Lycaeides has implications for our understanding of contemporary evolution and the maintenance of genetic variation in the wild.

Sustained treatment with an α5 GABA A receptor negative allosteric modulator delays excitatory circuit development while maintaining GABAergic neurotransmission.

α5 subunit GABA type A receptor (GABAAR) preferring negative allosteric modulators (NAMs) are cognitive enhancers with antidepressant-like effects. α5-NAM success in treating mouse models of neurodevelopmental disorders with excessive inhibition have led to Phase 2 clinical trials for Down syndrome. Despite in vivo efficacy, no study has examined the effects of continued α5-NAM treatment on inhibitory and excitatory synapse plasticity to identify mechanisms of action. Here we used L-655,708, an imidazobenzodiazepine that acts as a highly selective but weak α5-NAM, to investigate the impact of sustained treatment on hippocampal neuron synapse and dendrite development. We show that 2-day pharmacological reduction of α5-GABAAR signaling from DIV12-14, when GABAARs contribute to depolarization, delays dendritic spine maturation and the NMDA receptor (NMDAR) GluN2B/GluN2A developmental shift. In contrast, α5-NAM treatment from DIV19-21, when hyperpolarizing GABAAR signaling predominates, enhances surface synaptic GluN2A while decreasing GluN2B. Despite changes in NMDAR subtype surface levels and localization, total levels of key excitatory synapse proteins were largely unchanged, and mEPSCs were unaltered. Importantly, 2-day α5-NAM treatment does not alter the total surface levels or distribution of α5-GABAARs, reduce the gephyrin inhibitory synaptic scaffold, or impair phasic or tonic inhibition. Furthermore, α5-NAM inhibition of the GABAAR tonic current in mature neurons is maintained after 2-day α5-NAM treatment, suggesting reduced tolerance liability, in contrast to other clinically relevant GABAAR-targeting drugs such as benzodiazepines. Together, these results show that α5-GABAARs contribute to dendritic spine maturation and excitatory synapse development via a NMDAR dependent mechanism without perturbing overall neuronal excitability.

Impact of the COVID-19 Pandemic on Acute Stroke Care, Time Metrics, Outcomes, and Racial Disparities in a Southeast Michigan Health System.

BACKGROUND: COVID-19 has impacted acute stroke care with several reports showing worldwide drops in stroke caseload during the pandemic. We studied the impact of COVID-19 on acute stroke care in our health system serving Southeast Michigan as we rolled out a policy to limit admissions and transfers. METHODS: in this retrospective study conducted at two stroke centers, we included consecutive patients presenting to the ED for whom a stroke alert was activated during the period extending from 3/20/20 to 5/20/20 and a similar period in 2019. We compared demographics, time metrics, and discharge outcomes between the two groups. RESULTS: of 385 patients presented to the ED during the two time periods, 58% were African American. There was a significant decrease in the number of stroke patients presenting to the ED and admitted to the hospital between the two periods (p <0.001). In 2020, patients had higher presenting NIHSS (median: 2 vs 5, p = 0.012), discharge NIHSS (median: 2 vs 3, p = 0.004), and longer times from LKW to ED arrival (4.8 vs 9.4 h, p = 0.031) and stroke team activation (median: 10 vs 15 min, p = 0.006). In 2020, stroke mimics rates were lower among African Americans. There were fewer hospitalizations (p <0.001), and transfers from outside facilities (p = 0.015). CONCLUSION: a trend toward faster stroke care in the ED was observed during the pandemic along with dramatically reduced numbers of ED visits, hospitalizations and stroke mimics. Delayed ED presentations and higher stroke severity characterized the African American population, highlighting deepening of racial disparities during the pandemic.

Treatment of Partial Thickness Burns: A Prospective, Randomized Controlled Trial Comparing Four Routinely Used Burns Dressings in an Ambulatory Care Setting.

This prospective, randomized controlled trial study compared the effects of four dressings for adult partial thickness burns, focusing on re-epithelialization time and cost effectiveness. Adults with partial thickness burns meeting inclusion criteria were randomized to either Biobrane™, Acticoat™, Mepilex® Ag, or Aquacel® Ag. Primary endpoint for analysis was >95% re-epithelialization. Incremental cost-effectiveness ratios were calculated based on dressing costs. Dominance probabilities between treatment arms were calculated from bootstrap resampling trial data. One hunderd thirty-one partial thickness burn wounds in 119 patients were randomized. Adjusting for sex, age, smoking status, burn mechanism, TBSA, and first aid adequacy, Mepilex® Ag had a reduced time to re-epithelialization compared to Biobrane™ (IRR: 1.26; 95% CI: 1.07-1.48, P < .01). Economic analysis showed that there was a 99%, 71%, and 53% probability that Mepilex® Ag dominated (cheaper and more effective) Biobrane™, Acticoat™, and Aquacel® Ag, respectively. Mepilex® Ag achieved faster re-epithelialization and better cost effectiveness. Patient satisfaction and comfort seems better with Biobrane™ although not reflected within the end outcome of the healed wound. It is the patients' (after extensive education) and clinicians' choice, level of experience, and availability of products in praxis that will guide the decision as to which the product is used individually on which patient.

An asymmetric sheath controls flagellar supercoiling and motility in the leptospira spirochete.

Spirochete bacteria, including important pathogens, exhibit a distinctive means of swimming via undulations of the entire cell. Motility is powered by the rotation of supercoiled 'endoflagella' that wrap around the cell body, confined within the periplasmic space. To investigate the structural basis of flagellar supercoiling, which is critical for motility, we determined the structure of native flagellar filaments from the spirochete Leptospira by integrating high-resolution cryo-electron tomography and X-ray crystallography. We show that these filaments are coated by a highly asymmetric, multi-component sheath layer, contrasting with flagellin-only homopolymers previously observed in exoflagellated bacteria. Distinct sheath proteins localize to the filament inner and outer curvatures to define the supercoiling geometry, explaining a key functional attribute of this spirochete flagellum.

An Examination of Athletic Trainers' Occupational Recovery Experiences During Time After Work.

CONTEXT: Although researchers have directed scholars toward investigating the effectiveness of the nonwork personal time of athletic trainers (ATs), no one has characterized the occupational recovery experiences of ATs. OBJECTIVE: To examine the reliability and validity of the Recovery Experience Questionnaire (REQ) for use in AT populations. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: A total of 144 ATs (71 men, 73 women) working in a variety of National Collegiate Athletic Association sports across all levels of competition. MAIN OUTCOME MEASURE(S): The REQ was administered to assess the AT recovery experience. RESULTS: Preliminary evidence emerged for the reliability (ω = 0.80-0.90) and validity of the REQ for use in AT populations. Weak linear relationships were identified between stress and perceptions of psychological detachment (r = -0.314, P < .001), mastery (r = -0.179, P = .32), control (r = -0.284, P = .001), and relaxation (r = -0.157, P = .06). CONCLUSIONS: Our results support measuring and applying occupational recovery for AT stress and work-life balance. Given that occupational recovery as a construct was only weakly related to stress, it is clearly a unique and distinct variable worth considering within the work-life balance line of inquiry.

CTA-for-All: Impact of Emergency Computed Tomographic Angiography for All Patients With Stroke Presenting Within 24 Hours of Onset.

Background and Purpose- We sought to evaluate the impact of a Computed Tomographic Angiography (CTA) for All emergency stroke imaging protocol on outcome after large vessel occlusion (LVO). Methods- On July 1, 2017, the Henry Ford Health System implemented the policy of performing CTA and noncontrast computed tomography together as an initial imaging study for all patients with acute ischemic stroke (AIS) presenting within 24 hours of last known well, regardless of baseline National Institutes of Health Stroke Scale score. Previously, CTA was reserved for patients presenting within 6 hours with a National Institutes of Health Stroke Scale score ≥6. We compared treatment processes and outcomes between patients with AIS admitted 1 year before (n=388) and after (n=515) protocol implementation. Results- After protocol implementation, more AIS patients underwent CTA (91% versus 61%; P<0.001) and had CTA performed at the same time as the initial noncontrast computed tomography scan (78% versus 35%; P<0.001). Median time from emergency department arrival to CTA was also shorter (29 [interquartile range, 16-53] versus 43 [interquartile range, 29-112] minutes; P<0.001), more cases of LVO were detected (166 versus 96; 32% versus 25% of all AIS; P=0.014), and more mechanical thrombectomy procedures were performed (108 versus 68; 21% versus 18% of all AIS; P=0.196). Among LVO patients who presented within 6 hours of last known well, median time from last known well to mechanical thrombectomy was shorter (3.5 [interquartile range, 2.8-4.8] versus 4.1 [interquartile range, 3.3-5.6] hours; P=0.038), and more patients were discharged with a favorable outcome (Glasgow Outcome Scale 4-5, 53% versus 37%; P=0.029). The odds of having a favorable outcome after protocol implementation was not significant (odds ratio, 1.84 [95% CI, 0.98-3.45]; P=0.059) after controlling for age and baseline National Institutes of Health Stroke Scale score. Conclusions- Performing CTA and noncontrast computed tomography together as an initial assessment for all AIS patients presenting within 24 hours of last known well improved LVO detection, increased the mechanical thrombectomy treatment population, hastened intervention, and was associated with a trend toward improved outcome among LVO patients presenting within 6 hours of symptom onset.

Genomic evidence of genetic variation with pleiotropic effects on caterpillar fitness and plant traits in a model legume.

Plant-insect interactions are ubiquitous, and have been studied intensely because of their relevance to damage and pollination in agricultural plants, and to the ecology and evolution of biodiversity. Variation within species can affect the outcome of these interactions. Specific genes and chemicals that mediate these interactions have been identified, but genome- or metabolome-scale studies might be necessary to better understand the ecological and evolutionary consequences of intraspecific variation for plant-insect interactions. Here, we present such a study. Specifically, we assess the consequences of genome-wide genetic variation in the model plant Medicago truncatula for Lycaeides melissa caterpillar growth and survival (larval performance). Using a rearing experiment and a whole-genome SNP data set (>5 million SNPs), we found that polygenic variation in M. truncatula explains 9%-41% of the observed variation in caterpillar growth and survival. Genetic correlations among caterpillar performance and other plant traits, including structural defences and some anonymous chemical features, suggest that multiple M. truncatula alleles have pleiotropic effects on plant traits and caterpillar performance (or that substantial linkage disequilibrium exists among distinct loci affecting subsets of these traits). A moderate proportion of the genetic effect of M. truncatula alleles on L. melissa performance can be explained by the effect of these alleles on the plant traits we measured, especially leaf toughness. Taken together, our results show that intraspecific genetic variation in M. truncatula has a substantial effect on the successful development of L. melissa caterpillars (i.e., on a plant-insect interaction), and further point toward traits potentially mediating this genetic effect.

Depolarizing, inhibitory GABA type A receptor activity regulates GABAergic synapse plasticity via ERK and BDNF signaling.

γ-aminobutyric acid (GABA) begins as the key excitatory neurotransmitter in newly forming circuits, with chloride efflux from GABA type A receptors (GABAARs) producing membrane depolarization, which promotes calcium entry, dendritic outgrowth and synaptogenesis. As development proceeds, GABAergic signaling switches to inhibitory hyperpolarizing neurotransmission. Despite the evidence of impaired GABAergic neurotransmission in neurodevelopmental disorders, little is understood on how agonist-dependent GABAAR activation controls the formation and plasticity of GABAergic synapses. We have identified a weakly depolarizing and inhibitory GABAAR response in cortical neurons that occurs during the transition period from GABAAR depolarizing excitation to hyperpolarizing inhibitory activity. We show here that treatment with the GABAAR agonist muscimol mediates structural changes that diminish GABAergic synapse strength through postsynaptic and presynaptic plasticity via intracellular Ca2+ stores, ERK and BDNF/TrkB signaling. Muscimol decreases synaptic localization of surface γ2 GABAARs and gephyrin postsynaptic scaffold while ß2/3 non-γ2 GABAARs accumulate in the synapse. Concurrent with this structural plasticity, muscimol treatment decreases synaptic currents while enhancing the γ2 containing benzodiazepine sensitive GABAAR tonic current in an ERK dependent manner. We further demonstrate that GABAAR activation leads to a decrease in presynaptic GAD65 levels via BDNF/TrkB signaling. Together these data reveal a novel mechanism for agonist induced GABAergic synapse plasticity that can occur on the timescale of minutes, contributing to rapid modification of synaptic and circuit function.

Crossing the lines between epilepsy syndromes: a myoclonic epilepsy variant with prominent eyelid myoclonia and atonic components.

Accurate diagnosis of a distinct epilepsy syndrome is based on well-defined electroclinical features that differentiate separate nosological entities. In clinical practice, however, syndromes may overlap and cases may present with unusual manifestations posing a diagnostic challenge. This heterogeneity has been documented in several cases presenting with eyelid myoclonia with or without absences (EMA) diagnosed either as Jeavons syndrome (JS) variants or as genetic generalised epilepsies defined by the presence of this unique clinical entity. The hallmark of JS is the triad: (1) eyelid myoclonia with or without absences, (2) eye closure-induced paroxysms, and (3) photosensitivity. The presence of massive myoclonus, intellectual disability, or slowing of the EEG background are not typical features of the syndrome and may cause delay in making the correct diagnosis. Adding to the variability of clinical features, we describe two female paediatric patients with probable genetic epilepsy who presented with EMA but demonstrated clear atypical features, such as prominent myoclonic seizures, atonic components on video-EEG, and cognitive impairment. We also note the presence of interictal and ictal posterior discharges during eyelid myoclonia in one, supporting similar previous observations leading to consideration of EMA as an occipital cortex-initiated seizure activity. [Published with video sequences on www.epilepticdisorders.com].

Clinical Diagnostic Tests Versus MRI Diagnosis of ACL Tears.

Clinical Scenario: The anterior cruciate ligament (ACL) injury is a common knee injury within varying athletic levels. Clinical diagnostic tests and magnetic resonance imaging (MRI) are two methods of evaluating ACL injuries. Clinical Question: Are clinical diagnostic tests as accurate as MRI when diagnosing ACL tears? Summary of Key Findings: Three cross-sectional design studies were included. One study found that clinical diagnostic tests were superior to MRI when diagnosing an ACL tear. Another study found that clinical diagnostic tests were equal to MRI when measuring sensitivity, but scored higher in specificity, positive predictive value, negative predictive value, and diagnostic accuracy. The last study found that clinical diagnostic tests scored higher than MRI on specificity and positive predictive value, were equal when measuring accuracy, and scored lower when measuring sensitivity and negative predictive value. Clinical Bottom Line: The evidence supports the use of clinical diagnostic tests when diagnosing an ACL tear. Strength of Recommendation: Level 2-3.