Percutaneous mechanical thrombectomy in acute pulmonary embolism: Outcomes from a safety-net hospital.

BACKGROUND: Our study aims to present clinical outcomes of mechanical thrombectomy (MT) in a safety-net hospital. METHODS: This is a retrospective study of intermediate or high-risk pulmonary embolism (PE) patients who underwent MT between October 2020 and May 2023. The primary outcome was 30-day mortality. RESULTS: Among 61 patients (mean age 57.6 years, 47% women, 57% Black) analyzed, 12 (19.7%) were classified as high-risk PE, and 49 (80.3%) were intermediate-risk PE. Of these patients, 62.3% had Medicaid or were uninsured, 50.8% lived in a high poverty zip code. The prevalence of normotensive shock in intermediate-risk PE patients was 62%. Immediate hemodynamic improvements included 7.4 mmHg mean drop in mean pulmonary artery pressure (-21.7%, p < 0.001) and 93% had normalization of their cardiac index postprocedure. Thirty-day mortality for the entire cohort was 5% (3 patients) and 0% when restricted to the intermediate-risk group. All 3 patients who died at 30 days presented with cardiac arrest. There were no differences in short-term mortality based on race, insurance type, citizenship status, or socioeconomic status. All-cause mortality at most recent follow up was 13.1% (mean follow up time of 13.4 ± 8.5 months). CONCLUSION: We extend the findings from prior studies that MT demonstrates a favorable safety profile with immediate improvement in hemodynamics and a low 30-day mortality in patients with acute PE, holding true even with relatively higher risk and more vulnerable population within a safety-net hospital.

TPWshiny: an interactive R/Shiny app to explore cell line transcriptional responses to anti-cancer drugs.

SUMMARY: The NCI Transcriptional Pharmacodynamics Workbench (NCI TPW) is an extensive compilation of directly measured transcriptional responses to anti-cancer agents across the well-characterized NCI-60 cancer cell lines. The NCI TPW data are publicly available through a web interface that allows limited user interaction with the data. We developed 'TPWshiny' as a standalone, easy to install, R application to facilitate more interactive data exploration.With no programming skills required, TPWshiny provides an intuitive and comprehensive graphical interface to help researchers understand the response of tumor cell lines to 15 therapeutic agents. The data are presented in interactive scatter plots, heatmaps, time series and Venn diagrams. Data can be queried by drug concentration, time point, gene and tissue type. Researchers can download the data for further analysis. AVAILABILITY AND IMPLEMENTATION: Users can download the ready-to-use, self-extracting package for Windows or macOS, and R source code from the project website (https://brb.nci.nih.gov/TPWshiny/). TPWshiny documentation and additional information can be found on the project website.

Comparisons of global tests on intersection hypotheses and their application in matched parallel gatekeeping procedures.

A clinical trial often has primary and secondary endpoints and comparisons of high and low doses of a study drug to a control. Multiplicity is not only caused by the multiple comparisons of study drugs versus the control, but also from the hierarchical structure of the hypotheses. Closed test procedures were proposed as general methods to address multiplicity. Two commonly used tests for intersection hypotheses in closed test procedures are the Simes test and the average method. When the treatment effect of a less efficacious dose is not much smaller than the treatment effect of a more efficacious dose for a specific endpoint, the average method has better power than the Simes test for the comparison of two doses versus control. Accordingly, for inferences for primary and secondary endpoints, the matched parallel gatekeeping procedure based on the Simes test for testing intersection hypotheses is extended here to allow the average method for such testing. This procedure is further extended to clinical trials with more than two endpoints as well as to clinical trials with more than two active doses and a control.

Identification of novel cerebellar developmental transcriptional regulators with motif activity analysis.

BACKGROUND: The work of the FANTOM5 Consortium has brought forth a new level of understanding of the regulation of gene transcription and the cellular processes involved in creating diversity of cell types. In this study, we extended the analysis of the FANTOM5 Cap Analysis of Gene Expression (CAGE) transcriptome data to focus on understanding the genetic regulators involved in mouse cerebellar development. RESULTS: We used the HeliScopeCAGE library sequencing on cerebellar samples over 8 embryonic and 4 early postnatal times. This study showcases temporal expression pattern changes during cerebellar development. Through a bioinformatics analysis that focused on transcription factors, their promoters and binding sites, we identified genes that appear as strong candidates for involvement in cerebellar development. We selected several candidate transcriptional regulators for validation experiments including qRT-PCR and shRNA transcript knockdown. We observed marked and reproducible developmental defects in Atf4, Rfx3, and Scrt2 knockdown embryos, which support the role of these genes in cerebellar development. CONCLUSIONS: The successful identification of these novel gene regulators in cerebellar development demonstrates that the FANTOM5 cerebellum time series is a high-quality transcriptome database for functional investigation of gene regulatory networks in cerebellar development.

Adjunctive Brexpiprazole and Functioning in Major Depressive Disorder: A Pooled Analysis of Six Randomized Studies Using the Sheehan Disability Scale.

BACKGROUND: Patients with major depressive disorder and inadequate response to antidepressant treatments may experience a prolonged loss of functioning. This post hoc analysis aimed to determine the effect of adjunctive brexpiprazole on functioning in such patients. METHODS: A pooled analysis of data from the 6-week, randomized, double-blind treatment phases of 6 studies of adjunctive brexpiprazole (2 and 3 mg/d in fixed-dose studies; 1-3 mg/d in flexible-dose studies) vs placebo in patients with major depressive disorder and inadequate response to antidepressant treatments (NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT00797966, NCT01052077). Functioning was measured by change in Sheehan Disability Scale score from baseline to week 6. RESULTS: Considering Sheehan Disability Scale mean score across all 6 studies (n = 2066 randomized), the least squares mean difference between antidepressant treatments + brexpiprazole and antidepressant treatments + placebo at week 6 was -0.40 (95% CI: -0.56, -0.23; P < .0001). Antidepressant treatments + brexpiprazole showed a greater benefit than antidepressant treatments + placebo on the social life (-0.45; -0.63, -0.27; P < .001) and family life (-0.50; -0.70, -0.31; P < .001) items but not on the work/studies item (-0.16; -0.38, 0.06; P = .16). Pooled analyses of just the (1) fixed-dose, (2) flexible-dose, and (3) Phase 3 studies showed the same pattern of benefits for antidepressant treatments + brexpiprazole. CONCLUSIONS: Brexpiprazole, as adjunct to antidepressant treatments, improved functioning in patients with major depressive disorder and inadequate response to antidepressant treatments.

A Long-Term, Open-Label Study to Evaluate the Safety and Tolerability of Brexpiprazole as Adjunctive Therapy in Adults With Major Depressive Disorder.

BACKGROUND: Long-term treatment is recommended in major depressive disorder (MDD) to prevent relapse and to restore functioning. The aim of this study (Orion; NCT01360866) was to assess the long-term safety, tolerability, and efficacy of open-label treatment with adjunctive brexpiprazole in adult patients with MDD. METHODS: Patients rolled over into this 52-week study (amended to 26 weeks) from 3 randomized, double-blind, placebo-controlled studies. Patients received brexpiprazole 0.5 to 3 mg/d (flexible dose) adjunct to their current antidepressant treatment. The primary outcome variable was the frequency and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed as a secondary objective using clinical rating scales. RESULTS: A total of 2944 patients were enrolled (1547 for 52 weeks, 1397 for 26 weeks), of whom 1895 (64.4%) completed the study. The TEAEs with incidence of 5% or greater were weight increase (17.7%), somnolence (8.0%), headache (7.2%), akathisia (6.7%), increased appetite (6.3%), insomnia (6.3%), fatigue (6.1%), viral upper respiratory tract infection (5.4%), and anxiety (5.2%). Most TEAEs were mild or moderate in severity. The mean increase in body weight was 2.7 kg to week 26 and 3.2 kg to week 52; 25.8% of patients had a weight increase of 7% or greater at any postbaseline visit. There were no clinically relevant findings related to extrapyramidal symptoms, prolactin, lipids, or glucose. Patients' symptoms and functioning showed continual improvement. CONCLUSIONS: Adjunctive treatment with open-label brexpiprazole 0.5 to 3 mg/d was generally well tolerated for up to 52 weeks in patients with MDD and was associated with continued improvement in efficacy measures and functional outcomes.

Correction to: Relatively frequent switching of transcription start sites during cerebellar development.

CORRECTION: The authors of the original article [1] would like to recognize the critical contribution of core members of the FANTOM5 Consortium, who played the critical role of HeliScopeCAGE sequencing experiments, quality control of tag reads and processing of the raw sequencing data.

Discovery of Transcription Factors Novel to Mouse Cerebellar Granule Cell Development Through Laser-Capture Microdissection.

Laser-capture microdissection was used to isolate external germinal layer tissue from three developmental periods of mouse cerebellar development: embryonic days 13, 15, and 18. The cerebellar granule cell-enriched mRNA library was generated with next-generation sequencing using the Helicos technology. Our objective was to discover transcriptional regulators that could be important for the development of cerebellar granule cells-the most numerous neuron in the central nervous system. Through differential expression analysis, we have identified 82 differentially expressed transcription factors (TFs) from a total of 1311 differentially expressed genes. In addition, with TF-binding sequence analysis, we have identified 46 TF candidates that could be key regulators responsible for the variation in the granule cell transcriptome between developmental stages. Altogether, we identified 125 potential TFs (82 from differential expression analysis, 46 from motif analysis with 3 overlaps in the two sets). From this gene set, 37 TFs are considered novel due to the lack of previous knowledge about their roles in cerebellar development. The results from transcriptome-wide analyses were validated with existing online databases, qRT-PCR, and in situ hybridization. This study provides an initial insight into the TFs of cerebellar granule cells that might be important for development and provide valuable information for further functional studies on these transcriptional regulators.

A case study in identifying targeted patients population in major depressive disorder by enhanced enrichment design.

Despite advances in clinical trial design, failure rates near 80% in phase 2 and 50% in phase 3 have recently been reported. The challenges to successful drug development are particularly acute in central nervous system trials such as for pain, schizophrenia, mania, and depression because high-placebo response rates lessen assay sensitivity, diminish estimated treatment effect sizes, and thereby decrease statistical power. This paper addresses the importance of rigorous patient selection in major depressive disorder trials through an enhanced enrichment paradigm. This approach led to a redefinition of an ongoing, blinded phase 3 trial algorithm for patient inclusion (1) to eliminate further randomization of transient placebo responders and (2) to exclude previously randomized transient responders from the primary analysis of the double blind phase of the trial. It is illustrated for a case study for the comparison between brexpiprazole + antidepressant therapy and placebo + antidepressant therapy. Analysis of the primary endpoint showed that efficacy of brexpiprazole versus placebo could not be established statistically if the original algorithm for identification of placebo responders was used, but the enhanced enrichment approach did statistically demonstrate efficacy. Additionally, the enhanced enrichment approach identified a target population with a clinically meaningful treatment effect. Through its successful identification of a target population, the innovative enhanced enrichment approach enabled the demonstration of a positive treatment effect in a very challenging area of depression research.

Relatively frequent switching of transcription start sites during cerebellar development.

BACKGROUND: Alternative transcription start site (TSS) usage plays important roles in transcriptional control of mammalian gene expression. The growing interest in alternative TSSs and their role in genome diversification spawned many single-gene studies on differential usages of tissue-specific or temporal-specific alternative TSSs. However, exploration of the switching usage of alternative TSS usage on a genomic level, especially in the central nervous system, is largely lacking. RESULTS: In this study, We have prepared a unique set of time-course data for the developing cerebellum, as part of the FANTOM5 consortium ( http://fantom.gsc.riken.jp/5/ ) that uses their innovative capturing of 5' ends of all transcripts followed by Helicos next generation sequencing. We analyzed the usage of all transcription start sites (TSSs) at each time point during cerebellar development that provided information on multiple RNA isoforms that emerged from the same gene. We developed a mathematical method that systematically compares the expression of different TSSs of a gene to identify temporal crossover and non-crossover switching events. We identified 48,489 novel TSS switching events in 5433 genes during cerebellar development. This includes 9767 crossover TSS switching events in 1511 genes, where the dominant TSS shifts over time. CONCLUSIONS: We observed a relatively high prevalence of TSS switching in cerebellar development where the resulting temporally-specific gene transcripts and protein products can play important regulatory and functional roles.

Beyond the Hammett Effect: Using Strain to Alter the Landscape of Electrochemical Potentials.

The substitution of sterically bulky groups at precise locations along the periphery of fused-ring aromatic systems is demonstrated to increase electrochemical oxidation potentials by preventing relaxation events in the oxidized state. Phenothiazines, which undergo significant geometric relaxation upon oxidation, are used as fused-ring models to showcase that electron-donating methyl groups, which would generally be expected to lower oxidation potential, can lead to increased oxidation potentials when used as the steric drivers. Reduction events remain inaccessible through this molecular design route, a critical characteristic for electrochemical systems where high oxidation potentials are required and in which reductive decomposition must be prevented, as in high-voltage lithium-ion batteries. This study reveals a new avenue to alter the redox characteristics of fused-ring systems that find wide use as electroactive elements across a number of developing technologies.

Brexpiprazole in patients with schizophrenia: overview of short- and long-term phase 3 controlled studies.

OBJECTIVE: Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies. METHODS: Patients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2-4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1-4 mg), 52-week, placebo-controlled maintenance study. RESULTS: The efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of -20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs. CONCLUSIONS: Overall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.

CbGRiTS: cerebellar gene regulation in time and space.

The mammalian CNS is one of the most complex biological systems to understand at the molecular level. The temporal information from time series transcriptome analysis can serve as a potent source of associative information between developmental processes and regulatory genes. Here, we introduce a new transcriptome database called, Cerebellar Gene Regulation in Time and Space (CbGRiTS). This dataset is populated with transcriptome data across embryonic and postnatal development from two standard mouse strains, C57BL/6J and DBA/2J, several recombinant inbred lines and cerebellar mutant strains. Users can evaluate expression profiles across cerebellar development in a deep time series with graphical interfaces for data exploration and link-out to anatomical expression databases. We present three analytical approaches that take advantage of specific aspects of the time series for transcriptome analysis. We demonstrate the use of CbGRiTS dataset as a community resource to explore patterns of gene expression and develop hypotheses concerning gene regulatory networks in brain development.

Transaural experiments and a revised duplex theory for the localization of low-frequency tones.

The roles of interaural time difference (ITD) and interaural level difference (ILD) were studied in free-field source localization experiments for sine tones of low frequency (250-750 Hz). Experiments combined real-source trials with virtual trials created through transaural synthesis based on real-time ear canal measurements. Experiments showed the following: (1) The naturally occurring ILD is physically large enough to exert an influence on sound localization well below 1000 Hz. (2) An ILD having the same sign as the ITD modestly enhances the perceived azimuth of tones for all values of the ITD, and it eliminates left-right confusions that otherwise occur when the interaural phase difference (IPD) passes 180°. (3) Increasing the ILD to large, implausible values can decrease the perceived laterality while also increasing front-back confusions. (4) Tone localization is more directly related to the ITD than to the IPD. (5) An ILD having a sign opposite to the ITD promotes a slipped-cycle ITD, sometimes with dramatic effects on localization. Because the role of the ITD itself is altered by the ILD, the duplex processing of ITD and ILD reflects more than mere trading; the effect of the ITD can be reversed in sign.

Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice.

microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1)(G93A) rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1(G93A) mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS.

Predicting the timing of dynamic events through sound: Bouncing balls.

Dynamic information in acoustical signals produced by bouncing objects is often used by listeners to predict the objects' future behavior (e.g., hitting a ball). This study examined factors that affect the accuracy of motor responses to sounds of real-world dynamic events. In experiment 1, listeners heard 2-5 bounces from a tennis ball, ping-pong, basketball, or wiffle ball, and would tap to indicate the time of the next bounce in a series. Across ball types and number of bounces, listeners were extremely accurate in predicting the correct bounce time (CT) with a mean prediction error of only 2.58% of the CT. Prediction based on a physical model of bouncing events indicated that listeners relied primarily on temporal cues when estimating the timing of the next bounce, and to a lesser extent on the loudness and spectral cues. In experiment 2, the timing of each bounce pattern was altered to correspond to the bounce timing pattern of another ball, producing stimuli with contradictory acoustic cues. Nevertheless, listeners remained highly accurate in their estimates of bounce timing. This suggests that listeners can adopt their estimates of bouncing-object timing based on acoustic cues that provide most veridical information about dynamic aspects of object behavior.

CAGE-defined promoter regions of the genes implicated in Rett Syndrome.

BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes. RESULTS: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum. CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome.

Relationship between the mixed venous-to-arterial carbon dioxide gradient and the cardiac index in acute pulmonary embolism.

AIMS: Among patients with acute pulmonary embolism (PE) undergoing mechanical thrombectomy, the cardiac index (CI) is frequently reduced even among those without a clinically apparent shock. The purpose of this study is to describe the mixed venous-to-arterial carbon dioxide gradient (CO2 gap), a surrogate of perfusion adequacy, among patients with acute PE undergoing mechanical thrombectomy. METHODS AND RESULTS: This was a single-centre retrospective study of consecutive patients with PE undergoing mechanical thrombectomy and simultaneous pulmonary artery catheterization over a 3-year period. Of 107 patients, 97 had simultaneous mixed venous and arterial blood gas measurements available. The CO2 gap was elevated (>6 mmHg) in 51% of the cohort and in 49% of patients with intermediate-risk PE. A reduced CI (≤2.2 L/min/m2) was associated with an increased odds [odds ratio = 7.9; 95% confidence interval (CI) 3.49-18.1, P < 0.001] for an elevated CO2 gap. There was an inverse relationship between the CI and the CO2 gap. For every 1 L/min/m2 decrease in the CI, the CO2 gap increased by 1.3 mmHg (P = 0.001). Among patients with an elevated baseline CO2 gap >6 mmHg, thrombectomy improved the CO2 gap, CI, and mixed venous oxygen saturation. When the CO2 gap was dichotomized above and below 6, there was no difference in the in-hospital mortality rate (9 vs. 0%; P = 0.10; hazard ratio: 1.24; 95% CI 0.97-1.60; P = 0.085). CONCLUSION: Among patients with acute PE undergoing mechanical thrombectomy, the CO2 gap is abnormal in nearly 50% of patients and inversely related to the CI. Further studies should examine the relationship between markers of perfusion and outcomes in this population to refine risk stratification.