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Chapter 4 - Contribution of RADx® Tech to the Rapid Development of COVID-19 Diagnostic Tests
- Edited by Steven C. Schachter, Harvard Medical School, Wade E. Bolton, VentureWell/Rapid Acceleration of Diagnostics (RADx)
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- Book:
- Accelerating Diagnostics in a Time of Crisis
- Published online:
- 06 January 2024
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- 07 March 2024, pp 74-87
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Summary
Rapid Acceleration of Diagnostics (RADx®) Tech was the key diagnostics component of a three-pronged national strategy, including vaccines and therapeutics, to respond to the COVID-19 pandemic. Unprecedented in the scale of its mission, its budget, its accelerated time frame, the extent of cross-government agency collaboration and information exchange, and the blending of business, academic, and investment best practices, RAD Tech successfully launched dozens of US Food and Drug Administration Emergency Use Authorization diagnostic tests, established a new model for rapidly translating diagnostic tests from the laboratory to the marketplace, and accelerated public acceptance of home-based diagnostic tests. This chapter provides an overview of the processes utilized by RADx Tech during the COVID-19 pandemic to improve clinical laboratory tests and identify, evaluate, support, validate, and commercialize innovative point-of-care and home-based tests that directly detected the presence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus.
FC30: The relationships between neuroticism, social connection and cognition
- Jennifer Bethell, Melissa K. Andrew, Paul Mick, Debra Morgan, Megan E. O’Connell, Natalie A. Phillips, Steven Stewart, Jennifer D. Walker, Walter Wittich, Katherine S. McGilton
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- Journal:
- International Psychogeriatrics / Volume 35 / Issue S1 / December 2023
- Published online by Cambridge University Press:
- 02 February 2024, pp. 92-94
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Background:
Social connection is associated with better health, including reduced risk of dementia. Personality traits are also linked to cognitive outcomes; neuroticism is associated with increased risk of dementia. Personality traits and social connection are also associated with each other. Taken together, evidence suggests the potential impacts of neuroticism and social connection on cognitive outcomes may be linked. However, very few studies have simultaneously examined the relationships between personality, social connection and health.
Research objective:We tested the association between neuroticism and cognitive measures while exploring the potential mediating roles of aspects of social connection (loneliness and social isolation).
Method:We conducted a cross-sectional study with a secondary analysis of the Canadian Longitudinal Study on Aging (CLSA) Comprehensive Cohort, a sample of Canadians aged 45 to 85 years at baseline. We used only self-reported data collected at the first follow-up, between 2015 and 2018 (n= 27,765). We used structural equation modelling to assess the association between neuroticism (exposure) and six cognitive measures (Rey Auditory Verbal Learning Test immediate recall and delayed recall, Animal Fluency Test, Mental Alternation Test, Controlled Oral Word Association Test and Stroop Test interference ratio), with direct and indirect effects (through social isolation and loneliness). We included age, education and hearing in the models and stratified all analyses by sex, females (n= 14,133) and males (n=13,632).
Preliminary results of the ongoing study:We found positive, statistically significant associations between neuroticism and social isolation (p<0.05) and loneliness (p<0.05), for both males and females. We also found inverse, statistically significant associations between neuroticism and all cognitive measures (p<0.05), except the Stroop Test interference ratio. In these models, there was consistent evidence of indirect effects (through social isolation and loneliness) and, in some cases, evidence of direct effects. We found sex differences in the model results.
Conclusion:Our findings suggest that the association between neuroticism and cognitive outcomes may be mediated by aspects of social connection and differ by sex. Understanding if and how modifiable risk factors mediate the association between personality and cognitive outcomes would help develop and target intervention strategies that improve social connection and brain health.
Comparison of coercive practices in worldwide mental healthcare: overcoming difficulties resulting from variations in monitoring strategies
- Martha K. Savage, Peter Lepping, Giles Newton-Howes, Richard Arnold, Vincent S. Staggs, Steven Kisely, Toshio Hasegawa, Keith S. Reid, Eric O. Noorthoorn
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- Journal:
- BJPsych Open / Volume 10 / Issue 1 / January 2024
- Published online by Cambridge University Press:
- 11 January 2024, e26
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Background
Coercive or restrictive practices such as compulsory admission, involuntary medication, seclusion and restraint impinge on individual autonomy. International consensus mandates reduction or elimination of restrictive practices in mental healthcare. To achieve this requires knowledge of the extent of these practices.
AimsWe determined rates of coercive practices and compared them across countries.
MethodWe identified nine country- or region-wide data-sets of rates and durations of restrictive practices in Australia, England, Germany, Ireland, Japan, New Zealand, The Netherlands, the USA and Wales. We compared the data-sets with each other and with mental healthcare indicators in World Health Organization and Organisation for Economic Cooperation and Development reports.
ResultsThe types and definitions of reported coercive practices varied considerably. Reported rates were highly variable, poorly reported and tracked using a diverse array of measures. However, we were able to combine duration measures to examine numbers of restrictive practices per year per 100 000 population for each country. The rates and durations of seclusion and restraint differed by factors of more than 100 between countries, with Japan showing a particularly high number of restraints.
ConclusionsWe recommend a common set of international measures, so that finer comparisons within and between countries can be made, and monitoring of trends to see whether alternatives to restraint are successful. These measurements should include information about the total numbers, durations and rates of coercive measures. We urge the World Health Organization to include these measures in their Mental Health Atlas.
53 2-Back Performance Does Not Differ Between Cognitive Training Groups in Older Adults Without Dementia
- Nicole D Evangelista, Jessica N Kraft, Hanna K Hausman, Andrew O’Shea, Alejandro Albizu, Emanuel M Boutzoukas, Cheshire Hardcastle, Emily J Van Etten, Pradyumna K Bharadwaj, Hyun Song, Samantha G Smith, Steven DeKosky, Georg A Hishaw, Samuel Wu, Michael Marsiske, Ronald Cohen, Gene E Alexander, Eric Porges, Adam J Woods
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 360-361
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Objective:
Cognitive training is a non-pharmacological intervention aimed at improving cognitive function across a single or multiple domains. Although the underlying mechanisms of cognitive training and transfer effects are not well-characterized, cognitive training has been thought to facilitate neural plasticity to enhance cognitive performance. Indeed, the Scaffolding Theory of Aging and Cognition (STAC) proposes that cognitive training may enhance the ability to engage in compensatory scaffolding to meet task demands and maintain cognitive performance. We therefore evaluated the effects of cognitive training on working memory performance in older adults without dementia. This study will help begin to elucidate non-pharmacological intervention effects on compensatory scaffolding in older adults.
Participants and Methods:48 participants were recruited for a Phase III randomized clinical trial (Augmenting Cognitive Training in Older Adults [ACT]; NIH R01AG054077) conducted at the University of Florida and University of Arizona. Participants across sites were randomly assigned to complete cognitive training (n=25) or an education training control condition (n=23). Cognitive training and the education training control condition were each completed during 60 sessions over 12 weeks for 40 hours total. The education training control condition involved viewing educational videos produced by the National Geographic Channel. Cognitive training was completed using the Posit Science Brain HQ training program, which included 8 cognitive training paradigms targeting attention/processing speed and working memory. All participants also completed demographic questionnaires, cognitive testing, and an fMRI 2-back task at baseline and at 12-weeks following cognitive training.
Results:Repeated measures analysis of covariance (ANCOVA), adjusted for training adherence, transcranial direct current stimulation (tDCS) condition, age, sex, years of education, and Wechsler Test of Adult Reading (WTAR) raw score, revealed a significant 2-back by training group interaction (F[1,40]=6.201, p=.017, η2=.134). Examination of simple main effects revealed baseline differences in 2-back performance (F[1,40]=.568, p=.455, η2=.014). After controlling for baseline performance, training group differences in 2-back performance was no longer statistically significant (F[1,40]=1.382, p=.247, η2=.034).
Conclusions:After adjusting for baseline performance differences, there were no significant training group differences in 2-back performance, suggesting that the randomization was not sufficient to ensure adequate distribution of participants across groups. Results may indicate that cognitive training alone is not sufficient for significant improvement in working memory performance on a near transfer task. Additional improvement may occur with the next phase of this clinical trial, such that tDCS augments the effects of cognitive training and results in enhanced compensatory scaffolding even within this high performing cohort. Limitations of the study include a highly educated sample with higher literacy levels and the small sample size was not powered for transfer effects analysis. Future analyses will include evaluation of the combined intervention effects of a cognitive training and tDCS on nback performance in a larger sample of older adults without dementia.
2 Choline as a neurodevelopmental intervention for children with fetal alcohol spectrum disorder: Long-term associations with white matter microstructure and executive function
- Blake A. Gimbel, Mary E. Anthony, Abigail M. Ernst, Donovan J. Roediger, Erik de Water, Judith K. Eckerle, Christopher J. Boys, Joshua P. Radke, Bryon A. Mueller, Anita J. Fuglestad, Steven H. Zeisel, Michael K. Georgieff, Jeffrey R. Wozniak
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 613-614
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Objective:
Fetal alcohol spectrum disorder (FASD) is a life-long condition, and few interventions have been developed to improve the neurodevelopmental course in this population. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. In this study, we examine treatment group differences in executive function (EF) outcomes and diffusion MRI of the corpus callosum using the Neurite Orientation Dispersion and Density Index (NODDI) biophysical model.
Participants and Methods:The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5- to 5-year-olds with FASD. Participants in this long-term follow-up study included 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up evaluation included measures of executive functioning (WISC-V Picture Span and Digit Span; DKEFS subtests) and diffusion MRI (NODDI).
Results:Children who received choline early in development outperformed those in the placebo group across a majority of EF tasks at long-term follow-up (effect sizes ranged from -0.09 to 1.27). Children in the choline group demonstrated significantly better performance on several tasks of lower-order executive function skills (i.e., DKEFS Color Naming [Cohen's d = 1.27], DKEFS Word Reading [Cohen's d = 1.13]) and showed potentially better white matter microstructure organization (as indicated by lower orientation dispersion; Cohen's d = -1.26) in the splenium of the corpus callosum compared to the placebo group. In addition, when collapsing across treatment groups, higher white matter microstructural organization was associated with better performance on several EF tasks (WISC-V Digit Span; DKEFS Number Sequencing and DKEFS Word Reading).
Conclusions:These findings highlight long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that changes in white matter organization may represent an important target of choline in this population. Unique to this study is the use of contemporary biophysical modeling of diffusion MRI data in youth with FASD. Findings suggest this neuroimaging approach may be particularly useful for identifying subtle white matter differences in FASD as well as neurobiological responses to early intervention associated with important cognitive functions.
2 Higher White Matter Hyperintensity Load Adversely Affects Pre-Post Proximal Cognitive Training Performance in Healthy Older Adults
- Emanuel M Boutzoukas, Andrew O’Shea, Jessica N Kraft, Cheshire Hardcastle, Nicole D Evangelista, Hanna K Hausman, Alejandro Albizu, Emily J Van Etten, Pradyumna K Bharadwaj, Samantha G Smith, Hyun Song, Eric C Porges, Alex Hishaw, Steven T DeKosky, Samuel S Wu, Michael Marsiske, Gene E Alexander, Ronald Cohen, Adam J Woods
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 671-672
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Objective:
Cognitive training has shown promise for improving cognition in older adults. Aging involves a variety of neuroanatomical changes that may affect response to cognitive training. White matter hyperintensities (WMH) are one common age-related brain change, as evidenced by T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR) MRI. WMH are associated with older age, suggestive of cerebral small vessel disease, and reflect decreased white matter integrity. Higher WMH load associates with reduced threshold for clinical expression of cognitive impairment and dementia. The effects of WMH on response to cognitive training interventions are relatively unknown. The current study assessed (a) proximal cognitive training performance following a 3-month randomized control trial and (b) the contribution of baseline whole-brain WMH load, defined as total lesion volume (TLV), on pre-post proximal training change.
Participants and Methods:Sixty-two healthy older adults ages 65-84 completed either adaptive cognitive training (CT; n=31) or educational training control (ET; n=31) interventions. Participants assigned to CT completed 20 hours of attention/processing speed training and 20 hours of working memory training delivered through commercially-available Posit Science BrainHQ. ET participants completed 40 hours of educational videos. All participants also underwent sham or active transcranial direct current stimulation (tDCS) as an adjunctive intervention, although not a variable of interest in the current study. Multimodal MRI scans were acquired during the baseline visit. T1- and T2-weighted FLAIR images were processed using the Lesion Segmentation Tool (LST) for SPM12. The Lesion Prediction Algorithm of LST automatically segmented brain tissue and calculated lesion maps. A lesion threshold of 0.30 was applied to calculate TLV. A log transformation was applied to TLV to normalize the distribution of WMH. Repeated-measures analysis of covariance (RM-ANCOVA) assessed pre/post change in proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures in the CT group compared to their ET counterparts, controlling for age, sex, years of education and tDCS group. Linear regression assessed the effect of TLV on post-intervention proximal composite and sub-composite, controlling for baseline performance, intervention assignment, age, sex, years of education, multisite scanner differences, estimated total intracranial volume, and binarized cardiovascular disease risk.
Results:RM-ANCOVA revealed two-way group*time interactions such that those assigned cognitive training demonstrated greater improvement on proximal composite (Total Training Composite) and sub-composite (Processing Speed Training Composite, Working Memory Training Composite) measures compared to their ET counterparts. Multiple linear regression showed higher baseline TLV associated with lower pre-post change on Processing Speed Training sub-composite (ß = -0.19, p = 0.04) but not other composite measures.
Conclusions:These findings demonstrate the utility of cognitive training for improving postintervention proximal performance in older adults. Additionally, pre-post proximal processing speed training change appear to be particularly sensitive to white matter hyperintensity load versus working memory training change. These data suggest that TLV may serve as an important factor for consideration when planning processing speed-based cognitive training interventions for remediation of cognitive decline in older adults.
1 Task-Based Functional Connectivity and Network Segregation of the Useful Field of View (UFOV) fMRI task
- Jessica N Kraft, Hanna K Hausman, Cheshire Hardcastle, Alejandro Albizu, Andrew O’Shea, Nicole D Evangelista, Emanuel M Boutzoukas, Emily J Van Etten, Pradyumna K Bharadwaj, Hyun Song, Samantha G Smith, Steven T DeKosky, Georg A Hishaw, Samuel Wu, Michael Marsiske, Ronald Cohen, Eric Porges, Adam J Woods
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 606-607
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Objective:
Interventions using a cognitive training paradigm called the Useful Field of View (UFOV) task have shown to be efficacious in slowing cognitive decline. However, no studies have looked at the engagement of functional networks during UFOV task completion. The current study aimed to (a) assess if regions activated during the UFOV fMRI task were functionally connected and related to task performance (henceforth called the UFOV network), (b) compare connectivity of the UFOV network to 7 resting-state functional connectivity networks in predicting proximal (UFOV) and near-transfer (Double Decision) performance, and (c) explore the impact of network segregation between higher-order networks and UFOV performance.
Participants and Methods:336 healthy older adults (mean age=71.6) completed the UFOV fMRI task in a Siemens 3T scanner. UFOV fMRI accuracy was calculated as the number of correct responses divided by 56 total trials. Double Decision performance was calculated as the average presentation time of correct responses in log ms, with lower scores equating to better processing speed. Structural and functional MRI images were processed using the default pre-processing pipeline within the CONN toolbox. The Artifact Rejection Toolbox was set at a motion threshold of 0.9mm and participants were excluded if more than 50% of volumes were flagged as outliers. To assess connectivity of regions associated with the UFOV task, we created 10 spherical regions of interest (ROIs) a priori using the WFU PickAtlas in SPM12. These include the bilateral pars triangularis, supplementary motor area, and inferior temporal gyri, as well as the left pars opercularis, left middle occipital gyrus, right precentral gyrus and right superior parietal lobule. We used a weighted ROI-to-ROI connectivity analysis to model task-based within-network functional connectivity of the UFOV network, and its relationship to UFOV accuracy. We then used weighted ROI-to-ROI connectivity analysis to compare the efficacy of the UFOV network versus 7 resting-state networks in predicting UFOV fMRI task performance and Double Decision performance. Finally, we calculated network segregation among higher order resting state networks to assess its relationship with UFOV accuracy. All functional connectivity analyses were corrected at a false discovery threshold (FDR) at p<0.05.
Results:ROI-to-ROI analysis showed significant within-network functional connectivity among the 10 a priori ROIs (UFOV network) during task completion (all pFDR<.05). After controlling for covariates, greater within-network connectivity of the UFOV network associated with better UFOV fMRI performance (pFDR=.008). Regarding the 7 resting-state networks, greater within-network connectivity of the CON (pFDR<.001) and FPCN (pFDR=. 014) were associated with higher accuracy on the UFOV fMRI task. Furthermore, greater within-network connectivity of only the UFOV network associated with performance on the Double Decision task (pFDR=.034). Finally, we assessed the relationship between higher-order network segregation and UFOV accuracy. After controlling for covariates, no significant relationships between network segregation and UFOV performance remained (all p-uncorrected>0.05).
Conclusions:To date, this is the first study to assess task-based functional connectivity during completion of the UFOV task. We observed that coherence within 10 a priori ROIs significantly predicted UFOV performance. Additionally, enhanced within-network connectivity of the UFOV network predicted better performance on the Double Decision task, while conventional resting-state networks did not. These findings provide potential targets to optimize efficacy of UFOV interventions.
78 BVMT-R Learning Ratio Moderates Cognitive Training Gains in Useful Field of View Task in Healthy Older Adults
- Cheshire Hardcastle, Jessica N. Kraft, Hanna K. Hausman, Andrew O’Shea, Alejandro Albizu, Nicole D. Evangelista, Emanuel Boutzoukas, Emily J. Van Etten, Pradyumna K. Bharadwaj, Hyun Song, Samantha G. Smith, Eric Porges, Steven DeKosky, Georg A. Hishaw, Samuel Wu, Michael Marsiske, Ronald Cohen, Gene E. Alexander, Adam J. Woods
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 180-181
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Objective:
Cognitive training using a visual speed-of-processing task, called the Useful Field of View (UFOV) task, reduced dementia risk and reduced decline in activities of daily living at a 10-year follow-up in older adults. However, there is variability in the level of cognitive gains after cognitive training across studies. One potential explanation for this variability could be moderating factors. Prior studies suggest variables moderating cognitive training gains share features of the training task. Learning trials of the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) recruit similar cognitive abilities and have overlapping neural correlates with the UFOV task and speed-ofprocessing/working memory tasks and therefore could serve as potential moderators. Exploring moderating factors of cognitive training gains may boost the efficacy of interventions, improve rigor in the cognitive training literature, and eventually help provide tailored treatment recommendations. This study explored the association between the HVLT-R and BVMT-R learning and the UFOV task, and assessed the moderation of HVLT-R and BVMT-R learning on UFOV improvement after a 3-month speed-ofprocessing/attention and working memory cognitive training intervention in cognitively healthy older adults.
Participants and Methods:75 healthy older adults (M age = 71.11, SD = 4.61) were recruited as part of a larger clinical trial through the Universities of Florida and Arizona. Participants were randomized into a cognitive training (n=36) or education control (n=39) group and underwent a 40-hour, 12-week intervention. Cognitive training intervention consisted of practicing 4 attention/speed-of-processing (including the UFOV task) and 4 working memory tasks. Education control intervention consisted of watching 40-minute educational videos. The HVLT-R and BVMT-R were administered at the pre-intervention timepoint as part of a larger neurocognitive battery. The learning ratio was calculated as: trial 3 total - trial 1 total/12 - trial 1 total. UFOV performance was measured at pre- and post-intervention time points via the POSIT Brain HQ Double Decision Assessment. Multiple linear regressions predicted baseline Double Decision performance from HVLT-R and BVMT-R learning ratios controlling for study site, age, sex, and education. A repeated measures moderation analysis assessed the moderation of HVLT-R and BVMT-R learning ratio on Double Decision change from pre- to post-intervention for cognitive training and education control groups.
Results:Baseline Double Decision performance significantly associated with BVMT-R learning ratio (β=-.303, p=.008), but not HVLT-R learning ratio (β=-.142, p=.238). BVMT-R learning ratio moderated gains in Double Decision performance (p<.01); for each unit increase in BVMT-R learning ratio, there was a .6173 unit decrease in training gains. The HVLT-R learning ratio did not moderate gains in Double Decision performance (p>.05). There were no significant moderations in the education control group.
Conclusions:Better visuospatial learning was associated with faster Double Decision performance at baseline. Those with poorer visuospatial learning improved most on the Double Decision task after training, suggesting that healthy older adults who perform below expectations may show the greatest training gains. Future cognitive training research studying visual speed-of-processing interventions should account for differing levels of visuospatial learning at baseline, as this could impact the magnitude of training outcomes.
6 Adjunctive Transcranial Direct Current Stimulation and Cognitive Training Alters Default Mode and Frontoparietal Control Network Connectivity in Older Adults
- Hanna K Hausman, Jessica N Kraft, Cheshire Hardcastle, Nicole D Evangelista, Emanuel M Boutzoukas, Andrew O’Shea, Alejandro Albizu, Emily J Van Etten, Pradyumna K Bharadwaj, Hyun Song, Samantha G Smith, Eric S Porges, Georg A Hishaw, Samuel Wu, Steven DeKosky, Gene E Alexander, Michael Marsiske, Ronald A Cohen, Adam J Woods
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 675-676
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Objective:
Aging is associated with disruptions in functional connectivity within the default mode (DMN), frontoparietal control (FPCN), and cingulo-opercular (CON) resting-state networks. Greater within-network connectivity predicts better cognitive performance in older adults. Therefore, strengthening network connectivity, through targeted intervention strategies, may help prevent age-related cognitive decline or progression to dementia. Small studies have demonstrated synergistic effects of combining transcranial direct current stimulation (tDCS) and cognitive training (CT) on strengthening network connectivity; however, this association has yet to be rigorously tested on a large scale. The current study leverages longitudinal data from the first-ever Phase III clinical trial for tDCS to examine the efficacy of an adjunctive tDCS and CT intervention on modulating network connectivity in older adults.
Participants and Methods:This sample included 209 older adults (mean age = 71.6) from the Augmenting Cognitive Training in Older Adults multisite trial. Participants completed 40 hours of CT over 12 weeks, which included 8 attention, processing speed, and working memory tasks. Participants were randomized into active or sham stimulation groups, and tDCS was administered during CT daily for two weeks then weekly for 10 weeks. For both stimulation groups, two electrodes in saline-soaked 5x7 cm2 sponges were placed at F3 (cathode) and F4 (anode) using the 10-20 measurement system. The active group received 2mA of current for 20 minutes. The sham group received 2mA for 30 seconds, then no current for the remaining 20 minutes.
Participants underwent resting-state fMRI at baseline and post-intervention. CONN toolbox was used to preprocess imaging data and conduct region of interest (ROI-ROI) connectivity analyses. The Artifact Detection Toolbox, using intermediate settings, identified outlier volumes. Two participants were excluded for having greater than 50% of volumes flagged as outliers. ROI-ROI analyses modeled the interaction between tDCS group (active versus sham) and occasion (baseline connectivity versus postintervention connectivity) for the DMN, FPCN, and CON controlling for age, sex, education, site, and adherence.
Results:Compared to sham, the active group demonstrated ROI-ROI increases in functional connectivity within the DMN following intervention (left temporal to right temporal [T(202) = 2.78, pFDR < 0.05] and left temporal to right dorsal medial prefrontal cortex [T(202) = 2.74, pFDR < 0.05]. In contrast, compared to sham, the active group demonstrated ROI-ROI decreases in functional connectivity within the FPCN following intervention (left dorsal prefrontal cortex to left temporal [T(202) = -2.96, pFDR < 0.05] and left dorsal prefrontal cortex to left lateral prefrontal cortex [T(202) = -2.77, pFDR < 0.05]). There were no significant interactions detected for CON regions.
Conclusions:These findings (a) demonstrate the feasibility of modulating network connectivity using tDCS and CT and (b) provide important information regarding the pattern of connectivity changes occurring at these intervention parameters in older adults. Importantly, the active stimulation group showed increases in connectivity within the DMN (a network particularly vulnerable to aging and implicated in Alzheimer’s disease) but decreases in connectivity between left frontal and temporal FPCN regions. Future analyses from this trial will evaluate the association between these changes in connectivity and cognitive performance post-intervention and at a one-year timepoint.
9 Connecting memory and functional brain networks in older adults: a resting state fMRI study
- Jori L Waner, Hanna K Hausman, Jessica N Kraft, Cheshire Hardcastle, Nicole D Evangelista, Andrew O’Shea, Alejandro Albizu, Emanuel M Boutzoukas, Emily J Van Etten, Pradyumna K Bharadwaj, Hyun Song, Samantha G Smith, Steven T DeKosky, Georg A Hishaw, Samuel S Wu, Michael Marsiske, Ronald Cohen, Gene E Alexander, Eric C Porges, Adam J Woods
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- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 527-528
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Objective:
Nonpathological aging has been linked to decline in both verbal and visuospatial memory abilities in older adults. Disruptions in resting-state functional connectivity within well-characterized, higherorder cognitive brain networks have also been coupled with poorer memory functioning in healthy older adults and in older adults with dementia. However, there is a paucity of research on the association between higherorder functional connectivity and verbal and visuospatial memory performance in the older adult population. The current study examines the association between resting-state functional connectivity within the cingulo-opercular network (CON), frontoparietal control network (FPCN), and default mode network (DMN) and verbal and visuospatial learning and memory in a large sample of healthy older adults. We hypothesized that greater within-network CON and FPCN functional connectivity would be associated with better immediate verbal and visuospatial memory recall. Additionally, we predicted that within-network DMN functional connectivity would be associated with improvements in delayed verbal and visuospatial memory recall. This study helps to glean insight into whether within-network CON, FPCN, or DMN functional connectivity is associated with verbal and visuospatial memory abilities in later life.
Participants and Methods:330 healthy older adults between 65 and 89 years old (mean age = 71.6 ± 5.2) were recruited at the University of Florida (n = 222) and the University of Arizona (n = 108). Participants underwent resting-state fMRI and completed verbal memory (Hopkins Verbal Learning Test - Revised [HVLT-R]) and visuospatial memory (Brief Visuospatial Memory Test - Revised [BVMT-R]) measures. Immediate (total) and delayed recall scores on the HVLT-R and BVMT-R were calculated using each test manual’s scoring criteria. Learning ratios on the HVLT-R and BVMT-R were quantified by dividing the number of stimuli (verbal or visuospatial) learned between the first and third trials by the number of stimuli not recalled after the first learning trial. CONN Toolbox was used to extract average within-network connectivity values for CON, FPCN, and DMN. Hierarchical regressions were conducted, controlling for sex, race, ethnicity, years of education, number of invalid scans, and scanner site.
Results:Greater CON connectivity was significantly associated with better HVLT-R immediate (total) recall (ß = 0.16, p = 0.01), HVLT-R learning ratio (ß = 0.16, p = 0.01), BVMT-R immediate (total) recall (ß = 0.14, p = 0.02), and BVMT-R delayed recall performance (ß = 0.15, p = 0.01). Greater FPCN connectivity was associated with better BVMT-R learning ratio (ß = 0.13, p = 0.04). HVLT-R delayed recall performance was not associated with connectivity in any network, and DMN connectivity was not significantly related to any measure.
Conclusions:Connectivity within CON demonstrated a robust relationship with different components of memory function as well across verbal and visuospatial domains. In contrast, FPCN only evidenced a relationship with visuospatial learning, and DMN was not significantly associated with memory measures. These data suggest that CON may be a valuable target in longitudinal studies of age-related memory changes, but also a possible target in future non-invasive interventions to attenuate memory decline in older adults.
Ten new insights in climate science 2023
- Mercedes Bustamante, Joyashree Roy, Daniel Ospina, Ploy Achakulwisut, Anubha Aggarwal, Ana Bastos, Wendy Broadgate, Josep G. Canadell, Edward R. Carr, Deliang Chen, Helen A. Cleugh, Kristie L. Ebi, Clea Edwards, Carol Farbotko, Marcos Fernández-Martínez, Thomas L. Frölicher, Sabine Fuss, Oliver Geden, Nicolas Gruber, Luke J. Harrington, Judith Hauck, Zeke Hausfather, Sophie Hebden, Aniek Hebinck, Saleemul Huq, Matthias Huss, M. Laurice P. Jamero, Sirkku Juhola, Nilushi Kumarasinghe, Shuaib Lwasa, Bishawjit Mallick, Maria Martin, Steven McGreevy, Paula Mirazo, Aditi Mukherji, Greg Muttitt, Gregory F. Nemet, David Obura, Chukwumerije Okereke, Tom Oliver, Ben Orlove, Nadia S. Ouedraogo, Prabir K. Patra, Mark Pelling, Laura M. Pereira, Åsa Persson, Julia Pongratz, Anjal Prakash, Anja Rammig, Colin Raymond, Aaron Redman, Cristobal Reveco, Johan Rockström, Regina Rodrigues, David R. Rounce, E. Lisa F. Schipper, Peter Schlosser, Odirilwe Selomane, Gregor Semieniuk, Yunne-Jai Shin, Tasneem A. Siddiqui, Vartika Singh, Giles B. Sioen, Youba Sokona, Detlef Stammer, Norman J. Steinert, Sunhee Suk, Rowan Sutton, Lisa Thalheimer, Vikki Thompson, Gregory Trencher, Kees van der Geest, Saskia E. Werners, Thea Wübbelmann, Nico Wunderling, Jiabo Yin, Kirsten Zickfeld, Jakob Zscheischler
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- Journal:
- Global Sustainability / Volume 7 / 2024
- Published online by Cambridge University Press:
- 01 December 2023, e19
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Non-technical summary
We identify a set of essential recent advances in climate change research with high policy relevance, across natural and social sciences: (1) looming inevitability and implications of overshooting the 1.5°C warming limit, (2) urgent need for a rapid and managed fossil fuel phase-out, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future contribution of natural carbon sinks, (5) intertwinedness of the crises of biodiversity loss and climate change, (6) compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems.
Technical summaryThe Intergovernmental Panel on Climate Change Assessment Reports provides the scientific foundation for international climate negotiations and constitutes an unmatched resource for researchers. However, the assessment cycles take multiple years. As a contribution to cross- and interdisciplinary understanding of climate change across diverse research communities, we have streamlined an annual process to identify and synthesize significant research advances. We collected input from experts on various fields using an online questionnaire and prioritized a set of 10 key research insights with high policy relevance. This year, we focus on: (1) the looming overshoot of the 1.5°C warming limit, (2) the urgency of fossil fuel phase-out, (3) challenges to scale-up carbon dioxide removal, (4) uncertainties regarding future natural carbon sinks, (5) the need for joint governance of biodiversity loss and climate change, (6) advances in understanding compound events, (7) accelerated mountain glacier loss, (8) human immobility amidst climate risks, (9) adaptation justice, and (10) just transitions in food systems. We present a succinct account of these insights, reflect on their policy implications, and offer an integrated set of policy-relevant messages. This science synthesis and science communication effort is also the basis for a policy report contributing to elevate climate science every year in time for the United Nations Climate Change Conference.
Social media summaryWe highlight recent and policy-relevant advances in climate change research – with input from more than 200 experts.
Clinical, behavioral, and electrophysiological profiles along a continuum of suicide risk: evidence from an implicit association task
- Steven J. Lamontagne, Jessica R. Gilbert, Paloma K. Zabala, Laura R. Waldman, Carlos A. Zarate, Jr, Elizabeth D. Ballard
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- Journal:
- Psychological Medicine / Volume 54 / Issue 7 / May 2024
- Published online by Cambridge University Press:
- 24 November 2023, pp. 1431-1440
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Background
An urgent need exists to identify neural correlates associated with differing levels of suicide risk and develop novel, rapid-acting therapeutics to modulate activity within these neural networks.
MethodsElectrophysiological correlates of suicide were evaluated using magnetoencephalography (MEG) in 75 adults with differing levels of suicide risk. During MEG scanning, participants completed a modified Life-Death Implicit Association Task. MEG data were source-localized in the gamma (30–58 Hz) frequency, a proxy measure of excitation-inhibition balance. Dynamic causal modeling was used to evaluate differences in connectivity estimates between risk groups. A proof-of-concept, open-label, pilot study of five high risk participants examined changes in gamma power after administration of ketamine (0.5 mg/kg), an NMDAR antagonist with rapid anti-suicide ideation effects.
ResultsImplicit self-associations with death were stronger in the highest suicide risk group relative to all other groups, which did not differ from each other. Higher gamma power for self-death compared to self-life associations was found in the orbitofrontal cortex for the highest risk group and the insula and posterior cingulate cortex for the lowest risk group. Connectivity estimates between these regions differentiated the highest risk group from the full sample. Implicit associations with death were not affected by ketamine, but enhanced gamma power was found for self-death associations in the left insula post-ketamine compared to baseline.
ConclusionsDifferential implicit cognitive processing of life and death appears to be linked to suicide risk, highlighting the need for objective measures of suicidal states. Pharmacotherapies that modulate gamma activity, particularly in the insula, may help mitigate risk.
Clinicaltrials.gov identifier: NCT02543983, NCT00397111.
GHOSTly flute music: drumlins, moats and the bed of Thwaites Glacier
- Richard B. Alley, Nick Holschuh, Byron Parizek, Lucas K. Zoet, Kiya Riverman, Atsuhiro Muto, Knut Christianson, Elisabeth Clyne, Sridhar Anandakrishnan, Nathan T. Stevens
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- Journal:
- Annals of Glaciology / Volume 63 / Issue 87-89 / September 2022
- Published online by Cambridge University Press:
- 23 August 2023, pp. 153-157
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Glacier-bed characteristics that are poorly known and modeled are important in projected sea-level rise from ice-sheet changes under strong warming, especially in the Thwaites Glacier drainage of West Antarctica. Ocean warming may induce ice-shelf thinning or loss, or thinning of ice in estuarine zones, reducing backstress on grounded ice. Models indicate that, in response, more-nearly-plastic beds favor faster ice loss by causing larger flow acceleration, but more-nearly-viscous beds favor localized near-coastal thinning that could speed grounding-zone retreat into interior basins where marine-ice-sheet instability or cliff instability could develop and cause very rapid ice loss. Interpretation of available data indicates that the bed is spatially mosaicked, with both viscous and plastic regions. Flow against bedrock topography removes plastic lubricating tills, exposing bedrock that is eroded on up-glacier sides of obstacles to form moats with exposed bedrock tails extending downglacier adjacent to lee-side soft-till bedforms. Flow against topography also generates high-ice-pressure zones that prevent inflow of lubricating water over distances that scale with the obstacle size. Extending existing observations to sufficiently large regions, and developing models assimilating such data at the appropriate scale, present large, important research challenges that must be met to reliably project future forced sea-level rise.
Agricultural Research Service Weed Science Research: Past, Present, and Future
- Stephen L. Young, James V. Anderson, Scott R. Baerson, Joanna Bajsa-Hirschel, Dana M. Blumenthal, Chad S. Boyd, Clyde D. Boyette, Eric B. Brennan, Charles L. Cantrell, Wun S. Chao, Joanne C. Chee-Sanford, Charlie D. Clements, F. Allen Dray, Stephen O. Duke, Kayla M. Eason, Reginald S. Fletcher, Michael R. Fulcher, John F. Gaskin, Brenda J. Grewell, Erik P. Hamerlynck, Robert E. Hoagland, David P. Horvath, Eugene P. Law, John D. Madsen, Daniel E. Martin, Clint Mattox, Steven B. Mirsky, William T. Molin, Patrick J. Moran, Rebecca C. Mueller, Vijay K. Nandula, Beth A. Newingham, Zhiqiang Pan, Lauren M. Porensky, Paul D. Pratt, Andrew J. Price, Brian G. Rector, Krishna N. Reddy, Roger L. Sheley, Lincoln Smith, Melissa C. Smith, Keirith A. Snyder, Matthew A. Tancos, Natalie M. West, Gregory S. Wheeler, Martin M. Williams, Julie Wolf, Carissa L. Wonkka, Alice A. Wright, Jing Xi, Lew H. Ziska
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- Journal:
- Weed Science / Volume 71 / Issue 4 / July 2023
- Published online by Cambridge University Press:
- 16 August 2023, pp. 312-327
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The U.S. Department of Agriculture–Agricultural Research Service (USDA-ARS) has been a leader in weed science research covering topics ranging from the development and use of integrated weed management (IWM) tactics to basic mechanistic studies, including biotic resistance of desirable plant communities and herbicide resistance. ARS weed scientists have worked in agricultural and natural ecosystems, including agronomic and horticultural crops, pastures, forests, wild lands, aquatic habitats, wetlands, and riparian areas. Through strong partnerships with academia, state agencies, private industry, and numerous federal programs, ARS weed scientists have made contributions to discoveries in the newest fields of robotics and genetics, as well as the traditional and fundamental subjects of weed–crop competition and physiology and integration of weed control tactics and practices. Weed science at ARS is often overshadowed by other research topics; thus, few are aware of the long history of ARS weed science and its important contributions. This review is the result of a symposium held at the Weed Science Society of America’s 62nd Annual Meeting in 2022 that included 10 separate presentations in a virtual Weed Science Webinar Series. The overarching themes of management tactics (IWM, biological control, and automation), basic mechanisms (competition, invasive plant genetics, and herbicide resistance), and ecosystem impacts (invasive plant spread, climate change, conservation, and restoration) represent core ARS weed science research that is dynamic and efficacious and has been a significant component of the agency’s national and international efforts. This review highlights current studies and future directions that exemplify the science and collaborative relationships both within and outside ARS. Given the constraints of weeds and invasive plants on all aspects of food, feed, and fiber systems, there is an acknowledged need to face new challenges, including agriculture and natural resources sustainability, economic resilience and reliability, and societal health and well-being.
Central-line team effort: Recognizing insertion-site concerns in nursing homes
- Kristine P. Nguyen, Raveena D. Singh, Raheeb Saavedra, Shruti K. Gohil, John T. Billimek, Steven P. Tam, Karl E. Steinberg, Lori Porter, Susan S. Huang
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 44 / Issue 11 / November 2023
- Published online by Cambridge University Press:
- 04 August 2023, pp. 1887-1889
- Print publication:
- November 2023
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Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals
- Cecilia A. Hinojosa, Amanda Liew, Xinming An, Jennifer S. Stevens, Archana Basu, Sanne J. H. van Rooij, Stacey L. House, Francesca L. Beaudoin, Donglin Zeng, Thomas C. Neylan, Gari D. Clifford, Tanja Jovanovic, Sarah D. Linnstaedt, Laura T. Germine, Scott L. Rauch, John P. Haran, Alan B. Storrow, Christopher Lewandowski, Paul I. Musey, Phyllis L. Hendry, Sophia Sheikh, Christopher W. Jones, Brittany E. Punches, Michael C. Kurz, Robert A. Swor, Lauren A. Hudak, Jose L. Pascual, Mark J. Seamon, Elizabeth M. Datner, Anna M. Chang, Claire Pearson, David A. Peak, Roland C. Merchant, Robert M. Domeier, Niels K. Rathlev, Paulina Sergot, Leon D. Sanchez, Steven E. Bruce, Mark W. Miller, Robert H. Pietrzak, Jutta Joormann, Diego A. Pizzagalli, John F. Sheridan, Steven E. Harte, James M. Elliott, Ronald C. Kessler, Karestan C. Koenen, Samuel A. McLean, Kerry J. Ressler, Negar Fani
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- Journal:
- Psychological Medicine / Volume 54 / Issue 2 / January 2024
- Published online by Cambridge University Press:
- 13 June 2023, pp. 338-349
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Background
Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians.
MethodsIn total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance.
ResultsThree trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12.
ConclusionsOur findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.
P.011 Is the effect of the vagus nerve stimulation different in lesional and nonlesional medically resistant epilepsies?
- R Moshref, J Burneo, M Jones, D Steven, K Macdougall, A SullerMarti
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- Journal:
- Canadian Journal of Neurological Sciences / Volume 50 / Issue s2 / June 2023
- Published online by Cambridge University Press:
- 05 June 2023, p. S60
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Background: The incidence of drug resistant epilepsy (DRE) is around 30% patients with epilepsy. Vagus nerve stimulation (VNS) is offered to patients who are not candidates for epilepsy resective surgery, however the results of lesional cases has not been explored previously Methods: The study was a retrospective cohort study that involved patients with DRE implanted with VNS at the Epilepsy program at Western University, Ontario. We classified our VNS cohort based on brain imaging of lesional (L) and nonlesional (NL) epilepsy. Results: The median age was 31.8 years, 70.69% were females. The VNS-L group average age was 31.8 years and the NL 35.2 years. The most common abnormality was nodular heterotropias 31.34% (n=9). 16 patients underwent palliative procedures before the VNS implantation, 12 in VNS-L and 4 in VNS-NL. The median period of follow-up was 69.97 months. 62% of the VNS-L group had a seizure reduction of 50% or greater, compared to 41.38% in the VNS-NL group. Seizure freedom was 10.34% in VNS-L, compared to 6.99% in VNS-NL. Conclusions: This is the first study reporting the outcome of VNS in lesional cases. Our results suggest that VNS in lesional cases is effective. However, a large multicenteric study is needed.
Post-Traumatic Cognitions Inventory (PTCI): psychometric properties in clients with serious mental illness and co-occurring PTSD
- Weili Lu, Kim T. Mueser, Philip T. Yanos, Amanda Siriram, Yuane Jia, Alyssa Leong, Steven M. Silverstein, Jennifer Gottlieb, Mary K. Jankowski
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- Journal:
- Behavioural and Cognitive Psychotherapy / Volume 51 / Issue 5 / September 2023
- Published online by Cambridge University Press:
- 22 May 2023, pp. 459-474
- Print publication:
- September 2023
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Background:
People with post-traumatic stress disorder (PTSD) exhibit negative cognitions, predictive of PTSD severity. The Post-Traumatic Cognitions Inventory (PTCI) is a widely used instrument measuring trauma-related cognitions and beliefs with three subscales: negative thoughts of self (SELF), negative cognitions about the world (WORLD), and self-blame (BLAME).
Aims:The current study attempted to validate the use of the PTCI in people with serious mental illness (SMI), who have greater exposure to trauma and elevated rates of PTSD, using confirmatory factor analysis (CFA) and examining convergent and divergent correlations with relevant constructs.
Method:Participants were 432 individuals with SMI and co-occurring PTSD diagnosis based on the Clinician Administered PTSD Scale, who completed PTCI and other clinical ratings.
Results:CFAs provided adequate support for Foa’s three-factor model (SELF, WORLD, BLAME), and adequate support for Sexton’s four-factor model that also included a COPE subscale. Both models achieved measurement invariance at configural, metric and scalar levels for three diagnostic groups: schizophrenia, bipolar and major depression, as well as for ethnicity (White vs Black), and gender (male vs female). Validity of both models was supported by significant correlations between PTCI subscales, and self-reported and clinician assessed PTSD symptoms and associated symptoms.
Conclusions:Findings provide support for the psychometric properties of the PTCI and the conceptualization of Sexton’s four-factor and Foa’s three-factor models of PTCI among individuals diagnosed with SMI (Foa et al., 1999).
319 Optimizing Urinary cell mRNA profiling of kidney allograft recipients: Development of a home processing protocol for noninvasive diagnosis of T cell mediated rejection and BK virus nephropathy
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- Thalia Salinas, Carol Li, Catherine Snopkowski, Gabriel Stryjniak, Divya Shankaranarayanan, Shady Albakry, Ruchuang Ding, Vijay K. Sharma, Steven P. Salvatore, Surya V. Seshan, Darshana M. Dadhania, Thangamani Muthukumar, Manikkam Suthanthiran
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue s1 / April 2023
- Published online by Cambridge University Press:
- 24 April 2023, pp. 95-96
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OBJECTIVES/GOALS: Development of a user friendly home kit that enables kidney transplant recipients to process urine at home and post the lysate containing RNA to a Core Laboratory would simplify urinary cell mRNA profiling and facilitate longitudinal monitoring. We report our home processing protocol and investigation of its diagnostic performance characteristics. METHODS/STUDY POPULATION: We developed a home processing protocol (HPP) consisting of urine filtration and lysis of urinary cells, both performed at home by the kidney transplant recipients (KTR) themselves, followed by isolation of total RNA from the lysate and mRNA enrichment using a silica-membrane-based cartridge, both performed at the Core Laboratory. Using the HPP, total RNA was isolated from kidney allograft biopsy-matched urines and absolute copy numbers of CD3εmRNA, CXCL10 mRNA, and 18S rRNA, components of the Clinical Trials in Organ Transplantation 04 (CTOT-04) three-gene TCMR diagnostic signature, and urinary cell BKV VP1 mRNA copy number, were measured using customized RT-qPCR assays. RESULTS/ANTICIPATED RESULTS: CTOT-04 three-gene TCMR diagnostic signature scores in urine processed using HPP discriminated KTR with TCMR (12 TCMR biopsies from 11 KTR) from KTR with no TCMR/BKVN (29 No TCMR/No BKVN biopsies from 29 KTR) (P=0.0005, Mann-Whitney test), and AUROC was 0.84 (95% CI, 0.69 to 0.98). TCMR was diagnosed with sensitivity of 67% (95% CI, 35 to 89) at a specificity of 86% (95% CI, 67 to 95) using the CTOT-04 validated cutpoint of -1.213 (P=0.0016,Fisher exact test). BKV VP1 mRNA copy number in urine processed with HPP discriminated KTR with BKVN (n=7) from KTR with no TCMR/BKVN (n=29) and AUROC was 1.0 (95% CI, 1.00 to 1.00). BKVN was diagnosed with a sensitivity of 86% (95% CI, 42 to 99) at specificity of 100% (95% CI, 85 to 100) with the previously validated cutpoint of 6.5x10^8 BKV VP1 mRNA copies/μg of RNA (P DISCUSSION/SIGNIFICANCE: Urine processed using the HPP predicted TCMR and BKVN in KTR. The HPP represents not only a significant advance towards portability of urinary cell mRNA profiling but also should improve patient management by minimizing visits for urine collection.
Safety and efficacy of KarXT (Xanomeline Trospium) in Schizophrenia in the Phase 3, Randomized, Double-Blind, Placebo-Controlled EMERGENT-2 Trial
- Christoph U. Correll, Andrew C. Miller, Sharon Sawchak, Inder Kaul, Steven M. Paul, Stephen K. Brannan
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 220
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Introduction
KarXT combines the M1/M4 preferring muscarinic receptor agonist xanomeline and the peripherally restricted anticholinergic trospium. In the phase 2 EMERGENT-1 study, KarXT met the primary endpoint of a significant reduction in Positive and Negative Syndrome Scale (PANSS) total score through week 5 vs placebo, improved other key secondary efficacy measures, and was generally well tolerated.
MethodsEMERGENT-2 was a phase 3, randomized, double-blind, placebo-controlled, 5-week trial of KarXT in acutely psychotic patients with schizophrenia in the inpatient setting. Eligible patients were randomized 1:1 to KarXT or matched placebo. Dosing of KarXT (mg xanomeline/mg trospium) started at 50 mg/20 mg BID and increased to a maximum of 125 mg/30 mg BID. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Key secondary endpoints included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, and PANSS negative Marder factor scores compared with placebo. Efficacy analyses were performed using the modified intent-to-treat population (patients with ≥1 dose of study medication, a baseline PANSS assessment, and ≥1 postbaseline PANSS assessment). All patients receiving ≥1 dose of study drug were included in safety analyses.
Results252 US patients were enrolled. KarXT demonstrated a statistically significant and clinically meaningful 9.6-point reduction from baseline to week 5 (effect size=0.61) in PANSS total score vs placebo (p<0.0001); a significant improvement in PANSS total score was demonstrated starting at week 2 (first postbaseline rating) and continued through the study end. KarXT also met key secondary endpoints. Results at week 5 included a 2.9-point reduction in PANSS positive subscale score with KarXT vs placebo (p<0.0001), a 1.8-point reduction in PANSS negative subscale score with KarXT vs placebo (p=0.0055), and a 2.2-point reduction in PANSS negative Marder factor score with KarXT vs placebo (p=0.0022). KarXT was generally well tolerated. Overall discontinuation rates were similar with KarXT (25%) and placebo (21%). The overall treatment-emergent adverse events (TEAEs) rate for KarXT and placebo was 75% and 58%, respectively. Discontinuation rates related to TEAEs were similar between KarXT (7%) and placebo (6%). Rates of serious TEAEs were similar with KarXT and placebo (2%, each group); no serious TEAEs were determined to be drug related. The most common TEAEs (≥5%) with KarXT were all mild to moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, blood pressure increases, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea. KarXT was not associated with sedation/somnolence, weight gain, and extrapyramidal symptoms.
ConclusionsKarXT has the potential to be the first in a new class of treatments for patients with schizophrenia and a promising alternative to postsynaptic dopamine D2 receptor antagonists.
FundingKaruna Therapeutics, Inc.