Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro.

The diverse bacterial communities that colonize the gastrointestinal tract play an essential role in maintaining immune homeostasis through the production of critical metabolites such as short chain fatty acids (SCFA), and this can be disrupted by antibiotic use. However, few studies have addressed the effects of specific antibiotics longitudinally on the microbiome and immunity. We evaluated the effects of four specific antibiotics; enrofloxacin, cephalexin, paromomycin, and clindamycin; in healthy female rhesus macaques. All antibiotics disrupted the microbiome, including reduced abundances of fermentative bacteria and increased abundances of potentially pathogenic bacteria, including Enterobacteriaceae in stool, and decreased Helicobacteraceae in the colon. This was associated with decreased SCFAs, indicating altered bacterial metabolism. Importantly, antibiotic use also substantially altered local immune responses, including increased neutrophils and Th17 cells in the colon. Furthermore, we observed increased soluble-CD14 in plasma, indicating microbial translocation. These data provide a longitudinal evaluation of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Background Inactivating missense mutations in the SPOP gene, encoding speckle‐type poxvirus and zinc‐finger protein, are one of the most common genetic alterations in prostate cancer. Methods We retrospectively identified 72 consecutive prostate cancer patients with somatic SPOP mutations, through next‐generation sequencing analysis, who were treated at the Johns Hopkins Hospital. We evaluated clinical and genomic characteristics of this SPOP‐mutant subset. Results SPOP alterations were clustered in the MATH domain, with hotspot mutations involving the F133 and F102 residues. The most frequent concurrent genetic alterations were in APC (16/72 [22%]), PTEN (13/72 [18%]), and TP53 (11/72 [15%]). SPOP‐mutant cancers appeared to be mutually exclusive with tumors harboring the TMPRSS2‐ERG fusion, and were significantly enriched for Wnt pathway (APC, CTNNB1) mutations and de‐enriched for TP53/PTEN/RB1 alterations. Patients with mtSPOP had durable responses to androgen deprivation therapy (ADT) with a median time‐to‐castration‐resistance of 42.0 (95% confidence interval [CI], 25.7–60.8) months. However, time‐to‐castration‐resistance was significantly shorter in SPOP‐mutant patients with concurrent TP53 mutations (hazard ratio [HR] 4.53; p = 0.002), HRD pathway (ATM, BRCA1/2, and CHEK2) mutations (HR 3.19; p = 0.003), and PI3K pathway (PTEN, PIK3CA, and AKT1) alterations (HR 2.69; p = 0.004). In the castration‐resistant prostate cancer setting, median progression‐free survival was 8.9 (95% CI, 6.7–NR) months on abiraterone and 7.3 (95% CI, 3.2–NR) months on enzalutamide. There were no responses to PARP inhibitor treatment. Conclusions SPOP‐mutant prostate cancers represent a unique subset with absent ERG fusions and frequent Wnt pathway alterations, with potentially greater dependency on androgen signaling and enhanced responsiveness to ADT. Outcomes are best for SPOP‐altered patients without other concurrent mutations.

We examined the comparative efficacies of first-line abiraterone and enzalutamide in pre- and postdocetaxel settings in castration-resistant prostate cancer (CRPC) through a trial level meta-analysis. A mixed method approach was applied to 19 unique studies containing 17 median overall survival (OS) estimates and 13 median radiographic progression-free survival (PFS) estimates. We employed a random-effects meta-analysis to compare efficacies of abiraterone and enzalutamide with respect to OS and PFS. In the predocetaxel setting, enzalutamide use was associated with an increase in median OS of 5.9 months (p < 0.001), hazard ratio (HR) = 0.81, and an increase in median PFS of 8.3 months (p < 0.001), HR = 0.47 compared to abiraterone. The advantage of enzalutamide improved after adjusting for baseline Gleason score to 19.5 months (p < 0.001) and 14.6 months (p < 0.001) in median OS and PFS, respectively. In the postdocetaxel setting, the advantage of enzalutamide use was nominally significant for median PFS (1.2 months p = 0.02 without adjustment and 2.2 months and p = 0.0007 after adjustment); there was no significant difference in median OS between the two agents. The results from this comprehensive meta-analysis suggest a survival advantage with the use of first-line enzalutamide over abiraterone in CRPC and highlight the need for prospective clinical trials.

BACKGROUND The recovery and rehabilitation of trauma survivors may be long and challenging. Patients may be prone to psychiatric disorders, cognitive impairments, and decreased quality of life. The objective of this review was to determine whether there is a role for psychological interventions in reducing the incidence and severity of psychiatric sequelae in trauma survivors. METHODS MEDLINE, PubMed, SCOPUS, and Google Scholar were searched for published articles. We searched for articles published between 1990 and 2018 with adult subjects, and limited our search to articles published in English. Randomized controlled trials that evaluated various psychiatric interventions in trauma patients on the effects of psychiatric outcomes were included for analysis. The articles were independently reviewed for eligibility by two different reviewers. A meta-analysis was performed on nine studies with similar interventions, outcomes measured, and patient populations. RESULTS Nine hundred thirty-four articles were identified [830 articles identified through database search, and 107 through article references]. Sixty-nine full-text articles were reviewed for eligibility. Of these, 33 were included for qualitative analysis. Thirteen studies evaluating the effect of cognitive behavioral therapy (CBT)-based interventions on the severity of posttraumatic stress disorder (PTSD), anxiety, and depression symptoms underwent meta-analysis. While CBT-treated patients experienced clinically significant decreases in symptom severity, there were no statistically significant differences between treatment and control groups at follow-up for PTSD, anxiety, and depression. CONCLUSION Compared with usual care, CBT-based interventions may not be effective in decreasing or preventing PTSD, anxiety, or depression symptoms in trauma survivors. LEVEL OF EVIDENCE Systematic Review, level III.