Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).

This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.

T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).

PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).

PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.

Prior reports of healthcare-associated respiratory syncytial virus (RSV) have been limited to cases diagnosed after the third day of hospitalization. The omission of other healthcare settings where RSV transmission may occur underestimates the true incidence of healthcare-associated RSV.

Retrospective cross-sectional study.

United States RSV Hospitalization Surveillance Network (RSV-NET) during 2016–2017 through 2018–2019 seasons.

Laboratory-confirmed RSV-related hospitalizations in an eight-county catchment area in Tennessee.

Surveillance data from RSV-NET were used to evaluate the population-level burden of healthcare-associated RSV. The incidence of healthcare-associated RSV was determined using the traditional definition (i.e., positive RSV test after hospital day 3) in addition to often under-recognized cases associated with recent post-acute care facility admission or a recent acute care hospitalization for a non-RSV illness in the preceding 7 days.

Among the 900 laboratory-confirmed RSV-related hospitalizations, 41 (4.6%) had traditionally defined healthcare-associated RSV. Including patients with a positive RSV test obtained in the first 3 days of hospitalization and who were either transferred to the hospital directly from a post-acute care facility or who were recently discharged from an acute care facility for a non-RSV illness in the preceding 7 days identified an additional 95 cases (10.6% of all RSV-related hospitalizations).

RSV is an often under-recognized healthcare-associated infection. Capturing other healthcare exposures that may serve as the initial site of viral transmission may provide more comprehensive estimates of the burden of healthcare-associated RSV and inform improved infection prevention strategies and vaccination efforts.

Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.

We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).

Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.

Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.

In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.

The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

Passive oxygenation with non-rebreather face mask (NRFM) has been used during cardiac arrest as an alternative to positive pressure ventilation (PPV) with bag-valve-mask (BVM) to minimize chest compression disruptions. A dual-channel pharyngeal oxygen delivery device (PODD) was created to open obstructed upper airways and provide oxygen at the glottic opening. It was hypothesized for this study that the PODD can deliver oxygen as efficiently as BVM or NRFM and oropharyngeal airway (OPA) in a cardiopulmonary resuscitation (CPR) manikin model.

Oxygen concentration was measured in test lungs within a resuscitation manikin. These lungs were modified to mimic physiologic volumes, expansion, collapse, and recoil. Automated compressions were administered. Five trials were performed for each of five arms: (1) CPR with 30:2 compression-to-ventilation ratio using BVM with 15 liters per minute (LPM) oxygen; continuous compressions with passive oxygenation using (2) NRFM and OPA with 15 LPM oxygen, (3) PODD with 10 LPM oxygen, (4) PODD with 15 LPM oxygen; and (5) control arm with compressions only.

Mean peak oxygen concentrations were: (1) 30:2 CPR with BVM 49.3% (SD = 2.6%); (2) NRFM 47.7% (SD = 0.2%); (3) PODD with 10 LPM oxygen 52.3% (SD = 0.4%); (4) PODD with 15 LPM oxygen 62.7% (SD = 0.3%); and (5) control 21% (SD = 0%). Oxygen concentrations rose rapidly and remained steady with passive oxygenation, unlike 30:2 CPR with BVM, which rose after each ventilation and decreased until the next ventilation cycle (sawtooth pattern, mean concentration 40% [SD = 3%]).

Continuous compressions and passive oxygenation with the PODD resulted in higher lung oxygen concentrations than NRFM and BVM while minimizing CPR interruptions in a manikin model.

Profiling patients on a proposed ‘immunometabolic depression’ (IMD) dimension, described as a cluster of atypical depressive symptoms related to energy regulation and immunometabolic dysregulations, may optimise personalised treatment.

To test the hypothesis that baseline IMD features predict poorer treatment outcomes with antidepressants.

Data on 2551 individuals with depression across the iSPOT-D (n = 967), CO-MED (n = 665), GENDEP (n = 773) and EMBARC (n = 146) clinical trials were used. Predictors included baseline severity of atypical energy-related symptoms (AES), body mass index (BMI) and C-reactive protein levels (CRP, three trials only) separately and aggregated into an IMD index. Mixed models on the primary outcome (change in depressive symptom severity) and logistic regressions on secondary outcomes (response and remission) were conducted for the individual trial data-sets and pooled using random-effects meta-analyses.

Although AES severity and BMI did not predict changes in depressive symptom severity, higher baseline CRP predicted smaller reductions in depressive symptoms (n = 376, βpooled = 0.06, P = 0.049, 95% CI 0.0001–0.12, I2 = 3.61%); this was also found for an IMD index combining these features (n = 372, βpooled = 0.12, s.e. = 0.12, P = 0.031, 95% CI 0.01–0.22, I2 = 23.91%), with a higher – but still small – effect size compared with CRP. Confining analyses to selective serotonin reuptake inhibitor users indicated larger effects of CRP (βpooled = 0.16) and the IMD index (βpooled = 0.20). Baseline IMD features, both separately and combined, did not predict response or remission.

Depressive symptoms of people with more IMD features improved less when treated with antidepressants. However, clinical relevance is limited owing to small effect sizes in inconsistent associations. Whether these patients would benefit more from treatments targeting immunometabolic pathways remains to be investigated.

The Brief Visuospatial Memory Test-Revised (BVMT-R) Recognition Discrimination (RD) index has emerged as an embedded performance validity test (PVT). However, there do not appear to be any studies that have examined its utility in Spanish-speaking samples. This pilot study examined the classification accuracy of the BVMT-R RD for detecting performance invalidity in a Spanish-speaking forensic sample.

This cross-sectional study utilized a sample of 89 Spanish speakers that were administered the BVMT-R during an outpatient neuropsychological evaluation. Out of the 89 Spanish speakers, 43 were subjects in litigation, 32 were neurological patients evaluated for clinical purposes, and 14 were healthy controls. The sample was 67% male/33% female, 53% South American, 33% Caribbean (Dominican, Puerto Rican, Cuban), 10% Central American, 3% North American (Mexican), and 1% Spanish, with a mean age of 44.2 years (SD = 14.2; range = 20-78) and mean education of 11 years (SD = 3.7; range = 0-20). Test administration for each patient was completed in Spanish by a fluent, Spanish-speaking examiner. In total, 64/89 (72%) were classified as valid and 25/89 (28%) as invalid based on performance across the Test of Memory Malingering (TOMM), at least one additional PVT (Rey-15 item memory test; Rey Dot Counting Test; Reliable Digit Span; WHO-AVLT recognition trial) and objective diagnostic criteria identifying invalid performance. Analyses included three univariate analyses of variance (ANOVA), with the groups (healthy vs neurological vs litigation) as independent variables and performance on BVMT-RD as the dependent variable.

Statistically significant differences among the groups were found F(2,86)=8.32, p < .001). Post-hoc analysis (Scheffe test) showed the mean of the litigation group to be significantly lower than the means of the other two groups (healthy and neurological), which showed no difference between them. An ANOVA with validity groups as the fixed factor and BVMT-R RD index as the dependent variable was significant F(1,85)= 21.02, p <.001). Results of a ROC curve analysis yielded statistically significant AUC (.794). The optimal cut-score was BVMT-R RD < 5 (48% sensitivity/88% specificity).

Results of the BVMT-R RD index in this Spanish-speaking population differed by subgroup, with worse performance seen in individuals involved in litigation, compared to those who were not (healthy and neurological). Notably, the BVMT-R RD index significantly differentiated validity groups, maintaining adequate sensitivity and good specificity. Overall, results demonstrate promise for BVMT-RD as a PVT for Spanish-speaking populations.

It has been posited that alcohol use may confound the association between greater concussion history and poorer neurobehavioral functioning. However, while greater alcohol use is positively correlated with neurobehavioral difficulties, the association between alcohol use and concussion history is not well understood. Therefore, this study investigated the cross-sectional and longitudinal associations between cumulative concussion history, years of contact sport participation, and health-related/psychological factors with alcohol use in former professional football players across multiple decades.

Former professional American football players completed general health questionnaires in 2001 and 2019, including demographic information, football history, concussion/medical history, and health-related/psychological functioning. Alcohol use frequency and amount was reported for three timepoints: during professional career (collected retrospectively in 2001), 2001, and 2019. During professional career and 2001 alcohol use frequency included none, 1-2, 3-4, 5-7 days/week, while amount included none, 12, 3-5, 6-7, 8+ drinks/occasion. For 2019, frequency included never, monthly or less, 2-4 times/month, 2-3 times/week, >4 times/week, while amount included none, 1-2, 3-4, 5-6, 7-9, 10+ drinks/occasion. Scores on a screening measure for Alcohol Use Disorder (CAGE) were also available at during professional career and 2001 timepoints. Concussion history was recorded in 2001 and binned into five groups: 0, 1-2, 3-5, 6-9, 10+. Depression and pain interference were assessed via PROMIS measures at all timepoints. Sleep disturbance was assessed in 2001 via separate instrument and with PROMIS Sleep Disturbance in 2019. Spearman’s rho correlations tested associations between concussion history and years of sport participation with alcohol use across timepoints, and whether poor health functioning (depression, pain interference, sleep disturbance) in 2001 and 2019 were associated with alcohol use both within and between timepoints.

Among the 351 participants (Mage=47.86[SD=10.18] in 2001), there were no significant associations between concussion history or years of contact sport participation with CAGE scores or alcohol use frequency/amount during professional career, 2001, or 2019 (rhos=-.072-.067, ps>.05). In 2001, greater depressive symptomology and sleep disturbance were related to higher CAGE scores (rho=.209, p<.001; rho=.176, p<.001, respectively), while greater depressive symptomology, pain interference, and sleep disturbance were related to higher alcohol use frequency (rho=.176, p=.002; rho=.109, p=.045; rho=.132, p=.013, respectively) and amount/occasion (rho=.215, p<.001; rho=.127, p=.020; rho=.153, p=.004, respectively). In 2019, depressive symptomology, pain interference, and sleep disturbance were not related to alcohol use (rhos=-.047-.087, ps>.05). Between timepoints, more sleep disturbance in 2001 was associated with higher alcohol amount/occasion in 2019 (rho=.115, p=.036).

Increased alcohol intake has been theorized to be a consequence of greater concussion history, and as such, thought to confound associations between concussion history and neurobehavioral function later in life. Our findings indicate concussion history and years of contact sport participation were not significantly associated with alcohol use cross-sectionally or longitudinally, regardless of alcohol use characterization. While higher levels of depression, pain interference, and sleep disturbance in 2001 were related to greater alcohol use in 2001, they were not associated cross-sectionally in 2019. Results support the need to concurrently address health-related and psychological factors in the implementation of alcohol use interventions for former NFL players, particularly earlier in the sport discontinuation timeline.

Traumatic brain injury and cardiovascular disease (CVD) are modifiable risk factors for cognitive decline and dementia. Greater concussion history can potentially increase risk for cerebrovascular changes associated with cognitive decline and may compound effects of CVD. We investigated the independent and dynamic effects of CVD/risk factor burden and concussion history on cognitive function and odds of mild cognitive impairment (MCI) diagnoses in older former National Football League (NFL) players.

Former NFL players, ages 50-70 (N=289; mean age=61.02±5.33 years), reported medical history and completed the Brief Test of Adult Cognition by Telephone (BTACT). CVD/risk factor burden was characterized as ordinal (0-3+) based on the sum of the following conditions: coronary artery disease/myocardial infarction, chronic obstructive pulmonary disease, hypertension, hyperlipidemia, sleep apnea, type-I and II diabetes. Cognitive outcomes included BTACT Executive Function and Episodic Memory Composite Z-scores (standardized on age- and education-based normative data), and the presence of physician diagnosed (self-reported) MCI. Concussion history was discretized into five groups: 0, 1-2, 3-5, 6-9, 10+. Linear and logistic regression models were fit to test independent and joint effects of concussion history and CVD burden on cognitive outcomes and odds of MCI. Race (dichotomized as White and Non-white due to sample distribution) was included in models as a covariate.

Greater CVD burden (unstandardized beta [standard error]; B=-0.10[0.42], p=.013, and race (B=0.622[0.09], p<.001), were associated with lower executive functioning. Compared to those with 0 prior concussions, no significant differences were observed for those with 1-2, 3-5, 6-9, or 10+ prior concussions (ps >.05). Race (B=0.61[.13], p<.001), but not concussion history or CVD burden, was associated with episodic memory. There was a trend for lower episodic memory scores among those with 10+ prior concussion compared to those with no prior concussions (B=-0.49[.25], p=.052). There were no significant differences in episodic memory among those with 1-2, 3-5, or 6-9 prior concussions compared to those with 0 prior concussions (ps>.05). CVD burden (B=0.35[.13], p=.008), race (greater odds in Non-white group; B=0.82[.29], p=.005), and greater concussion history (higher odds of diagnosis in 10+ group compared to those with 0 prior concussions; B=2.19[0.78], p<.005) were associated with higher odds of MCI diagnosis. Significant interaction effects between concussion history and CVD burden were not observed for any outcome (ps >.05).

Lower executive functioning and higher odds of MCI diagnosis were associated with higher CVD burden and race. Very high concussion history (10+) was selectively associated with higher odds of MCI diagnosis. Reduction of these modifiable factors may mitigate adverse outcomes in older contact sport athletes. In former athletes, consideration of CVD burden is particularly pertinent when assessing executive dysfunction, considered to be a common cognitive feature of traumatic encephalopathy syndrome, as designated by the recent diagnostic criteria. Further research should investigate the social and structural determinants contributing to racial disparities in long-term health outcomes within former NFL players.

This retrospective study compared base rates of failure on a series of standalone and embedded performance validity tests (PVTs) in a sample of Spanish-speaking forensic litigants and explored the impact of demographic factors on PVT performance.

62 Spanish-speaking participants involved in litigation (primarily for work-related mTBI) underwent outpatient neuropsychological evaluation. Country of origin spanned South American (56.5%), Caribbean (22.5%), Central American (16.1%), North American (3.2%), and Spanish (1.6%) regions. Of this sample, 56 completed the Test of Memory Malingering (TOMM), 45 completed the Rey Fifteen Item Test (RFIT), and 49 completed the Dot Counting Test (DCT). Embedded validity measures, Reliable Digit Span (RDS) and the WHO-Auditory Verbal Learning Test (WHO-AVLT) were completed by 32 and 48 participants, respectively.

Effects of age (M=42.4, SD=11.72) and region of origin did not significantly impact overall performance on any measure. Mean scores across all standalone PVTs were below cutoffs, which have been previously suggested for use with Spanish-speaking populations (TOMM <40, RFIT total <21, DCT e-score >18). Overall base rates of failure were as follows: 52.5% TOMM (T1 M= 37.5, SD=10.7; T2 M=35.1, SD=10.6), 64.9% RFIT (M=17.8, SD=7.8) 57.6% DCT (M=18.3, SD=8.8), 51.1% RDS (M=6.1, SD=1.6), 29.4% WHO-AVLT (M=10.7, SD=3.9. Years of education (M=9.98, 3.96) was significantly correlated with RFIT total score (r(43) = .48, p<.01) and DCT e-score (r(47) = -.34, p<.05. When stratified by level of education (0-6, 7-11, and 12+), a large discrepancy in base rate of failure was observed on the RFIT, with failures in 92% of participants with less than six years of education, as compared to 52% and 59% failure in those with 7-11 and 12+ years, respectively. Variability in base rates of DCT failure across levels of education, although less extreme than on the RFIT, again demonstrated higher rates of failure in participants with less than six years of education (0-6: 71%, 7-11: 54%, 12+: 52%).

These findings add to the existing literature surrounding measurement of suboptimal effort in Spanish-speaking populations. Base rates of PVT failure on both standalone and embedded measures were generally much higher than those reported in prior studies of forensic or compensation-seeking groups, including some with Spanish speaking participants. These high rates of failure are likely attributable, at least in part, to sample characteristics, due to the high proportion of individuals engaged in litigation associated with workplace injuries on construction sites at the study location. Such findings illustrate the importance of a thorough effort assessment for this population. Finally, results demonstrating reduced specificity of the RFIT in Spanish-speaking participants with less than six years of education, suggesting caution is warranted for its use in neuropsychological evaluations with such individuals.