An autonomous debating system.

Artificial intelligence (AI) is defined as the ability of machines to perform tasks that are usually associated with intelligent beings. Argument and debate are fundamental capabilities of human intelligence, essential for a wide range of human activities, and common to all human societies. The development of computational argumentation technologies is therefore an important emerging discipline in AI research1. Here we present Project Debater, an autonomous debating system that can engage in a competitive debate with humans. We provide a complete description of the system's architecture, a thorough and systematic evaluation of its operation across a wide range of debate topics, and a detailed account of the system's performance in its public debut against three expert human debaters. We also highlight the fundamental differences between debating with humans as opposed to challenging humans in game competitions, the latter being the focus of classical 'grand challenges' pursued by the AI research community over the past few decades. We suggest that such challenges lie in the 'comfort zone' of AI, whereas debating with humans lies in a different territory, in which humans still prevail, and for which novel paradigms are required to make substantial progress.

Mouse embryo CoCoPUTs: novel murine transcriptomic-weighted usage website featuring multiple strains, tissues, and stages.

Mouse (Mus musculus) models have been heavily utilized in developmental biology research to understand mammalian embryonic development, as mice share many genetic, physiological, and developmental characteristics with humans. New explorations into the integration of temporal (stage-specific) and transcriptional (tissue-specific) data have expanded our knowledge of mouse embryo tissue-specific gene functions. To better understand the substantial impact of synonymous mutational variations in the cell-state-specific transcriptome on a tissue's codon and codon pair usage landscape, we have established a novel resource-Mouse Embryo Codon and Codon Pair Usage Tables (Mouse Embryo CoCoPUTs). This webpage not only offers codon and codon pair usage, but also GC, dinucleotide, and junction dinucleotide usage, encompassing four strains, 15 murine embryonic tissue groups, 18 Theiler stages, and 26 embryonic days. Here, we leverage Mouse Embryo CoCoPUTs and employ the use of heatmaps to depict usage changes over time and a comparison to human usage for each strain and embryonic time point, highlighting unique differences and similarities. The usage similarities found between mouse and human central nervous system data highlight the translation for projects leveraging mouse models. Data for this analysis can be directly retrieved from Mouse Embryo CoCoPUTs. This cutting-edge resource plays a crucial role in deciphering the complex interplay between usage patterns and embryonic development, offering valuable insights into variation across diverse tissues, strains, and stages. Its applications extend across multiple domains, with notable advantages for biotherapeutic development, where optimizing codon usage can enhance protein expression; one can compare strains, tissues, and mouse embryonic stages in one query. Additionally, Mouse Embryo CoCoPUTs holds great potential in the field of tissue-specific genetic engineering, providing insights for tailoring gene expression to specific tissues for targeted interventions. Furthermore, this resource may enhance our understanding of the nuanced connections between usage biases and tissue-specific gene function, contributing to the development of more accurate predictive models for genetic disorders.

New approaches to predict the effect of co-occurring variants on protein characteristics.

Predicting the effect of a mutated gene before the onset of symptoms of genetic diseases would greatly facilitate diagnosis and potentiate early intervention. There have been myriad attempts to predict the effects of single-nucleotide variants. However, the applicability of these efforts does not scale to co-occurring variants. Furthermore, an increasing number of protein therapeutics contain co-occurring nucleotide variations, adding uncertainty during development to the safety and efficiency of these drugs. Co-occurring nucleotide variants may often have synergistic, additive, or antagonistic effects on protein attributes, further complicating the task of outcome prediction. We tested four models based on the cooperative and antagonistic effects of co-occurring variants to predict pathogenicity and effectiveness of protein therapeutics. A total of 30 attributes, including amino acid and nucleotide features, as well as existing single-variant effect prediction tools, were considered on the basis of previous studies on single-nucleotide variants. Importantly, the effects of synonymous variants, often seen in protein therapeutics, were also included in our models. We used 12 datasets of people with monogenic diseases and controls with co-occurring genetic variants to evaluate the accuracy of our models, accomplishing a degree of accuracy comparable to that of prediction tools for single-nucleotide variants. More importantly, our framework is generalizable to new, well-curated datasets of monogenic diseases and new variant scoring tools. This approach successfully assists in addressing the challenging task of predicting the effect of co-occurring variants on pathogenicity and protein effectiveness and is applicable for a wide range of protein therapeutics and genetic diseases.

Neural activation changes following attention bias modification treatment or a selective serotonin reuptake inhibitor for social anxiety disorder.

BACKGROUND: Delineation of changes in neural function associated with novel and established treatments for social anxiety disorder (SAD) can advance treatment development. We examined such changes following selective serotonin reuptake inhibitor (SSRI) and attention bias modification (ABM) variant - gaze-contingent music reward therapy (GC-MRT), a first-line and an emerging treatments for SAD. METHODS: Eighty-one patients with SAD were allocated to 12-week treatments of either SSRI or GC-MRT, or waitlist (ns = 22, 29, and 30, respectively). Baseline and post-treatment functional magnetic resonance imaging (fMRI) data were collected during a social-threat processing task, in which attention was directed toward and away from threat/neutral faces. RESULTS: Patients who received GC-MRT or SSRI showed greater clinical improvement relative to patients in waitlist. Compared to waitlist patients, treated patients showed greater activation increase in the right inferior frontal gyrus and anterior cingulate cortex when instructed to attend toward social threats and away from neutral stimuli. An additional anterior cingulate cortex cluster differentiated between the two active groups. Activation in this region increased in ABM and decreased in SSRI. In the ABM group, symptom change was positively correlated with neural activation change in the dorsolateral prefrontal cortex. CONCLUSIONS: Brain function measures show both shared and treatment-specific changes following ABM and SSRI treatments for SAD, highlighting the multiple pathways through which the two treatments might work. Treatment-specific neural responses suggest that patients with SAD who do not fully benefit from SSRI or ABM may potentially benefit from the alternative treatment, or from a combination of the two. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03346239. https://clinicaltrials.gov/ct2/show/NCT03346239.

Elevated integration within the reward network underlies vulnerability to distress.

Distress tolerance (DT), the capability to persist under negative circumstances, underlies a range of psychopathologies. It has been proposed that DT may originate from the activity and connectivity in diverse neural networks integrated by the reward system. To test this hypothesis, we examined the link between DT and integration and segregation in the reward network as derived from resting-state functional connectivity data. DT was measured in 147 participants from a large community sample using the Behavioral Indicator of Resiliency to Distress task. Prior to DT evaluation, participants underwent a resting-state functional magnetic resonance imaging scan. For each participant, we constructed a whole-brain functional connectivity network and calculated the degree of reward network integration and segregation based on the extent to which reward network nodes showed functional connections within and outside their network. We found that distress-intolerant participants demonstrated heightened reward network integration relative to the distress-tolerant participants. In addition, these differences in integration were higher relative to the rest of the brain and, more specifically, the somatomotor network, which has been implicated in impulsive behavior. These findings support the notion that increased integration in large-scale brain networks may constitute a risk for distress intolerance and its psychopathological correlates.

Identification of T-Cell Epitopes Using a Combined In-Silico and Experimental Approach in a Mouse Model for SARS-CoV-2.

Following viral infection, T-cells are crucial for an effective immune response to intracellular pathogens, including respiratory viruses. During the COVID-19 pandemic, diverse assays were required in pre-clinical trials to evaluate the immune response following vaccination against SARS-CoV-2 and assess the response following exposure to the virus. To assess the nature and potency of the cellular response to infection or vaccination, a reliable and specific activity assay was needed. A cellular activity assay based on the presentation of short peptides (epitopes) allows the identification of T cell epitopes displayed on different alleles of the MHC, shedding light on the strength of the immune response towards antigens and aiding in antigen design for vaccination. In this report, we describe two approaches for scanning T cell epitopes on the surface glycoprotein of the SARS-CoV-2 (spike), which is utilized for attachment and entry and serves as an antigen in many vaccine candidates. We demonstrate that epitope scanning is feasible using peptide libraries or computational scanning combined with a cellular activity assay. Our scans identified four CD8 T cell epitopes, including one novel undescribed epitope. These epitopes enabled us to establish a reliable T-cell response assay, which was examined and used in various experimental mouse models for SARS-CoV-2 infection and vaccination. These approaches could potentially aid in future antigen design for vaccination and establish cellular activity assays against uncharacterized antigens of emerging pathogens.

A randomized controlled trial of supervised remotely-delivered attention bias modification for posttraumatic stress disorder.

BACKGROUND: Many individuals with posttraumatic stress disorder (PTSD) have limited access to first-line treatments, warranting the development of remotely-delivered treatments. Attention bias modification (ABM), targeting perturbed threat-related attentional patterns, shows promise when delivered in-person. However, previous studies found ABM to be ineffective when delivered remotely. Randomized clinical trials usually applied two variations of ABM: ABM away from threat or attention control training (ACT) balancing attention between threat-related and neutral stimuli. We tested remotely-delivered ACT/ABM with tighter supervision and video-based interactions that resemble in-clinic protocols. We expected to replicate the results of in-clinic trials, in which ACT outperformed ABM for PTSD. METHODS: In this double-blinded, parallel-group randomized controlled trial, 60 patients diagnosed with PTSD were randomized (ABM n = 30; ACT n = 30). Patients performed eight bi-weekly remotely-delivered supervised ABM/ACT sessions. Symptoms were assessed pre- and post-treatment with Clinician-Administered PTSD Scale 5 (CAPS-5) severity score and PTSD diagnosis as the primary outcomes. Current depressive episode, current anxiety-related comorbidity, and time elapsed since the trauma were examined as potential moderators of treatment outcome. RESULTS: Significant decrease in CAPS-5 severity scores and PTSD diagnosis was observed following both ACT and ABM with no between-group difference. Patients without depression or whose trauma occurred more recently had greater symptom reduction in the ACT than the ABM group. CONCLUSIONS: Contrary to our expectation, symptoms decreased similarly following ACT and ABM. Moderator analyses suggest advantage for ACT in non-depressed patients and patients whose trauma occurred more recently. Further refinements in remotely-delivered ABM/ACT may be needed.

Attention allocation to negatively-valenced stimuli in PTSD is associated with reward-related neural pathways.

BACKGROUND: In a recent eye-tracking study we found a differential dwell time pattern for negatively-valenced and neutral faces among patients with posttraumatic stress disorder (PTSD), trauma-exposed healthy control (TEHCs), and healthy control (HC) participants. Here, we explored whether these group differences relate to resting-state functional connectivity (rsFC) patterns of brain areas previously linked to both attention processes and PTSD. These encompass the amygdala, dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and nucleus accumbens (NAcc). METHODS: Ten minutes magnetic resonance imaging rsFC scans were recorded in 17 PTSD patients, 21 TEHCs, and 16 HCs. Participants then completed a free-viewing eye-tracking task assessing attention allocation outside the scanner. Dwell time on negatively-valenced stimuli (DT%) were assessed relative to functional connectivity in the aforementioned seed regions of interest (amygdala, dACC, dlPFC, vlPFC, and NAcc) to whole-brain voxel-wise rsFC. RESULTS: As previously reported, group differences occurred in attention allocation to negative-valence stimuli, with longer dwell time on negatively valence stimuli in the PTSD and TEHC groups than the HC group. Higher DT% correlated with weaker NAcc-orbitofrontal cortex (OFC) connectivity in patients with PTSD. Conversely, a positive association emerged in the HC group between DT% and NAcc-OFC connectivity. CONCLUSIONS: While exploratory in nature, present findings may suggest that reward-related brain areas are involved in disengaging attention from negative-valenced stimuli, and possibly in regulating ensuing negative emotions.

Resting state connectivity predictors of symptom change during gaze-contingent music reward therapy of social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is common, first-line treatments are often only partially effective, and reliable predictors of treatment response are lacking. Here, we assessed resting state functional connectivity (rsFC) at pre-treatment and during early treatment as a potential predictor of response to a novel attention bias modification procedure, gaze-contingent music reward therapy (GC-MRT). METHODS: Thirty-two adults with SAD were treated with GC-MRT. rsFC was assessed with multi-voxel pattern analysis of fMRI at pre-treatment and after 2-3 weeks. For comparison, 20 healthy control (HC) participants without treatment were assessed twice for rsFC over the same time period. All SAD participants underwent clinical evaluation at pre-treatment, early-treatment (week 2-3), and post-treatment. RESULTS: SAD and depressive symptoms improved significantly from pre-treatment to post-treatment. After 2-3 weeks of treatment, decreased connectivity between the executive control network (ECN) and salience network (SN), and increased connectivity within the ECN predicted improvement in SAD and depressive symptoms at week 8. Increased connectivity between the ECN and default mode network (DMN) predicted greater improvement in SAD but not depressive symptoms at week 8. Connectivity within the DMN decreased significantly after 2-3 weeks of treatment in the SAD group, while no changes were found in HC over the same time interval. CONCLUSION: We identified early changes in rsFC during a course of GC-MRT for SAD that predicted symptom change. Connectivity changes within the ECN, ECN-DMN, and ECN-SN may be related to mechanisms underlying the clinical effects of GC-MRT and warrant further study in controlled trials.

Blunted neurobiological reactivity and attentional bias to threat underlie stress-related disorders in women survivors of intimate partner violence.

BACKGROUND: Intimate partner violence (IPV) alters women's neurobiological stress response systems. We propose that individual differences early in the attentional processing of threats are associated with these neurobiological mechanisms and contribute to mental illness in this population. METHODS: We assessed attentional bias in relation to threat (AB) in women survivors of IPV (n = 69) and controls (n = 36), and examined overall cortisol secretion using hair cortisol (HC), and stress responsiveness measuring salivary cortisol and α-amylase (sAA) before (T0), and after (T1, T2) an acute psychosocial stress task (Trier Social Stress Test). We used repeated-measures ANCOVAs to explore the associations between Group (IPV, control) and AB with acute stress response, and regression models to examine the associations with mental health symptoms. RESULTS: There were no between-group differences in HC levels. An interaction between Group and AB was found regarding cortisol reactivity (p < 0.05). IPV women with threat avoidance AB showed a blunted cortisol response compared to controls and to IPV participants with threat vigilance AB. The association between sAA reactivity and the interaction between Group, AB, and time approached significance (p = 0.07), with a trend to lower sAA levels particularly in IPV women with threat avoidance AB. Group and cortisol reactivity were associated with symptoms of depression, generalized anxiety, and post-traumatic stress disorder (8-20% explained variance). CONCLUSIONS: Threat avoidance AB is associated with blunted acute cortisol response among women exposed to chronic stress (IPV). Experiencing IPV and acute cortisol response appear to be clearly implicated in long-term mental health problems.

Analysis of 3.5 million SARS-CoV-2 sequences reveals unique mutational trends with consistent nucleotide and codon frequencies.

BACKGROUND: Since the onset of the SARS-CoV-2 pandemic, bioinformatic analyses have been performed to understand the nucleotide and synonymous codon usage features and mutational patterns of the virus. However, comparatively few have attempted to perform such analyses on a considerably large cohort of viral genomes while organizing the plethora of available sequence data for a month-by-month analysis to observe changes over time. Here, we aimed to perform sequence composition and mutation analysis of SARS-CoV-2, separating sequences by gene, clade, and timepoints, and contrast the mutational profile of SARS-CoV-2 to other comparable RNA viruses. METHODS: Using a cleaned, filtered, and pre-aligned dataset of over 3.5 million sequences downloaded from the GISAID database, we computed nucleotide and codon usage statistics, including calculation of relative synonymous codon usage values. We then calculated codon adaptation index (CAI) changes and a nonsynonymous/synonymous mutation ratio (dN/dS) over time for our dataset. Finally, we compiled information on the types of mutations occurring for SARS-CoV-2 and other comparable RNA viruses, and generated heatmaps showing codon and nucleotide composition at high entropy positions along the Spike sequence. RESULTS: We show that nucleotide and codon usage metrics remain relatively consistent over the 32-month span, though there are significant differences between clades within each gene at various timepoints. CAI and dN/dS values vary substantially between different timepoints and different genes, with Spike gene on average showing both the highest CAI and dN/dS values. Mutational analysis showed that SARS-CoV-2 Spike has a higher proportion of nonsynonymous mutations than analogous genes in other RNA viruses, with nonsynonymous mutations outnumbering synonymous ones by up to 20:1. However, at several specific positions, synonymous mutations were overwhelmingly predominant. CONCLUSIONS: Our multifaceted analysis covering both the composition and mutation signature of SARS-CoV-2 gives valuable insight into the nucleotide frequency and codon usage heterogeneity of SARS-CoV-2 over time, and its unique mutational profile compared to other RNA viruses.

Cellular and humoral response to the fourth BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL.

We assessed the humoral and cellular response to the fourth BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL. A total of 67 patients with CLL and 85 age matched controls tested for serologic response and pseudo-neutralization assay. We also tested the functional T-cell response by interferon gamma (IFNγ) to spike protein in 26 patients. Two weeks after the fourth vaccine antibody serologic response was evident in 37 (55.2%) patients with CLL, 20 /22 (91%) of treatment naïve, and 9/32 (28%) patients with ongoing therapy, compared with 100% serologic response in age matched controls. The antibody titer increased by 10-fold in patients with CLL, however, still 88-folds lower than age matched controls. Predictors of better chances of post fourth vaccination serologic response were previous positive serologies after second, third, and pre-fourth vaccination, neutralizing assay, and treatment naïve patients. T-cell response improved from 42.3% before the fourth vaccine to 84.6% 2 weeks afterwards. During the time period of 3 months after the fourth vaccination, 14 patients (21%) developed COVID-19 infection, all recovered uneventfully. Our data demonstrate that fourth SARS-CoV-2 vaccination improves serologic response in patients with CLL to a lesser extent than healthy controls and induces functional T-cell response.

Haemodynamics and oxygenation in the lower-limb muscles of young ambulatory adults with cerebral palsy.

AIM: To evaluate muscle haemodynamics and oxygen metabolism in adults with cerebral palsy (CP) at rest and during exercise. METHOD: This cross-sectional study included 12 adults with spastic CP (four females, eight males; mean age [SD] 29 years 6 months [7 years 10.8 months]) and 13 typically developing individuals (seven females, six males; mean age [SD] 26 years 6 months [1 year 1.9 months]). Near-infrared spectroscopy was used to assess changes in muscle blood flow (mBF), muscle oxygen consumption (mVO2 ), and muscle oxygen saturation in the vastus lateralis and rectus femoris muscles during three conditions: rest, low load at 20% maximum voluntary contraction (MVC), and high load at 80% MVC. RESULTS: MBF was lower in participants with CP than in typically developing participants at rest (p < 0.001) and at 20% MVC (p = 0.007) in both muscles. Increased load caused a reduction in mBF in typically developing participants and an increase in CP. MVO2 in typically developing participants increased from rest to 20% MVC and was reduced at 80% MVC compared with 20% MVC. In participants with CP, there was no change with load in the rectus femoris muscle; however, there was an increase in the vastus lateralis muscle from rest to 20% MVC, and 80% MVC had a similar value. Muscle saturation was higher in participants with CP across all conditions (vastus lateralis, p < 0.001; rectus femoris, p = 0.0518). INTERPRETATION: Oxidative metabolism in CP is not limited by oxygen delivery (mBF), because high muscle saturation suggests oxygen availability. Adults with CP demonstrate muscular responses to exercise that are inconsistent with typical high-workload activation, probably because of inefficient fibre recruitment and secondary anomalies.

Neuromodulation of Visual Cortex Reduces the Intensity of Intrusive Memories.

Aversive events can be reexperienced as involuntary and spontaneous mental images of the event. Given that the vividness of retrieved mental images is coupled with elevated visual activation, we tested whether neuromodulation of the visual cortex would reduce the frequency and negative emotional intensity of intrusive memories. Intrusive memories of a viewed trauma film and their accompanied emotional intensity were recorded throughout 5 days. Functional connectivity, measured with resting-state functional magnetic resonance imaging prior to film viewing, was used as predictive marker for intrusions-related negative emotional intensity. Results indicated that an interaction between the visual network and emotion processing areas predicted intrusions' emotional intensity. To test the causal influence of early visual cortex activity on intrusions' emotional intensity, participants' memory of the film was reactivated by brief reminders 1 day following film viewing, followed by inhibitory 1 Hz repetitive transcranial magnetic stimulation (rTMS) over early visual cortex. Results showed that visual cortex inhibitory stimulation reduced the emotional intensity of later intrusions, while leaving intrusion frequency and explicit visual memory intact. Current findings suggest that early visual areas constitute a central node influencing the emotional intensity of intrusive memories for negative events. Potential neuroscience-driven intervention targets designed to downregulate the emotional intensity of intrusive memories are discussed.

On Graphical Models and Convex Geometry.

A mixture-model of beta distributions framework is introduced to identify significant correlations among P features when P is large. The method relies on theorems in convex geometry, which are used to show how to control the error rate of edge detection in graphical models. The proposed 'betaMix' method does not require any assumptions about the network structure, nor does it assume that the network is sparse. The results hold for a wide class of data-generating distributions that include light-tailed and heavy-tailed spherically symmetric distributions. The results are robust for sufficiently large sample sizes and hold for non-elliptically-symmetric distributions.

Early Immunogenicity and Safety of the Third Dose of BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine Among Adults Older Than 60 Years: Real-World Experience.

BACKGROUND: Despite high vaccine coverage, an increase in breakthrough coronavirus disease 2019 (COVID-19) infections, prompted administration of a third BNT162b2 dose to people aged >60 years in Israel since July 2021. Here, we report real-world immunogenicity following third dose. METHODS: Overall, 208 healthcare workers aged >60 years were included. Paired pre- and post-second and/or third dose immunoglobulin G (IgG) and neutralizing antibody titers were compared. A subpopulation of low responders to the second dose was also tested for T-cell activation. For 25 paired serum samples, we tested neutralization of wild-type vs neutralization of Delta and Lambda variants, pre- and post-third dose. Active surveillance of vaccine adverse events was conducted through surveys. RESULTS: A pronounced immune response was observed following the third dose, including a 33-fold and 51-fold increase in IgG and neutralizing antibody, respectively. The neutralizing antibody levels post-third dose were 9.34 times higher than post-second dose (geometric mean titer, 2598 [95% confidence interval {CI}, 2085-3237] vs 207 [95% CI, 126-339]). Nine previously low responders had a significant antibody increase post-third dose, and 7 of 9 showed increase in T-cell activation. Additionally, sera obtained post-third dose highly and comparably neutralized the wild-type and Delta and Lambda variants. Of 1056 responders to the adverse-event survey, none had serious events. CONCLUSIONS: We demonstrate a rapid and broad immune response to the third BNT162b2 dose in individuals >60 years of age.

Effective psychological therapy for PTSD changes the dynamics of specific large-scale brain networks.

In posttraumatic stress disorder (PTSD), re-experiencing of the trauma is a hallmark symptom proposed to emerge from a de-contextualised trauma memory. Cognitive therapy for PTSD (CT-PTSD) addresses this de-contextualisation through different strategies. At the brain level, recent research suggests that the dynamics of specific large-scale brain networks play an essential role in both the healthy response to a threatening situation and the development of PTSD. However, very little is known about how these dynamics are altered in the disorder and rebalanced after treatment and successful recovery. Using a data-driven approach and fMRI, we detected recurring large-scale brain functional states with high temporal precision in a population of healthy trauma-exposed and PTSD participants before and after successful CT-PTSD. We estimated the total amount of time that each participant spent on each of the states while being exposed to trauma-related and neutral pictures. We found that PTSD participants spent less time on two default mode subnetworks involved in different forms of self-referential processing in contrast to PTSD participants after CT-PTSD (mtDMN+ and dmDMN+ ) and healthy trauma-exposed controls (only mtDMN+ ). Furthermore, re-experiencing severity was related to decreased time spent on the default mode subnetwork involved in contextualised retrieval of autobiographical memories, and increased time spent on the salience and visual networks. Overall, our results support the hypothesis that PTSD involves an imbalance in the dynamics of specific large-scale brain network states involved in self-referential processes and threat detection, and suggest that successful CT-PTSD might rebalance this dynamic aspect of brain function.

Personalized attention control therapy for PTSD: effectiveness and moderators of outcome in a randomized controlled trial.

BACKGROUND: Previous randomized controlled trials (RCTs) suggest that attention control therapy (ACT), targeting aberrant fluctuations of attention toward and away from threats in patients with PTSD, may be effective in reducing symptoms. The current RCT examined whether the use of personalized-trauma stimuli enhances ACT efficacy in patients with PTSD. Additional moderators of treatment outcome were tested on an exploratory basis. METHODS: Sixty patients with PTSD were randomly assigned to either personalized ACT, non-personalized ACT, or a control condition. Changes in symptoms were examined across pre-treatment, post-treatment, and a 3-month follow-up. Attentional interference was examined pre- and post-treatment. Baseline clinical and cognitive indices as well as the time elapsed since the trauma were tested as potential moderators of treatment outcome. RESULTS: A significant reduction in clinical symptoms was noted for all three conditions with no between-group differences. Attention bias variability decreased following ACT treatment. Personalized ACT was more effective relative to the control condition when less time had elapsed since the trauma. Baseline clinical and cognitive indices did not moderate treatment outcome. CONCLUSIONS: In this RCT of patients with PTSD, ACT was no more effective in reducing PTSD symptoms than a control condition. The data also suggest a potential benefit of personalized ACT for patients who experienced their trauma more recently.

Immune Response to Third Dose BNT162b2 COVID-19 Vaccine Among Kidney Transplant Recipients-A Prospective Study.

Immune response to two SARS-CoV-2 mRNA vaccine doses among kidney transplant recipients (KTRs) is limited. We aimed to evaluate humoral and cellular response to a third BNT162b2 dose. In this prospective study, 190 KTRs were evaluated before and ∼3 weeks after the third vaccine dose. The primary outcomes were anti-spike antibody level >4160 AU/ml (neutralization-associated cutoff) and any seropositivity. Univariate and multivariate analyses were conducted to identify variables associated with antibody response. T-cell response was evaluated in a subset of participants. Results were compared to a control group of 56 healthcare workers. Among KTRs, we found a seropositivity rate of 70% (133/190) after the third dose (37%, 70/190, after the second vaccine dose); and 27% (52/190) achieved levels above 4160 AU/ml after the third dose, compared to 93% of controls. Variables associated with antibody response included higher antibody levels after the second dose (odds ratio [OR] 30.8 per log AU/ml, 95% confidence interval [CI]11-86.4, p < 0.001); and discontinuation of antimetabolite prior to vaccination (OR 9.1,95% CI 1.8-46.5, p = 0.008). T-cell response was demonstrated in 13% (7/53). In conclusion, third dose BNT162b2 improved immune response among KTRs, however 30% still remained seronegative. Pre-vaccination temporary immunosuppression reduction improved antibody response.

Preliminary nonclinical safety and immunogenicity of an rVSV-ΔG-SARS-CoV-2-S vaccine in mice, hamsters, rabbits and pigs.

rVSV-ΔG-SARS-CoV-2-S is a clinical stage (Phase 2) replication competent recombinant vaccine against SARS-CoV-2. To evaluate the safety profile of the vaccine, a series of non-clinical safety, immunogenicity and efficacy studies were conducted in four animal species, using multiple doses (up to 108 Plaque Forming Units/animal) and dosing regimens. There were no treatment-related mortalities or any noticeable clinical signs in any of the studies. Compared to unvaccinated controls, hematology and biochemistry parameters were unremarkable and no adverse histopathological findings. There was no detectable viral shedding in urine, nor viral RNA detected in whole blood or serum samples seven days post vaccination. The rVSV-ΔG-SARS-CoV-2-S vaccination gave rise to neutralizing antibodies, cellular immune responses, and increased lymphocytic cellularity in the spleen germinal centers and regional lymph nodes. No evidence for neurovirulence was found in C57BL/6 immune competent mice or in highly sensitive type I interferon knock-out mice. Vaccine virus replication and distribution in K18-human Angiotensin-converting enzyme 2-transgenic mice showed a gradual clearance from the vaccination site with no vaccine virus recovered from the lungs. The nonclinical data suggest that the rVSV-ΔG-SARS-CoV-2-S vaccine is safe and immunogenic. These results supported the initiation of clinical trials, currently in Phase 2.