Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular ...thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline.
In a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool.
Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 95% CI, 1.32–4.00; reperfusion common odds ratio =4.73 95% CI, 1.66–13.52) but not MLS (thrombectomy β=−0.27 95% CI, −1.52 to 0.98; reperfusion β=−0.78 95% CI, −3.07 to 1.50) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 95% CI, 0.33–5.20) but not functional improvement (odds ratio, 1.71 95% CI, 0.24–12.08).
In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.
In this phase 2 trial involving 104 patients with relapsing–remitting multiple sclerosis, patients who received rituximab on days 1 and 15 had fewer gadolinium-enhancing lesions on magnetic resonance ...imaging and fewer relapses during 48 weeks of follow-up than patients who received placebo. Rituximab was associated with more adverse events within 24 hours after the first infusion. The study was too small and short to assess uncommon adverse events or long-term safety.
Patients with relapsing–remitting multiple sclerosis who received rituximab on days 1 and 15 had fewer gadolinium-enhancing lesions on MRI and fewer relapses during 48 weeks of follow-up than patients who received placebo.
Multiple sclerosis, the prototypical inflammatory demyelinating disease of the central nervous system, is second only to trauma as a cause of acquired neurologic disability in young adults.
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Multiple sclerosis usually begins as a relapsing, episodic disorder (relapsing–remitting multiple sclerosis), evolving into a chronic neurodegenerative condition characterized by progressive neurologic disability.
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The traditional view of the pathophysiology of multiple sclerosis has held that inflammation is principally mediated by CD4+ type 1 helper T cells. Therapies (e.g., interferon beta and glatiramer acetate) developed on the basis of this theory decrease the relapse rate by approximately one third
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but do not fully . . .
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Introduction:
Characterization of the genetic etiology of heart failure (HF) provides an opportunitiy to advance understanding of causal human biology and to develop genomic tools for ...prediction and patient stratification. We conducted a multi-ancestry genome-wide association meta-analysis of HF and related subtypes in 1.9 million individuals.
Methods:
We investigated 10,199,961 common genetic variants for association with all-cause HF (145,795 cases); non-ischemic HF, defined as the absence of antecedent myocardial infarction and abnormal loading conditions (44,030 cases); and non-ischemic HF stratified by left ventricular ejection fraction (LVEF) (5,407 cases of LVEF <50% and 3,846 cases of LVEF 50%). By synthesizing evidence from functionally-informed fine-mapping, in silico gene prioritization, and multi-tissue transcriptome-wide association analysis, we prioritized likely causal variants, effector genes, and tissues for HF. We tested for enrichment of genes linked to Mendelian disorders within genomic loci for HF and assessed the genetic correlation of HF-related traits and their causal inter-relationships using Mendelian randomization.
Results:
We identified 56 independent genomic loci, including 39 novel, associated with all-cause HF; and additional 10 novel independent genomic loci among non-ischemic HF subtypes at P < 5 x 10-8. Genomic loci for HF were enriched for genes associated with Mendelian disorders of cardiomyopathy (Padjusted = 0.01) and arrhythmia (Padjusted = 0.0006). In 30 / 56 loci for all-cause HF, functionally-informed fine-mapping identified 5 or fewer likely causal variants. Genetically predicted expression levels of 266 genes across 49 human tissues were associated with HF at a false discovery rate <1%, 95 (36%) of which were also identified in heart tissue-specific analysis. Genetic correlation and causal associations were detected between upstream risk factors and traits of cardiac structure and function, yielding new insights into HF endophenotype relationships.
Conclusion:
These findings extend our understanding of the etiology of the HF syndrome and provide new opportunities to inform the development of new therapeutic strategies.
Ultrasound elasticity imaging techniques aim to provide a non-invasive characterization of tissue mechanical properties to detect pathological changes and monitor disease progression. Harmonic motion ...imaging (HMI) is an ultrasound-based elasticity imaging technique that utilizes an oscillatory acoustic radiation force to induce localized displacements and estimate relative tissue stiffness. Previous studies have applied a low amplitude modulation (AM) frequency of 25 or 50 Hz in HMI to assess the mechanical properties of different tissue types. In this study, we investigate the dependence of AM frequency in HMI and whether the frequency can be adjusted based on the size and mechanical properties of the underlying medium for enhanced image contrast and inclusion detection.
A tissue-mimicking phantom with embedded inclusions at different sizes and stiffnesses was imaged within a range of AM frequencies from 25 to 250 Hz at 25-Hz step size.
The AM frequency at which the maximum contrast and CNR are achieved depends on the size and stiffness of the inclusions. A general trend shows that contrast and CNR peak at higher frequencies for smaller inclusions. In addition, for some inclusions with the same size but different stiffnesses, the optimized AM frequency increases with the stiffness of the inclusion. Nevertheless, there is a shift between the frequencies at which the contrast peaks and those with maximum CNR. Finally, in agreement with the phantom findings, imaging an ex-vivo human specimen with a 2.7-cm breast tumor at a range of AM frequencies showed that the highest contrast and CNR are achieved at the AM frequency of 50 Hz.
These findings indicate that the AM frequency can be optimized in different applications of HMI, especially in the clinic, for improved detection and characterization of tumors with different geometries and mechanical properties.
Purpose:
Ultrasound neuromodulation is a promising noninvasive technique for controlling neural activity. Previous small animal studies suffered from low targeting specificity because of the low ...ultrasound frequencies (<690 kHz) used. In this study, the authors demonstrated the capability of focused ultrasound (FUS) neuromodulation in the megahertz-range to achieve superior targeting specificity in the murine brain as well as demonstrate modulation of both motor and sensory responses.
Methods:
FUS sonications were carried out at 1.9 MHz with 50% duty cycle, pulse repetition frequency of 1 kHz, and duration of 1 s. The robustness of the FUS neuromodulation was assessed first in sensorimotor cortex, where elicited motor activities were observed and recorded on videos and electromyography. Deeper brain regions were then targeted where pupillary dilation served as an indicative of successful modulation of subcortical brain structures.
Results:
Contralateral and ipsilateral movements of the hind limbs were repeatedly observed when the FUS was targeted at the sensorimotor cortex. Induced trunk and tail movements were also observed at different coordinates inside the sensorimotor cortex. At deeper targeted-structures, FUS induced eyeball movements (superior colliculus) and pupillary dilation (pretectal nucleus, locus coeruleus, and hippocampus). Histological analysis revealed no tissue damage associated with the FUS sonications.
Conclusions:
The motor movements and pupillary dilation observed in this study demonstrate the capability of FUS to modulate cortical and subcortical brain structures without inducing any damage. The variety of responses observed here demonstrates the capability of FUS to perform functional brain mapping.
Ultrasound can modulate activity in the central nervous system, including the induction of motor responses in rodents. Recent studies investigating ultrasound-induced motor movements have described ...mostly bilateral limb responses, but quantitative evaluations have failed to reveal lateralization or differences in response characteristics between separate limbs or how specific brain targets dictate distinct limb responses. This study uses high-resolution focused ultrasound (FUS) to elicit motor responses in anesthetized mice in vivo and four-limb electromyography (EMG) to evaluate the latency, duration and power of paired motor responses (n = 1768). The results indicate that FUS generates target-specific differences in electromyographic characteristics and that brain targets separated by as little as 1 mm can modulate the responses in individual limbs differentially. Exploiting these differences may provide a tool for quantifying the susceptibility of underlying neural volumes to FUS, understanding the functioning of the targeted neuroanatomy and aiding in mechanistic studies of this non-invasive neuromodulation technique.
Background: Massive high-throughput sequencing of short, hypervariable segments of the 16S ribosomal RNA (rRNA) gene has transformed the methodological landscape describing microbial diversity within ...and across complex biomes. However, several studies have shown that the methodology rather than the biological variation is responsible for the observed sample composition and distribution. This compromises meta-analyses, although this fact is often disregarded.
Results: To facilitate true meta-analysis of microbiome studies, we developed NG-Tax, a pipeline for 16S rRNA gene amplicon sequence analysis that was validated with different mock communities and benchmarked against
QIIME
as a frequently used pipeline. The microbial composition of 49 independently amplified mock samples was characterized by sequencing two variable 16S rRNA gene regions, V4 and V5-V6, in three separate sequencing runs on Illumina's HiSeq2000 platform. This allowed for the evaluation of important causes of technical bias in taxonomic classification: 1) run-to-run sequencing variation, 2) PCR-error, and 3) region/primer specific amplification bias. Despite the short read length (~140 nt) and all technical biases, the average specificity of the taxonomic assignment for the phylotypes included in the mock communities was 97.78%. On average 99.95% and 88.43% of the reads could be assigned to at least family or genus level, respectively, while assignment to 'spurious genera' represented on average only 0.21% of the reads per sample. Analysis of α- and β-diversity confirmed conclusions guided by biology rather than the aforementioned methodological aspects, which was not achieved with QIIME.
Conclusions: Different biological outcomes are commonly observed due to 16S rRNA region-specific performance. NG-Tax demonstrated high robustness against choice of region and other technical biases associated with 16S rRNA gene amplicon sequencing studies, diminishing their impact and providing accurate qualitative and quantitative representation of the true sample composition. This will improve comparability between studies and facilitate efforts towards standardization.
BACKGROUND AND PURPOSE—Hyperglycemia is a negative prognostic factor after acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy (EVT) in ...patients with large-vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of EVT in acute stroke.
METHODS—Seven randomized trials compared EVT with standard care between 2010 and 2017 (HERMES Collaboration highly effective reperfusion using multiple endovascular devices). One thousand seven hundred and sixty-four patients with large-vessel stroke were allocated to EVT (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome (modified Rankin Scale range, 0–6; lower scores indicating less disability) at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level.
RESULTS—Median (interquartile range) serum glucose on admission was 120 (104–140) mg/dL (6.6 mmol/L 5.7–7.7 mmol/L). EVT was better than standard care in the overall pooled-data analysis adjusted common odds ratio (acOR), 2.00 (95% CI, 1.69–2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose < or >90 mg/dL (5.0 mmol/L; P=0.019 for interaction; acOR, 3.81; 95% CI, 1.73–8.41 for patients < 90 mg/dL versus 1.83; 95% CI, 1.53–2.19 for patients >90 mg/dL), and glucose < or >100 mg/dL (5.5 mmol/L; P=0.004 for interaction; acOR, 3.17; 95% CI, 2.04–4.93 versus acOR, 1.72; 95% CI, 1.42–2.08) but not between subgroups above these levels of glucose.
CONCLUSIONS—EVT improved stroke outcomes compared with standard treatment regardless of glucose levels, but the treatment effects were larger at lower glucose levels, with significant interaction effects persisting up to 90 to 100 mg/dL (5.0–5.5 mmol/L). Whether tight control of glucose improves the efficacy of EVT after large-vessel stroke warrants appropriate testing.
The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such ...as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which limit the passage of substrate molecules from blood circulation to the brain. Focused ultrasound (FUS) with microbubbles can create a local and reversible detachment of the TJs. However, very little is known about the effect of FUS on the expression of efflux transporters. We investigated the in vivo effects of moderate acoustic pressures on both P-gp and BCRP expression for up to two weeks after sonication. Magnetic resonance-guided FUS was applied in the striatum of 12 rats. P-gp and BCRP expression were determined by immunohistochemistry at 1, 3, 7, and 14 days postFUS. Our results indicate that FUS-induced BBB opening is capable of (i) decreasing P-gp expression up to 3 days after sonication in both the treated and in the contralateral brain regions and is capable of (ii) overexpressing BCRP up to 7 days after FUS in the sonicated regions only. Our findings may help improve FUS-aided drug delivery strategies by considering both the mechanical effect on the TJs and the regulation of P-gp and BCRP.
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