Recurrent Glioblastoma-Molecular Underpinnings and Evolving Treatment Paradigms.

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

Short airway telomeres are associated with primary graft dysfunction and chronic lung allograft dysfunction.

Primary graft dysfunction (PGD) is a major risk factor for chronic lung allograft dysfunction (CLAD) following lung transplantation, but the mechanisms linking these pathologies are poorly understood. We hypothesized that the replicative stress induced by PGD would lead to erosion of telomeres, and that this telomere dysfunction could potentiate CLAD. In a longitudinal cohort of 72 lung transplant recipients with >6 years median follow-up time, we assessed tissue telomere length, PGD grade, and freedom from CLAD. Epithelial telomere length and fibrosis-associated gene expression were assessed on endobronchial biopsies taken at 2 to 4 weeks post-transplant by TeloFISH assay and nanoString digital RNA counting. Negative-binomial mixed-effects and Cox-proportional hazards models accounted for TeloFISH staining batch effects and subject characteristics including donor age. Increasing grade of PGD severity was associated with shorter airway epithelial telomere lengths (p = 0.01). Transcriptomic analysis of fibrosis-associated genes showed alteration in fibrotic pathways in airway tissue recovering from PGD, while telomere dysfunction was associated with inflammation and impaired remodeling. Shorter tissue telomere length was in turn associated with increased CLAD risk, with a hazard ratio of 1.89 (95% CI 1.16-3.06) per standard deviation decrease in airway telomere length, after adjusting for subject characteristics. PGD may accelerate telomere dysfunction, potentiating immune responses and dysregulated repair. Epithelial cell telomere dysfunction may represent one of several mechanisms linking PGD to CLAD.

Oral Delivery of Nanoparticles Carrying Ancestral Uricase Enzyme Protects against Hyperuricemia in Knockout Mice.

The therapeutic value of delivering recombinant uricase to human patients has been appreciated for decades. The development of therapeutic uricases has been hampered by the fact that humans do not encode an endogenous uricase and therefore most recombinant forms of the protein are recognized as foreign by the immune system and are therefore highly immunogenic. In order to both shield and stabilize the active enzyme, we encapsulated a functional ancestral uricase in recombinant, noninfectious Qß capsid nanoparticles and characterized its catalytic activity. Oral delivery of the nanoparticles moderated key symptoms of kidney dysfunction in uricase-knockout mice by lowering uric acid levels. Histological kidney samples of the treated mice suggest that delivery of recombinant uricase had a protective effect against the destructive effects of uric acid that lead to renal failure caused by hyperuricemia.

A Commentary on Electrographic Seizure Management and Clinical Outcomes in Critically Ill Children.

Continuous EEG (cEEG) monitoring is the gold standard for detecting electrographic seizures in critically ill children and the current consensus-based guidelines recommend urgent cEEG to detect electrographic seizures that would otherwise be undetected. The detection of seizures usually leads to the use of antiseizure medications, even though current evidence that treatment leads to important improvements in outcomes is limited, raising the question of whether the current strategies need re-evaluation. There is emerging evidence indicating that the presence of electrographic seizures is not associated with unfavorable neurological outcome, and thus treatment is unlikely to alter the outcomes in these children. However, a high seizure burden and electrographic status epilepticus is associated with unfavorable outcome and the treatment of status epilepticus is currently warranted. Ultimately, outcomes are more likely a function of etiology than of a direct effect of the seizures themselves. We suggest re-examining our current consensus toward aggressive treatment to abolish all electrographic seizures and recommend a tailored approach where therapeutic interventions are indicated when seizure burden breaches above a critical threshold that may be associated with adverse outcomes. Future studies should explicitly evaluate whether there is a positive impact of treating electrographic seizures or electrographic status epilepticus in order to justify continuing current approaches.

Prognostic Significance of Size, Location, and Number of Lymph Node Metastases in Endometrial Carcinoma.

Regional lymph node metastasis is a well-established negative predictive prognostic factor in endometrial carcinomas. Recently, our approach to the pathologic evaluation of lymph nodes in endometrial carcinomas has changed, mainly due to the utilization of immunohistochemical stains in the assessment of sentinel lymph nodes, which may result in the identification of previously unrecognized disease [particularly isolated tumor cells (ITCs)] on hematoxylin and eosin stained slides. However, the clinical significance of this finding is not entirely clear. Following the experience in other organs systems such as breast, the Eight Edition of the American Joint Committee on Cancer's Cancer Staging Manual has recommended utilizing the N0(i+) terminology for this finding, without impact in the final tumor stage. We performed a comparative retrospective multi-institutional survival analysis of 247 patients with endometrial carcinoma with regional lymph node metastasis of various sizes identified in nonsentinel lymphadenectomy, demonstrating that the cumulative survival of patients with isolated tumor cells in regional lymph nodes is not statistically different from patient with negative lymph nodes, and is statistically different from those with lymph nodes showing micrometastasis or larger metastatic deposits. In addition, we evaluated the prognostic implications of the number of involved regional lymph nodes, demonstrating a worsening prognosis as the number of involved lymph nodes increases from none to one, and from one to more than one. Our data suggests that regional lymph nodes with isolated tumor cells in patients with endometrial carcinoma should likely be considered, for staging purposes, as negative lymph nodes, simply indicating their presence with the (i+) terminology.

Development of a loop-mediated isothermal amplification assay for detection of Austropeplea tomentosa from environmental water samples.

Lymnaeid snails are key intermediate hosts for the development and survival of Fasciola spp., the causative agent of Fascioliasis which are economically important parasites infecting humans and livestock globally. The current control method for treating Fascioliasis is heavily reliant on anthelmintic drugs, particularly Triclabendazole (TCBZ) which has resulted in drug-resistant parasites and poses significant risk as there are no long-term efficacious alternatives available. Sustainable control measures at the farm level could include both parasite and snail control will play an important role in Fasciola spp. control and reduce the reliance on anthelmintic drugs. Implementation of such sustainable control measures requires effective identification of snails on the property however Lymnaeid snails are small and difficult to physically locate. Snail identification using an environmental DNA approach is a recent approach in which physically locating snails are not required. Austropeplea tomentosa, is the primary intermediate snail host for F. hepatica transmission in South-East Australia and we present an in-field loop-mediated isothermal amplification and water filtering method for the detection of A. tomentosa eDNA from water samples to improve current surveillance methods. This methodology is highly sensitive with a detection limit of 5 × 10- 6 ng/µL, detected in < 20 minutes, with cumulative sample preparation and amplification time under 1 hour. This proposed workflow could assist in monitoring areas to determine the risk of Fascioliasis infection and implement strategies to manage snail populations to ultimately reduce the risk of infection for humans and livestock. Supplementary Information: The online version contains supplementary material available at 10.1186/s44149-022-00061-9.

FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro.

Acute myeloid leukemia (AML)-the most frequent form of adult blood cancer-is characterized by heterogeneous mechanisms and disease progression. Developing an effective therapeutic strategy that targets metabolic homeostasis and energy production in immature leukemic cells (blasts) is essential for overcoming relapse and improving the prognosis of AML patients with different subtypes. With respect to metabolic regulation, fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that is vital to carbohydrate metabolism, since gluconeogenesis is the central pathway for the production of important metabolites and energy necessary to maintain normal cellular activities. Beyond its catalytic activity, FBP1 inhibits aerobic glycolysis-known as the "Warburg effect"-in cancer cells. Importantly, while downregulation of FBP1 is associated with carcinogenesis in major human organs, restoration of FBP1 in cancer cells promotes apoptosis and prevents disease progression in solid tumors. Recently, our large-scale sequencing analyses revealed FBP1 as a novel inducible therapeutic target among 17,757 vitamin-D-responsive genes in MV4-11 or MOLM-14 blasts in vitro, both of which were derived from AML patients with FLT3 mutations. To investigate FBP1's anti-leukemic function in this study, we generated a new AML cell line through lentiviral overexpression of an FBP1 transgene in vitro (named FBP1-MV4-11). Results showed that FBP1-MV4-11 blasts are more prone to apoptosis than MV4-11 blasts. Mechanistically, FBP1-MV4-11 blasts have significantly increased gene and protein expression of P53, as confirmed by the P53 promoter assay in vitro. However, enhanced cell death and reduced proliferation of FBP1-MV4-11 blasts could be reversed by supplementation with post-glycolytic metabolites in vitro. Additionally, FBP1-MV4-11 blasts were found to have impaired mitochondrial homeostasis through reduced cytochrome c oxidase subunit 2 (COX2 or MT-CO2) and upregulated PTEN-induced kinase (PINK1) expressions. In summary, this is the first in vitro evidence that FBP1-altered carbohydrate metabolism and FBP1-activated P53 can initiate leukemic death by activating mitochondrial reprogramming in AML blasts, supporting the clinical potential of FBP1-based therapies for AML-like cancers.

Environmental detection of Fasciola hepatica by loop-mediated isothermal amplification.

Fasciola hepatica, commonly referred to as liver flukes, is a substantial zoonotic parasitic disease of humans and livestock globally. While infection is readily controlled by anthelmintics, namely triclabendazole, the heavy reliance on triclabendazole has resulted in drug resistance appearing worldwide. Due to drug resistance, it is imperative to adopt an integrated parasite management program to preserve the efficacy of currently available anthelmintics. A integrated liver fluke management plan would benefit from a simple rapid, field-deployable diagnostic for detection of F. hepatica in environment and the host. Therefore, a rapid DNA test using loop-mediated isothermal amplification was developed and optimised for the detection of F. hepatica from faecal and water samples to enable the detection of parasites both within the host and from the environment. The assay presented here is fast, with amplification in ≤20 min, and highly sensitive, with a detection limit of 5 × 10-4 ng/µL. The workflow presented here provides a time to result of ≤60 min without requiring a commercial kit for the extraction of DNA from faecal and water samples, and pending further validation from field-samples, could potentially be used to enable real-time decision making to mitigate parasite prevalence on a farming property and with no requirement for sample transportation.

Development of molecular detection methods of Bovicola ovis from sheep fleece.

The sheep body louse (Bovicola ovis) commonly referred to as sheep lice are small chewing ectoparasites of sheep. Infection results in significant economic costs to the Australian sheep industry due to reduced wool quality caused by chronic itching from sheep rubbing and biting fleece. Treatment relies on use of insecticides; however, resistance has developed against pyrethroid and other insect growth regulator lousicides. There is urgent need to develop cost-effective lice management to reduce the use of insecticides, with the application of insecticidal treatments only applied when an infestation is detected. However, the current detection method relies on fleece parting for detection of B. ovis which is highly dependent on the skill of the inspector, the number of sheep examined, and the prevalence and severity of the infestation. To improve B. ovis detection, a highly sensitive (5 × 10-8 ng/µL) and specific multiplex quantitative PCR which simultaneously detects sheep lice and sheep DNA was developed. In addition, a B. ovis loop-mediated isothermal amplification (LAMP) assay was developed for field use. The B. ovis LAMP (Bov-LAMP) assay was optimized to reliably detect B. ovis from wool samples down to 5 × 10-6 ng/µL, with time to positive (Tp) < 10 min. Both assays demonstrate high sensitivity and specificity, enabling rapid identification of B. ovis DNA from sheep fleece samples and have the capacity to be used for ongoing management and surveillance of B. ovis in Australian sheep flocks.

Phylogenetic Articulation of Uric Acid Evolution in Mammals and How It Informs a Therapeutic Uricase.

The role of uric acid during primate evolution has remained elusive ever since it was discovered over 100 years ago that humans have unusually high levels of the small molecule in our serum. It has been difficult to generate a neutral or adaptive explanation in part because the uricase enzyme evolved to become a pseudogene in apes thus masking typical signals of sequence evolution. Adding to the difficulty is a lack of clarity on the functional role of uric acid in apes. One popular hypothesis proposes that uric acid is a potent antioxidant that increased in concentration to compensate for the lack of vitamin C synthesis in primate species ∼65 Ma. Here, we have expanded on our previous work with resurrected ancient uricase proteins to better resolve the reshaping of uricase enzymatic activity prior to ape evolution. Our results suggest that the pivotal death-knell to uricase activity occurred between 20 and 30 Ma despite small sequential modifications to its catalytic efficiency for the tens of millions of years since primates lost their ability to synthesize vitamin C, and thus the two appear uncorrelated. We also use this opportunity to demonstrate how molecular evolution can contribute to biomedicine by presenting ancient uricases to human immune cells that assay for innate reactivity against foreign antigens. A highly stable and highly catalytic ancient uricase is shown to elicit a lower immune response in more human haplotypes than other uricases currently in therapeutic development.

Hyperferritinemia: A Diagnostic Marker for Disseminated Neonatal Herpes Simplex Virus Infection?

Although the prognosis of neonatal herpes simplex virus (HSV) infection has improved with intravenous acyclovir, the morbidity and mortality of disseminated disease remains high. Transaminitis and thrombocytopenia have been reported to be sensitive markers of neonatal HSV disease; however, early diagnosis remains a challenge due to a lack of specific clinical and laboratory indicators for this disease process. Ferritin, an acute phase reactant known for its use in diagnosing hemophagocytic lymphohistiocytosis, has recently been reported as extremely elevated in neonates with disseminated HSV due to its high inflammatory nature. We report three cases of neonates at a single institution with hyperferritinemia in the setting of disseminated HSV. Based on this case series, we discuss whether ferritin can be used as an early diagnostic marker in the setting of suspected neonatal HSV disease. [Pediatric Annals. 2021;50(6):e264-e267.].

Effect of Chronic Methylphenidate Treatment in a Female Experimental Model of Parkinsonism.

Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of ADHD in males and females. However, a majority of previous studies investigated the effect of MPH in only males, and little is known regarding consequences of female exposure to MPH. This is unfortunate because the few studies that have been conducted indicate that females have a greater sensitivity to MPH. Previous research in male mice has shown that chronic exposure to MPH causes dopaminergic neurons within the nigrostriatal pathway to be more sensitive to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, estrogen has been shown to protect dopaminergic neurons from MPTP neurotoxicity. Therefore, in this study, we test the hypothesis that chronic MPH exposure in female mice will render dopaminergic neurons in the nigrostriatal pathway more sensitive to MPTP, and that estrogen may play a protective role. Interestingly, proestrus females exhibited greater sensitivity to MPTP, with significantly reduced dopaminergic neurons in the SN and significant increases in DA quinone production. Chronic MPH exposure contributed to GSH depletion, but surprisingly, it did not increase dopamine quinone levels or dopaminergic cell loss. There were no significant differences in anestrus animals, with the exception of a depletion in GSH seen when animals received chronic high-dose (10 mg/kg) MPH followed by MPTP. Thus, estrogen may actually sensitize neurons to MPTP in this model, and chronic MPH may contribute to GSH depletion within the striatum. This study provides insight into how chronic psychostimulant use may affect males and females differently.

Towards understanding the liver fluke transmission dynamics on farms: Detection of liver fluke transmitting snail and liver fluke-specific environmental DNA in water samples from an irrigated dairy farm in Southeast Australia.

Livestock production around the world is impacted by liver fluke (Fasciola spp.) infection resulting in serious economic losses to the beef, dairy and sheep industries with significant losses of about $90 million per annum in Australia. Triclabendazole (TCBZ) is the most effective anthelmintic treatment available to control liver fluke infections; however, the widespread emergence of TCBZ resistance in livestock threatens liver fluke control. Alternative control measures to lower exposure of livestock to liver fluke infection would help to preserve the usefulness of current anthelmintic treatments. Environmental DNA (eDNA) based identification of liver fluke and the intermediate snail host in the water bodies is a robust method to assess the risk of liver fluke infection on farms. In this study, we used a multiplex quantitative PCR assay of water samples to detect and quantify eDNA of Fasciola hepatica (F. hepatica) and Austropeplea tomentosa (A. tomentosa), a crucial intermediate snail host for liver fluke transmission in South-east Australia. Water samples were collected from an irrigation channel for a period of 7 months in 2016 (February, March, May, September, October, November and December) at a dairy farm located at Maffra, Victoria, South-east Australia. Using an effective eDNA extraction method, the multiplex qPCR assay allows for the independent but simultaneous detection of eDNA released from liver fluke life stages and snails using specific primers and a probe targeting the ITS-2 region of the liver fluke and snail, respectively, with minimal inhibition from contaminants in field collected water samples. The sensitivity of this assay to detect eDNA of liver fluke and snails was observed to be 14 fg and 50 fg, respectively, in the presence of field collected water samples. Differential levels of liver fluke and snail specific eDNA in water were observed at the time points analysed in this study. The successful detection of eDNA specific to liver fluke and snails from the field collected water samples provides a precedent for the use of this method as a monitoring tool to determine the prevalence of liver fluke and liver fluke-transmitting snails in irrigation regions. Further, this method has the enormous potential to allow an assessment of the liver fluke transmission zones on farms and to inform the application of effective control strategies.

Stabilization of Near-Infrared Fluorescent Proteins by Packaging in Virus-like Particles.

Near-IR fluorescent Qß virus-like particles (VLPs) were produced in a high yield by packaging highly red-shifted monomeric and dimeric versions of biliverdin-dependent fluorescent proteins within the capsid shell. The simple addition of biliverdin hydrochloride to the medium during or after Escherichia coli protein expression was enough to produce fully matured encapsidated fluorophores. The packaged near-IR proteins exhibited identical photochemical properties to their nonencapsidated analogues but were far more stable toward heat, chaotrope-induced denaturation, and proteolysis. Noninvasive in vivo imaging showed the VLPs to traffic primarily to the liver after systemic injection in mice, revealing that the particles were easily detected by a standard instrument.

Dopaminergic Effects of Major Bath Salt Constituents 3,4-Methylenedioxypyrovalerone (MDPV), Mephedrone, and Methylone Are Enhanced Following Co-exposure.

Designer drug mixtures popularized as "bath salts" often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in various combinations. However, most preclinical investigations have only assessed the effects of individual bath salt constituents, and little is known about whether co-exposure to MDPV, mephedrone, and methylone produces significant neuropharmacological interactions. This study evaluated and compared how MDPV, mephedrone, and methylone influence discrete brain tissue dopamine (DA) levels and motor stimulant responses in mice when administered alone and as a ternary mixture. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline or 1 or 10 mg/kg doses of MDPV, mephedrone, or methylone, or a cocktail of all three cathinones at doses of 1, 3.3, or 10 mg/kg each. The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure using HPLC-ECD. Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. MDPV, mephedrone, and methylone produced dose-related increases in mesolimbic and nigrostriatal DA levels that were significantly enhanced following their co-administration. In addition, mice treated with the cathinone cocktail displayed decreased locomotor activity on day 1 that was exacerbated by day 7 and not observed with any of the drugs alone. Our findings demonstrate a significant enhanced effect of MDPV, mephedrone, and methylone on both DA, and these effects on DA result in significant alterations in locomotor activity.

Incidental Gynecologic Tract Neoplasms in Women Undergoing Anterior Pelvic Exenteration for Urothelial Carcinoma.

Urothelial carcinoma (UC) invasive into the muscularis propria or tumors unresponsive to treatment are indications for cystectomy. In females, with the goal of achieving complete cancer eradication and for concerns of UC extension into the adjacent pelvic organs, this may also warrant resection of the gynecologic organs. This study is aimed to assess the prevalence of unanticipated gynecologic neoplasms in anterior pelvic exenteration specimens. A retrospective review of pathology reports to identify women undergoing anterior pelvic exenteration for UC was performed (N=221), and incidentally discovered gynecologic tract neoplasms were recorded. Concomitant malignant or premalignant lesions of the gynecologic tract were identified in 8 patients (3.6%). These included endometrial adenocarcinoma [endometrioid type, International Federation of Gynecology and Obstetrics grade 1 (n=2, 0.9%)], cervical high-grade squamous intraepithelial lesion (n=2, 0.9%), Sertoli-Leydig cell tumor of intermediate differentiation (n=1, 0.5%), endometrioid adenocarcinoma of the ovary (n=1, 0.5%), and high-grade serous carcinoma of the ovary (n=1, 0.5%) and fallopian tube (n=1, 0.5%). Benign uterine neoplasms included leiomyomas (n=81, 37%), adenomyoma (n=3, 1.4%), and adenomatoid tumors (n=2, 0.9%). Benign ovarian neoplasms included serous cystadenoma (n=7, 3%), serous cystadenofibroma (n=4, 2%), benign Brenner tumor (n=5, 2.3%), mature teratoma (n=4, 2%), stromal luteoma (n=2, 0.9%), mucinous cystadenoma (n=1, 0.5%), thecoma (n=1, 0.5%), and endometrioid cystadenoma (n=1, 0.5%). Involvement of the gynecologic tract by UC was identified in 11 patients (5%). Spread of UC to the reproductive organs is rare in anterior pelvic exenteration specimens. Coexisting neoplasms of the gynecologic tract are occasionally identified, therefore careful evaluation of these organs is necessary.

Development of a multiplex quantitative PCR assay for detection and quantification of DNA from Fasciola hepatica and the intermediate snail host, Austropeplea tomentosa, in water samples.

Liver fluke (Fasciola hepatica) infection is an increasing threat to livestock production resulting in serious economic losses to the beef, dairy and sheep industries in Australia and globally. Triclabendazole (TCBZ) is the main drug used to control liver fluke infections in Australia and the widespread emergence of TCBZ resistance in cattle and sheep threatens liver fluke control. Alternative control measures to lower exposure of livestock to fluke infection would be useful to help preserve the usefulness of current chemical flukicides. Environmental DNA (eDNA) sampling methodology and associated molecular techniques are suited to rapidly assess the presence of pathogens on farms. In the present study, we developed a water sampling method in combination with a multiplex quantitative PCR assay to detect and quantify DNA of F. hepatica and Austropeplea tomentosa (A. tomentosa), a crucial intermediate snail host for liver fluke transmission in South-east Australia. The multiplex qPCR assay allows for the independent detection of F. hepatica and A. tomentosa DNA using specific primers and a probe targeting the ITS-2 region of the liver fluke or snail. The method allows the highly specific and sensitive (minimal DNA detection levels to 14-50 fg) detection of F. hepatica or A. tomentosa. The method allows the detection of both liver fluke and snail eDNA in water samples. The effective quantification of liver fluke and snail eDNA in water samples using this assay could potentially allow researchers to both identify and monitor F. hepatica transmission zones on farming properties in South-east Australia which will better inform control strategies, with potential application of the assay worldwide.

Neurocognitive Comorbidities in Pediatric Epilepsy: Lessons in the Laboratory and Clinical Profile.

Children with epilepsy are at risk for a variety of neurocognitive comorbidities. Animal models have increased our understanding about the neurobiological mechanisms underlying the association between seizures and these comorbidities. This article starts with an overview of the current data on animal model research, studying the influence of early-life seizures, followed by a summary of potential cellular and molecular mechanisms by which seizures can affect cognitive development. We then describe specific abnormal neuropsychological profiles that accompany specific pediatric epilepsy syndromes. Finally, we offer a potential guideline to the treatment and management of children with epilepsy and its neurocognitive comorbidities.

A Randomized, Head-to-Head Study of Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder.

Virtual reality exposure therapy (VRET) is one of the few interventions supported by randomized controlled trials for the treatment of combat-related posttraumatic stress disorder (PTSD) in active duty service members. A comparative effectiveness study was conducted to determine if virtual reality technology itself improved outcomes, or if similar results could be achieved with a control exposure therapy (CET) condition. Service members with combat-related PTSD were randomly selected to receive nine weeks of VRET or CET. Assessors, but not therapists, were blinded. PTSD symptom improvement was assessed one week and 3 months after the conclusion of treatment using the clinician-administered PTSD scale (CAPS). A small crossover component was included. Results demonstrated that PTSD symptoms improved with both treatments, but there were no statistically significant differences between groups. Dropout rates were higher in VRET. Of those who received VRET, 13/42 (31%) showed >30% improvement on the CAPS, versus 16/43 (37%) who received CET. Three months after treatment, >30% improvement was seen in 10/33 (30%) of VRET participants and 12/33 (36%) in CET. Participants who crossed over (n = 11) showed no statistically significant improvements in a second round of treatment, regardless of condition. This study supported the utility of exposure therapy for PTSD, but did not support additional benefit by the inclusion of virtual reality.