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Psychopathology is a risk factor for accelerated biological aging and early mortality. We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge (“GrimAge residuals”), a DNA methylation biomarker of mortality risk relative to age. We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts ( n  = 647 [62.9% male, M age  = 52], n  = 434 [90% male, M age  = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates. Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts ( p s < 0.028). PTSD predicted GrimAge residuals in the younger ( p  = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition ( p adj  = 0.021), poorer memory recall ( p adj  = 0.023), cardiometabolic pathology ( p adj  < 0.001), oxidative stress ( p adj  = 0.003), astrocyte damage ( p adj  = 0.021), inflammation (C-reactive protein: p adj  < 0.001; IL-6: p adj  < 0.001), and immune functioning ( p adj  < 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: p adj  < 0.001; TNF-α: p adj  < 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex ( p adj  = 0.018) and left fusiform gyrus ( p adj  = 0.030), which are related to emotion regulation and facial recognition, respectively. Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment.

Recent studies suggest that close-range blast exposure (CBE), regardless of acute concussive symptoms, may have negative long-term effects on brain health and cognition; however, these effects are highly variable across individuals. One potential genetic risk factor that may impact recovery and explain the heterogeneity of blast injury's long-term cognitive outcomes is the inheritance of an apolipoprotein (APOE) ε4 allele, a well-known genetic risk factor for Alzheimer's disease. We hypothesized that APOE ε4 carrier status would moderate the impact of CBE on long-term cognitive outcomes. To test this hypothesis, we examined 488 post-9/11 veterans who completed assessments of neuropsychological functioning, psychiatric diagnoses, history of blast exposure, military and non-military mild traumatic brain injuries (mTBIs), and available APOE genotypes. We separately examined the effects of CBE on attention, memory, and executive functioning in individuals with and without the APOE ε4 allele. As predicted, we observed a differential impact of CBE status on cognition as a function of APOE ε4 status, in which CBE ε4 carriers displayed significantly worse neuropsychological performance, specifically in the domain of memory. These results persisted after adjusting for clinical, demographic, and genetic factors and were not observed when examining other neurotrauma variables (i.e., lifetime or military mTBI, distant blast exposure), though these variables displayed similar trends. These results suggest APOE ε4 carriers are more vulnerable to the impact of CBE on cognition and highlight the importance of considering genetic risk when studying cognitive effects of neurotrauma.

Evidence suggests that blast exposure has profound negative consequences for the health of the human brain, and that it may confer risk for the development of neurodegenerative diseases such as chronic traumatic encephalopathy and Alzheimer's disease (AD). Although the molecular mechanisms linking blast exposure to subsequent neurodegeneration is an active focus of research, recent studies suggest that genetic risk for AD may elevate the risk of neurodegeneration following traumatic brain injury (TBI). However, it is currently unknown if blast exposure also interacts with AD risk to promote neurodegeneration. In this study we examined whether apolipoprotein (APOE) ɛ4, a well-known genetic risk factor for AD, influenced the relationship between blast exposure and white matter integrity in a cohort of 200 Iraq and Afghanistan war veterans. Analyses revealed a significant interaction between close-range blast exposure (CBE) (close range being within 10 m) and APOE ɛ4 carrier status in predicting white matter abnormalities, measured by a voxelwise cluster-based method that captures spatial heterogeneity in white matter disruptions. This interaction remained significant after controlling for TBI, pointing to the specificity of CBE and APOE in white matter disruptions. Further, among veteran ɛ4 carriers exposed to close-range blast, we observed a positive association between the number of CBEs and the number of white matter abnormalities. These results raise the possibility that CBE interacts with AD genetic influences on neuropathological processes such as the degradation of white matter integrity.

Objectives: Research on the cognitive sequelae of mild traumatic brain injury (mTBI) suggests that, despite generally rapid recovery, difficulties may persist in the domain of cognitive control. The goal of this study was to examine whether individuals with chronic blast-related mTBI show behavioral or neural alterations associated with cognitive control. Methods: We collected event-related functional magnetic resonance imaging (fMRI) data during a flanker task in 17 individuals with blast-related mTBI and 16 individuals with blast-exposure without TBI (control). Results: Groups did not significantly differ in behavioral measures of cognitive control. Relative to the control group, the mTBI group showed greater deactivation of regions associated with the default mode network during the processing of errors. Additionally, error processing in the mTBI group was associated with enhanced negative coupling between the default mode network and the dorsal anterior cingulate cortex as well as the dorsolateral prefrontal cortex, regions of the salience and central executive networks that are associated with cognitive control. Conclusions: These results suggest that deactivation of default mode network regions and associated enhancements of connectivity with cognitive control regions may act as a compensatory mechanism for successful cognitive control task performance in mTBI. (JINS, 2018, 24, 1–11)

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta‐Analysis Military‐Relevant Brain Injury working group, we conducted a mega‐analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment‐related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI. Through collaborative mega‐analysis, we examined alterations in white matter asymmetry in deployment‐related traumatic brain injury in a sample of nearly 2600. We found greater asymmetry of the cingulum bundle that was not accounted for by other confounding variables. Cingulum microstructural organization was also associated with cognitive function.

The poly(ADP‐ribose) polymerase‐1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended‐release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib‐ER up to 800 mg once daily or 600 mg twice daily. Dose‐limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28‐day cycles). Seventy‐one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single‐dose veliparib‐ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration‐time curve compared with veliparib immediate‐release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib‐ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment‐related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib‐ER, versus veliparib‐IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA‐mutated breast cancers. Veliparib is active against tumors deficient in homologous DNA damage repair. This phase I study assessed the pharmacokinetics and safety of veliparib extended‐release (ER) versus veliparib immediate‐release (IR) in patients with advanced solid tumors. Veliparib‐ER, versus veliparib‐IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and breast cancer susceptibility gene‐mutated breast cancers.

This critical phenomenological study sought Native American student perspectives on intention and desired faculty response following self-disclosure of personal challenges in college writing assignments and discusses implications for faculty and for implementing trauma-informed writing pedagogy with students who are historically marginalized.

This critical phenomenological study sought Native American student perspectives on intention and desired faculty response following self-disclosure of personal challenges in college writing assignments and discusses implications for faculty and for implementing trauma-informed writing pedagogy with students who are historically marginalized.

Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer. We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II–III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2–3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]). Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer. AbbVie.