XBP1 variant 1 promotes mitosis of cancer cells involving upregulation of the polyglutamylase TTLL6.

XBP1 variant 1 (Xv1) is the most abundant XBP1 variant and is highly enriched across cancer types but nearly none in normal tissues. Its expression is associated with poor patients' survival and is specifically required for survival of malignant cells, but the underlying mechanism is not known. Here we report that Xv1 upregulates the polyglutamylase tubulin tyrosine ligase-like 6 (TTLL6) and promotes mitosis of cancer cells. Like the canonical XBP1, Xv1 mRNA undergoes unconventional splicing by IRE1α under endoplasmic reticulum stress, but it is also constitutively spliced by IRE1ß. The spliced Xv1 mRNA encodes the active form of Xv1 protein (Xv1s). RNA sequencing in HeLa cells revealed that Xv1s overexpression regulates expression of genes that are not involved in the canonical unfolded protein response, including TTLL6 as a highly upregulated gene. Gel shift assay and chromatin immunoprecipitation revealed that Xv1s bind to the TTLL6 promoter region. Knockdown of TTLL6 caused death of cancer cells but not benign and normal cells, similar to the effects of knocking down Xv1. Moreover, overexpression of TTLL6 partially rescued BT474 cells from apoptosis induced by either TTLL6 or Xv1 knockdown, supporting TTLL6 as an essential downstream effector of Xv1 in regulating cancer cell survival. TTLL6 is localized in the mitotic spindle of cancer cells. Xv1 or TTLL6 knockdown resulted in decreased spindle polyglutamylation and interpolar spindle, as well as congression failure, mitotic arrest and cell death. These findings suggest that Xv1 is essential for cancer cell mitosis, which is mediated, at least in part, by increasing TTLL6 expression.

Germinal Center T follicular helper (GC-Tfh) cell impairment in chronic HIV infection involves c-Maf signaling.

We have recently demonstrated that the function of T follicular helper (Tfh) cells from lymph nodes (LN) of HIV-infected individuals is impaired. We found that these cells were unable to provide proper help to germinal center (GC)-B cells, as observed by altered and inefficient anti-HIV antibody response and premature death of memory B cells. The underlying molecular mechanisms of this dysfunction remain poorly defined. Herein, we have used a unique transcriptional approach to identify these molecular defects. We consequently determined the transcriptional profiles of LN GC-Tfh cells following their interactions with LN GC-B cells from HIV-infected and HIV-uninfected individuals, rather than analyzing resting ex-vivo GC-Tfh cells. We observed that proliferating GC-Tfh cells from HIV-infected subjects were transcriptionally different than their HIV-uninfected counterparts, and displayed a significant downregulation of immune- and GC-Tfh-associated pathways and genes. Our results strongly demonstrated that MAF (coding for the transcription factor c-Maf) and its upstream signaling pathway mediators (IL6R and STAT3) were significantly downregulated in HIV-infected subjects, which could contribute to the impaired GC-Tfh and GC-B cell functions reported during infection. We further showed that c-Maf function was associated with the adenosine pathway and that the signaling upstream c-Maf could be partially restored by adenosine deaminase -1 (ADA-1) supplementation. Overall, we identified a novel mechanism that contributes to GC-Tfh cell impairment during HIV infection. Understanding how GC-Tfh cell function is altered in HIV is crucial and could provide critical information about the mechanisms leading to the development and maintenance of effective anti-HIV antibodies.

Clinical and genomic features of SPOP-mutant prostate cancer.

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.

CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis.

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. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded.

Drug perturbation gene set enrichment analysis (dpGSEA): a new transcriptomic drug screening approach.

BACKGROUND: In this study, we demonstrate that our modified Gene Set Enrichment Analysis (GSEA) method, drug perturbation GSEA (dpGSEA), can detect phenotypically relevant drug targets through a unique transcriptomic enrichment that emphasizes biological directionality of drug-derived gene sets. RESULTS: We detail our dpGSEA method and show its effectiveness in detecting specific perturbation of drugs in independent public datasets by confirming fluvastatin, paclitaxel, and rosiglitazone perturbation in gastroenteropancreatic neuroendocrine tumor cells. In drug discovery experiments, we found that dpGSEA was able to detect phenotypically relevant drug targets in previously published differentially expressed genes of CD4+T regulatory cells from immune responders and non-responders to antiviral therapy in HIV-infected individuals, such as those involved with virion replication, cell cycle dysfunction, and mitochondrial dysfunction. dpGSEA is publicly available at https://github.com/sxf296/drug_targeting . CONCLUSIONS: dpGSEA is an approach that uniquely enriches on drug-defined gene sets while considering directionality of gene modulation. We recommend dpGSEA as an exploratory tool to screen for possible drug targeting molecules.

A novel XBP1 variant is highly enriched in cancer tissues and is specifically required for cancer cell survival.

XBP1 is a basic leucine zipper (bZIP) transcription factor and a key mediator of the endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR). XBP1-mediated transcription facilitates cell adaptation to ER stress and also promotes tumor progression, while suppressing anti-tumor immunity. Here we report a novel XBP1 variant, namely XBP1 variant 1 (XBP1v1, Xv1 for short), that is specifically required for survival of cancer cells. Xv1 contains a cryptic first exon that is conserved only in humans and great apes. Comparing to XBP1, Xv1 encodes a protein with a different N-terminal sequence containing 25 amino acids. Analysis of RNAseq database reveals that Xv1 is broadly expressed across cancer types but almost none in normal tissues. Elevated Xv1 expression is associated with poor survival of patients with several types of cancer. Knockdown of Xv1 induces death of multiple cancer cell lines but has little effect on non-cancerous cells in vitro. Moreover, knockdown of Xv1 also inhibits growth of a xenograft breast tumor in mice. Together, our results indicate that Xv1 is essential for survival of cancer cells.

The role of collagenase ointment in acute burns: a systematic review and meta-analysis.

OBJECTIVE:: A systematic review and meta-analysis was performed to summarise the state of the literature in regard to the efficacy and uses of clostridial collagenase ointment (CCO) in the burn patient. METHOD:: A systematic review of articles available on PubMed, Scopus and OvidSP Medline was performed. Keywords used in the search process included burns, thermal injury, collagenase, enzymatic debridement, wound care. Reviews, case reports, independent abstracts, consensus and opinion papers were excluded. A meta-analysis was performed for articles fitting inclusion criteria. RESULTS:: Following screening, six relevant articles were identified for systematic review. Few studies, with limited sample sizes, argue that CCO may be an effective debriding agent. It may also accelerate wound healing and avoid the pain associated with mechanical debridement. CCO lacks antimicrobial activity but the risk of burn wound infection does not appear to be significantly different than when using silver-impregnated products. CCO is more expensive than traditional wound care products but may help halt burn depth conversion and prevent the need for surgery. CONCLUSION:: CCO may be a safe and effective debridement agent for burn wounds with respect to decreasing wound healing time and minimising pain without increasing the risk of infection. It should be used on a case-by-case basis due to its financial cost, which may be offset by its ability to manage burns non-operatively.

Telomere content measurement in human hematopoietic cells: Comparative analysis of qPCR and Flow-FISH techniques.

Abnormal telomere lengths have been linked to cancer and other hematologic disorders. Determination of mean telomere content (MTC) is traditionally performed by Southern blotting and densitometry, giving a mean telomere restriction fragment (TRF) value for the total cell population studied. Here, we compared a quantitative Polymerase Chain Reaction approach (qPCR) and a flow cytometric approach, fluorescence in situ hybridization (Flow-FISH), to evaluate telomere content distribution in total patient peripheral blood mononuclear cells or specific cell populations. Flow-FISH is based on in situ hybridization using a fluorescein-labeled peptide nucleic acid (PNA) (CCCTAA)3 probe and DNA staining with propidium iodide. We showed that both qPCR and Flow-FISH provide a robust measurement, with Flow-FISH measuring a relative content longer than qPCR at a single cell approach and that TRF2 fluorescence intensity did not correlate with MTC. Both methods showed comparable telomere content reduction with age, and the rate of relative telomere loss was similar. Published 2016 Wiley Periodicals Inc. This article is a US government work and, as such, is in the public domain in the United States of America.

Correction: Inferring school district learning modalities during the COVID-19 pandemic with a hidden Markov model.

[This corrects the article DOI: 10.1371/journal.pone.0292354.].

Inferring school district learning modalities during the COVID-19 pandemic with a hidden Markov model.

During the COVID-19 pandemic, many public schools across the United States shifted from fully in-person learning to alternative learning modalities such as hybrid and fully remote learning. In this study, data from 14,688 unique school districts from August 2020 to June 2021 were collected to track changes in the proportion of schools offering fully in-person, hybrid and fully remote learning over time. These data were provided by Burbio, MCH Strategic Data, the American Enterprise Institute's Return to Learn Tracker and individual state dashboards. Because the modalities reported by these sources were incomplete and occasionally misaligned, a model was needed to combine and deconflict these data to provide a more comprehensive description of modalities nationwide. A hidden Markov model (HMM) was used to infer the most likely learning modality for each district on a weekly basis. This method yielded higher spatiotemporal coverage than any individual data source and higher agreement with three of the four data sources than any other single source. The model output revealed that the percentage of districts offering fully in-person learning rose from 40.3% in September 2020 to 54.7% in June of 2021 with increases across 45 states and in both urban and rural districts. This type of probabilistic model can serve as a tool for fusion of incomplete and contradictory data sources in order to obtain more reliable data in support of public health surveillance and research efforts.

Hepatitic Variant of Graft-vs-Host Disease.

OBJECTIVES: Graft-vs-host disease (GVHD) of the liver is a complication of allogeneic hematopoietic stem cell transplantation with hepatitic and classic variants. We determined the percentage of hepatitic variant cases, compared clinicopathologic features of the two groups, and assessed prognostic factors. METHODS: Fifty liver biopsy specimens from 40 patients with GVHD were studied. RESULTS: Fifteen (30%) cases had moderate to marked lobular inflammation and were classified as a hepatitic variant. Bile duct damage was present in all cases. Ductular reaction, apoptosis. and endotheliitis were more commonly seen in the hepatitic variant. Hepatocyte ballooning was an independent poor prognostic factor. The median aspartate aminotransferase and alanine aminotransferase were higher in the hepatitic variant while alkaline phosphatase and bilirubin were higher in the classic group. Forty (80%) GVHD cases were more than 100 days after transplant, correlating to immunosuppression taper. There was response to treatment with increased immunosuppression in both groups, but time to normalization of liver function tests was higher in the hepatitic variant. CONCLUSIONS: Bile duct damage was the most consistent pathologic finding in our cohort and was present in all cases of GVHD. Moderate to marked lobular inflammation can be seen in GVHD in up to 30% of cases without any other coexisting cause. Hepatocyte ballooning is an independent poor prognostic factor.

Gecko: A time-series model for COVID-19 hospital admission forecasting.

During the COVID-19 pandemic, concerns about hospital capacity in the United States led to a demand for models that forecast COVID-19 hospital admissions. These short-term forecasts were needed to support planning efforts by providing decision-makers with insight about future demands for health care capacity and resources. We present a SARIMA time-series model called Gecko developed for this purpose. We evaluate its historical performance using metrics such as mean absolute error, predictive interval coverage, and weighted interval scores, and compare to alternative hospital admission forecasting models. We find that Gecko outperformed baseline approaches and was among the most accurate models for forecasting hospital admissions at the state and national levels from January-May 2021. This work suggests that simple statistical methods can provide a viable alternative to traditional epidemic models for short-term forecasting.

Differential CD4+ T-Cell Cytokine and Cytotoxic Responses Between Reactivation and Latent Phases of Herpes Zoster Infection.

Background: CD4+ T cells are a critical component of effective immune responses to varicella zoster virus (VZV), but their functional properties during the reactivation acute vs latent phase of infection remain poorly defined. Methods: Here we assessed the functional and transcriptomic properties of peripheral blood CD4+ T cells in persons with acute herpes zoster (HZ) compared to those with a prior history of HZ infection using multicolor flow cytometry and RNA sequencing. Results: We found significant differences between the polyfunctionality of VZV-specific total memory, effector memory, and central memory CD4+ T cells in acute vs prior HZ. VZV-specific CD4+ memory T-cell responses in acute HZ reactivation had higher frequencies of IFN-γ and IL-2 producing cells compared to those with prior HZ. In addition, cytotoxic markers were higher in VZV-specific CD4+ T cells than non-VZV-specific cells. Transcriptomic analysis of ex vivo total memory CD4+ T cells from these individuals showed differential regulation of T-cell survival and differentiation pathways, including TCR, cytotoxic T lymphocytes (CTL), T helper, inflammation, and MTOR signaling pathways. These gene signatures correlated with the frequency of IFN-γ and IL-2 producing cells responding to VZV. Conclusions: In summary, VZV-specific CD4+ T cells from acute HZ individuals had unique functional and transcriptomic features, and VZV-specific CD4+ T cells as a group had a higher expression of cytotoxic molecules including Perforin, Granzyme-B, and CD107a.

Real-world Effect of Monoclonal Antibody Treatment in COVID-19 Patients in a Diverse Population in the United States.

BACKGROUND: Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a promising treatment for limiting the progression of coronavirus disease 2019 (COVID-19) and decreasing strain on hospitals. Their use, however, remains limited, particularly in disadvantaged populations. METHODS: Electronic health records were reviewed from SARS-CoV-2 patients at a single medical center in the United States that initiated mAb infusions in January 2021 with the support of the US Department of Health and Human Services' National Disaster Medical System. Patients who received mAbs were compared with untreated patients from the time period before mAb availability who met eligibility criteria for mAb treatment. We used logistic regression to measure the effect of mAb treatment on the risk of hospitalization or emergency department (ED) visit within 30 days of laboratory-confirmed COVID-19. RESULTS: Of 598 COVID-19 patients, 270 (45%) received bamlanivimab and 328 (55%) were untreated. Two hundred thirty-one patients (39%) were Hispanic. Among treated patients, 5/270 (1.9%) presented to the ED or required hospitalization within 30 days of a positive SARS-CoV-2 test, compared with 39/328 (12%) untreated patients (P < .001). After adjusting for age, gender, and comorbidities, the risk of ED visit or hospitalization was 82% lower in mAb-treated patients compared with untreated patients (95% CI, 56%-94%). CONCLUSIONS: In this diverse, real-world COVID-19 patient population, mAb treatment significantly decreased the risk of subsequent ED visit or hospitalization. Broader treatment with mAbs, including in disadvantaged patient populations, can decrease the burden on hospitals and should be facilitated in all populations in the United States to ensure health equity.

Evaluating the Safety and Efficacy of Intraoperative Enteral Nutrition in Critically Ill Burn Patients: A Systematic Review and Meta-analysis.

Major burn injuries incite a hypermetabolic response, and the initiation of early enteral nutrition is the standard of care in patients with large burns and contributes to improved outcomes. Perioperative fasting is a common cause of caloric deficits in burn patients and can be obviated with intraoperative enteral nutrition. However, the risks and benefits of this practice are unknown, and there is a concern for aspiration. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of intraoperative enteral nutrition. We performed a systematic literature search using PubMed, Scopus, and OvidSP MEDLINE databases. We identified studies that evaluated the effects of intraoperative enteral nutrition in adult burn patients compared to those undergoing routine perioperative fasting. We performed a meta-analysis on the incidence of mortality, pneumonia, wound infections, and aspiration in burn patients receiving intraoperative enteral nutrition. We identified seven articles for qualitative review and four for quantitative review (N = 83 patients). There were no statistically significant increases in the risk of mortality (odds ratio [OR] = 1.28, 95% confidence interval [CI]: 0.49, 3.31), wound infections (OR = 0.71, 95% CI: 0.16, 3.24), pneumonia (OR = 2.1, 95% CI: 0.7, 6.1), and aspiration (OR = 1.14, 95% CI: 0.07, 18.75) in patients receiving intraoperative enteral nutrition. Within individual studies, intraoperative enteral nutrition patients received significantly more calories than standard fasting patients. Intraoperative enteral nutrition may increase nutritional intake in burn patients without an increase in complications; however, this is based on limited studies. Randomized controlled trials are needed before recommendations on intraoperative enteral nutrition practice can be made.

Stimulant Abuse in Burn Patients Is Associated With an Increased Use of Hospital Resources.

Stimulant (cocaine, methamphetamine, and amphetamine) abuse compromises the peripheral vasculature through endothelial injury. In combination with the physiologic derangements seen in burn injuries, patients abusing stimulants may have additional impairments in wound healing. A retrospective review from July 1, 2015 to July 1, 2018 was performed at an American Burn Association-verified burn center. Patients with positive urine toxicology results for stimulants (ST(+)), and those without (ST(-)), who sustained burn injuries were identified and matched by age and TBSA. The primary outcome was mortality, and secondary outcomes included total length of stay (LOS), and need-for-surgery (grafting). In total, 130 patients ST(+) and 133 ST(-) patients were identified. There were no significant differences in age (40.9 ± 13.5 vs 39.2 ± 23.7 years, P = 0.46), Inhalation Injury (12.3 vs 9.0%, P = 0.39), or nutritional status (prealbumin: 17.3 ± 6.1 vs 17.1 ± 12.7 mg/dl, P = 0.66; albumin: 3.5 ± 0.6 vs 3.6 ± 0.7 g/dl, P = 0.45). There were no differences in mortality (6.1 vs 4.5%, P = 0.55), intensive care unit LOS (9.3 ± 16.5 vs 10.2 ± 20.9 days, P = 0.81), wound infections (15.4 vs 23.9%, P = 0.07), or wound conversion (6.9 vs 3.0%, P = 0.14). ST(+) patients had a significantly longer LOS (15.0 ± 16.9 vs 10.7 ± 17.3 days, P = 0.04), greater tobacco use (56.9 vs 18.0%, P = 0.00001), and greater need for grafting (54.6 vs 33.1%, P = 0.0004). ST(+) patients require more hospital resources-surgical operations and hospital days-than ST(-) patients. The increased need for surgical intervention may partially explain the increase in hospital days, in addition to the observation that ST(+) patients had more complex disposition issues than ST(-) patients.

Correction: Antibiotic-induced microbiome perturbations are associated with significant alterations to colonic mucosal immunity in rhesus macaques.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Antibiotic-induced microbiome perturbations are associated with significant alterations to colonic mucosal immunity in rhesus macaques.

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 (SCFAs) 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 the 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 antibiotic-induced changes to the composition and function of colonic bacterial communities associated with specific alterations in mucosal and systemic immunity.

The role of psychological support interventions in trauma patients on mental health outcomes: A systematic review and meta-analysis.

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.

Efficacy of Abiraterone and Enzalutamide in Pre- and Postdocetaxel Castration-Resistant Prostate Cancer: A Trial-Level Meta-Analysis.

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.