Cluster randomized adaptive implementation trial comparing a standard versus enhanced implementation intervention to improve uptake of an effective re-engagement program for patients with serious mental illness

Abstract Background Persons with serious mental illness (SMI) are disproportionately burdened by premature mortality. This disparity is exacerbated by poor continuity of care with the health system. The Veterans Health Administration (VA) developed Re-Engage, an effective population-based outreach program to identify veterans with SMI lost to care and to reconnect them with VA services. However, such programs often encounter barriers getting implemented into routine care. Adaptive designs are needed when the implementation intervention requires augmentation within sites that do not initially respond to an initial implementation intervention. This protocol describes the methods used in an adaptive implementation design study that aims to compare the effectiveness of a standard implementation strategy (Replicating Effective Programs, or REP) with REP enhanced with External Facilitation (enhanced REP) to promote the uptake of Re-Engage. Methods/Design This study employs a four-phase, two-arm, longitudinal, clustered randomized trial design. VA sites (n = 158) across the United States with a designated Re-Engage provider, at least one Veteran with SMI lost to care, and who received standard REP during a six-month run-in phase. Subsequently, 88 sites with inadequate uptake were stratified at the cluster level by geographic region (n = 4) and VA regional service network (n = 20) and randomized to REP (n = 49) vs. enhanced REP (n = 39) in phase two. The primary outcome was the percentage of veterans on each facility outreach list documented on an electronic web registry. The intervention was at the site and network level and consisted of standard REP versus REP enhanced by external phone facilitation consults. At 12 months, enhanced REP sites returned to standard REP and 36 sites with inadequate participation received enhanced REP for six months in phase three. Secondary implementation outcomes included the percentage of veterans contacted directly by site providers and the percentage re-engaged in VA health services. Discussion Adaptive implementation designs consisting of a sequence of decision rules that are tailored based on a site’s uptake of an effective program may produce more relevant, rapid, and generalizable results by more quickly validating or rejecting new implementation strategies, thus enhancing the efficiency and sustainability of implementation research and potentially leading to the rollout of more cost-efficient implementation strategies. Trial registration Current Controlled Trials ISRCTN21059161 .http://deepblue.lib.umich.edu/bitstream/2027.42/112609/1/13012_2013_Article_711.pd

Organizational culture and climate as moderators of enhanced outreach for persons with serious mental illness: results from a cluster-randomized trial of adaptive implementation strategies

Abstract Background Organizational culture and climate are considered key factors in implementation efforts but have not been examined as moderators of implementation strategy comparative effectiveness. We investigated organizational culture and climate as moderators of comparative effectiveness of two sequences of implementation strategies (Immediate vs. Delayed Enhanced Replicating Effective Programs [REP]) combining Standard REP and REP enhanced with facilitation on implementation of an outreach program for Veterans with serious mental illness lost to care at Veterans Health Administration (VA) facilities nationwide. Methods This study is a secondary analysis of the cluster-randomized Re-Engage implementation trial that assigned 3075 patients at 89 VA facilities to either the Immediate or Delayed Enhanced REP sequences. We hypothesized that sites with stronger entrepreneurial culture, task, or relational climate would benefit more from Enhanced REP than Standard REP. Veteran- and site-level data from the Re-Engage trial were combined with site-aggregated measures of entrepreneurial culture and task and relational climate from the 2012 VA All Employee Survey. Longitudinal mixed-effects logistic models examined whether the comparative effectiveness of the Immediate vs. Delayed Enhanced REP sequences were moderated by culture or climate measures at 6 and 12 months post-randomization. Three Veteran-level outcomes related to the engagement with the VA system were assessed: updated documentation, attempted contact by coordinator, and completed contact. Results For updated documentation and attempted contact, Veterans at sites with higher entrepreneurial culture and task climate scores benefitted more from Enhanced REP compared to Standard REP than Veterans at sites with lower scores. Few culture or climate moderation effects were detected for the comparative effectiveness of the full sequences of implementation strategies. Conclusions Implementation strategy effectiveness is highly intertwined with contextual factors, and implementation practitioners may use knowledge of contextual moderation to tailor strategy deployment. We found that facilitation strategies provided with Enhanced REP were more effective at improving uptake of a mental health outreach program at sites with stronger entrepreneurial culture and task climate; Veterans at sites with lower levels of these measures saw more similar improvement under Standard and Enhanced REP. Within resource-constrained systems, practitioners may choose to target more intensive implementation strategies to sites that will most benefit from them. Trial registration ISRCTN: ISRCTN21059161 . Date registered: April 11, 2013.https://deepblue.lib.umich.edu/bitstream/2027.42/144775/1/13012_2018_Article_787.pd

A Transcriptional Enhancer from the Coding Region of ADAMTS5

The revelation that the human genome encodes only approximately 25,000 genes and thus cannot account for phenotypic complexity has been one of the biggest surprises in the post-genomic era. However, accumulating evidence suggests that transcriptional regulation may be in large part responsible for this observed mammalian complexity. Consequently, there has been a strong drive to locate cis-regulatory regions in mammalian genomes in order to understand the unifying principles governing these regions, including their genomic distribution. Although a number of systematic approaches have been developed, these all discount coding sequence.Using the computational tool PRI (Pattern-defined Regulatory Islands), which does not mask coding sequence, we identified a regulatory region associated with the gene ADAMTS5 that encompasses the entirety of the essential coding exon 2. We demonstrate through a combination of chromatin immunoprecipitation and reporter gene studies that this region can not only bind the myogenic transcription factors MYOD and myogenin and the E-protein HEB but can also function as a very strong myogenic transcriptional enhancer.Thus, we report the identification and detailed characterization of an exonic enhancer. Ultimately, this leads to the interesting question of why evolution would be so parsimonious in the functional assignment of sequence

Accuracy and reliability of diffusion imaging models

Diffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain\u27s white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927-1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL\u27s BedpostX [BPX], DSI Studio\u27s Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3\u27s Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed a novel Bayesian Multi-tensor Model-selection (BaMM) method and applied it to the popular ball-and-stick model used in BedpostX within the FSL software package. BaMM was robust to overfitting and showed high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, sufficient data and an overfitting resistant analysis method enhance precision diffusion imaging. For potential clinical applications of diffusion imaging, such as neurosurgical planning and deep brain stimulation (DBS), the quantities of data required to achieve diffusion imaging reliability are lower than those needed for functional MRI

Psilocybin desynchronizes the human brain

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trial

Fast assessment of long axis strain with standard cardiovascular magnetic resonance: a validation study of a novel parameter with reference values

Background: Assessment of longitudinal function with cardiovascular magnetic resonance (CMR) is limited to measurement of systolic excursion of the mitral annulus (MAPSE) or elaborate strain imaging modalities. The aim of this study was to develop a fast assessable parameter for the measurement of long axis strain (LAS) with CMR. Methods: 40 healthy volunteers and 125 patients with different forms of cardiomyopathy were retrospectively analyzed. Four different approaches for the assessment of LAS with CMR measuring the distance between the LV apex and a line connecting the origins of the mitral valve leaflets in enddiastole and endsystole were evaluated. Values for LAS were calculated according to the strain formula. Results: LAS derived from the distance of the epicardial apical border to the midpoint of the line connecting the mitral valve insertion points (LAS-epi/mid) proved to be the most reliable parameter for the assessment of LAS among the different approaches. LAS-epi/mid displayed the highest sensitivity (81.6 %) and specificity (97.5 %), furthermore showing the best correlation with feature tracking (FTI) derived transmural longitudinal strain (r = 0.85). Moreover, LAS-epi/mid was non-inferior to FTI in discriminating controls from patients (Area under the curve (AUC) = 0.95 vs. 0.94, p = NS). The time required for analysis of LAS-epi/mid was significantly shorter than for FTI (67 ± 8 s vs. 180 ± 14 s, p < 0.0001). Additionally, LAS-epi/mid performed significantly better than MAPSE (Delta AUC = 0.09; p < 0.005) and the ejection fraction (Delta AUC = 0.11; p = 0.0002). Reference values were derived from 234 selected healthy volunteers. Mean value for LAS-epi/mid was −17.1 ± 2.3 %. Mean values for men were significantly lower compared to women (−16.5 ± 2.2 vs. -17.9 ± 2.1 %; p < 0.0001), while LAS decreased with age. Conclusions: LAS-epi/mid is a novel and fast assessable parameter for the analysis of global longitudinal function with non-inferiority compared to transmural longitudinal strain

Psilocybin desynchronizes the human brain

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics

Magnetic fields in barred galaxies I. The atlas

The total and polarized radio continuum emission of 20 barred galaxies was observed with the Very Large Array (VLA) at 3, 6, 18 and 22 cm and with the Australia Telescope Compact Array (ATCA) at 6 cm and 13 cm. Maps at 30 arcsec angular resolution are presented here. Polarized emission (and therefore a large-scale regular magnetic field) was detected in 17 galaxies. Most galaxies of our sample are similar to non-barred galaxies with respect to the radio/far-infrared flux correlation and equipartition strength of the total magnetic field. Galaxies with highly elongated bars are not always radio-bright. We discuss the correlation of radio properties with the aspect ratio of the bar and other measures of the bar strength. We introduce a new measure of the bar strength, \Lambda, related to the quadrupole moment of the bar's gravitational potential. The radio surface brightness I of the barred galaxies in our sample is correlated with \Lambda, I \propto \Lambda^0.4+/-0.1, and thus is highest in galaxies with a long bar where the velocity field is distorted by the bar over a large fraction of the disc. In these galaxies, the pattern of the regular field is significantly different from that in non-barred galaxies. In particular, field enhancements occur upstream of the dust lanes where the field lines are oriented at large angles to the bar's major axis. Polarized radio emission seems to be a good indicator of large-scale non-axisymmetric motions.Comment: 29 pages with 66 PostScript figures. Accepted for publication in A&A. Figures 5-24 also available at http://www.mpifr-bonn.mpg.d

Anti-Human Tissue Factor Antibody Ameliorated Intestinal Ischemia Reperfusion-Induced Acute Lung Injury in Human Tissue Factor Knock-In Mice

BACKGROUND: Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS). Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human tissue factor knock-in (hTF-KI) transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859) were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v.) attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. CONCLUSIONS: This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies