W. G. (Bill) Hefner VA Medical Center

IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

The use of improvised explosive devices has become the hallmark of modern warfare and has resulted in an ever-increasing number of blast-related traumatic brain injuries (TBIs). Despite this fact, very little is actually known about the cognitive sequelae of blast-related TBIs. The purpose of the current study was to compare patterns of performance on neuropsychological measures in subjects who have sustained TBIs as a result of blast (or explosion) with those who have sustained TBIs from non-blast or blunt force trauma (motor vehicle accident, fall, assault, etc.). Participants were categorized as blast-related TBI or non-blast-related TBI and according to severity of injury (mild or moderate-to-severe). No main effects were observed in analysis of covariance between blast-related TBI participants and non-blast-related TBI participants across any of the neuropsychological variables, although an interaction was observed on a visual memory test showing stronger performance for mild blast-related and poorer performance for moderate-to-severe blast-related participants compared with both non-blast groups. Overall, the results do not provide any strong evidence that blast is categorically different from other TBI mechanisms, at least with regard to cognitive sequelae on select measures. Additional findings included a marginally increased incidence of reported posttraumatic stress disorder symptoms among blast-injured participants. (JINS, 2009, 15, 1-8.).

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

Traumatic brain injury (TBI) has a poorly understood pathology. Patients suffer from a variety of physical and cognitive effects that worsen as the type of trauma worsens. Some noninvasive insights into the pathophysiology of TBI are possible using magnetic resonance imaging (MRI), computed tomography (CT), and many other forms of imaging as well. A recent workshop was convened to evaluate the common data elements (CDEs) that cut across the imaging field and given the charge to review the contributions of the various imaging modalities to TBI and to prepare an overview of the various clinical manifestations of TBI and their interpretation. Technical details regarding state-of-the-art protocols for both MRI and CT are also presented with the hope of guiding current and future research efforts as to what is possible in the field. Stress was also placed on the potential to create a database of CDEs as a means to best record information from a given patient from the reading of the images.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

The primary causes of scrotal trauma are blunt, penetrating, degloving, and electrical burn injuries to scrotal contents. Knowledge of the scrotal anatomy and appropriate imaging techniques are key for accurate evaluation of scrotal injuries. Ultrasonography (US) is the first-line imaging modality to help guide therapy for scrotal trauma, except in degloving injury, which results in scrotal skin avulsion. Blunt injury (eg, from an athletic accident or motor vehicle collision) is the most common cause of scrotal trauma, followed by penetrating injury from gunshot or other assault. Trauma often may result in hematoma, hydrocele, hematocele, testicular fracture, or testicular rupture. The timely diagnosis of rupture, based on a US finding of discontinuity of the echogenic tunica albuginea, is critical because emergent surgery results in salvage of the testis in 80%-90% of rupture cases. The radiologist should be familiar also with other nuances associated with penetrating trauma, iatrogenic and postoperative complications, and electrical injury. Color flow and duplex Doppler imaging are highly useful techniques not only for assessing testicular viability and perfusion but also for evaluating associated vascular injuries such as pseudoaneurysms. A thorough familiarity with the US findings of scrotal trauma helps facilitate appropriate management. Supplemental material available at radiographics.rsnajnls.org/cgi/content/full/27/2/357/DC1.

Anaphylaxis is a severe, acute, life-threatening multisystem allergic reaction resulting from the release of a plethora of mediators from mast cells culminating in serious respiratory, cardiovascular and mucocutaneous manifestations that can be fatal. Medications, foods, latex, exercise, hormones (progesterone), and clonal mast cell disorders may be responsible. More recently, novel syndromes such as delayed reactions to red meat and hereditary alpha tryptasemia have been described. Anaphylaxis manifests as sudden onset urticaria, pruritus, flushing, erythema, angioedema (lips, tongue, airways, periphery), myocardial dysfunction (hypovolemia, distributive or mixed shock and arrhythmias), rhinitis, wheezing and stridor. Vomiting, diarrhea, scrotal edema, uterine cramps, vaginal bleeding, urinary incontinence, dizziness, seizures, confusion, and syncope may occur. The traditional (or classical) pathway is mediated via T cells, Th2 cytokines (such as IL-4 and 5), B cell production of IgE and subsequent crosslinking of the high affinity IgE receptor (FcεRI) on mast cells and basophils by IgE-antigen complexes, culminating in mast cell and basophil degranulation. Degranulation results in the release of preformed mediators (histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G and tumor necrosis factor alpha (TNF-α), and of de novo synthesized ones such as lipid mediators (cysteinyl leukotrienes), platelet activating factor (PAF), cytokines and growth factors such as vascular endothelial growth factor (VEGF). Of these, histamine, tryptase, cathepsin G, TNF-α, LTC4, PAF and VEGF can increase vascular permeability. Recent data suggest that mast cell-derived histamine and PAF can activate nitric oxide production from endothelium and set into motion a signaling cascade that leads to dilatation of blood vessels and dysfunction of the endothelial barrier. The latter, characterized by the opening of adherens junctions, leads to increased capillary permeability and fluid extravasation. These changes contribute to airway edema, hypovolemia, and distributive shock, with potentially fatal consequences. In this review, besides mechanisms (endotypes) underlying IgE-mediated anaphylaxis, we also provide a brief overview of IgG-, complement-, contact system-, cytokine- and mast cell-mediated reactions that can result in phenotypes resembling IgE-mediated anaphylaxis. Such classifications can lead the way to precision medicine approaches to the management of this complex disease.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

BACKGROUND: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear. RESULTS: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient's mice. In line with the results in humans, transplantation from 'high ferritin donors' resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient's mice. CONCLUSIONS: Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies. Video abstract.

High iron is a risk factor for type 2 diabetes mellitus (T2DM) and affects most of its cardinal features: decreased insulin secretion, insulin resistance, and increased hepatic gluconeogenesis. This is true across the normal range of tissue iron levels and in pathologic iron overload. Because of iron's central role in metabolic processes (e.g., fuel oxidation) and metabolic regulation (e.g., hypoxia sensing), iron levels participate in determining metabolic rates, gluconeogenesis, fuel choice, insulin action, and adipocyte phenotype. The risk of diabetes related to iron is evident in most or all tissues that determine diabetes phenotypes, with the adipocyte, beta cell, and liver playing central roles. Molecular mechanisms for these effects are diverse, although there may be integrative pathways at play. Elucidating these pathways has implications not only for diabetes prevention and treatment, but also for the pathogenesis of other diseases that are, like T2DM, associated with aging, nutrition, and iron.

BACKGROUND: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypothesized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients' survival. METHODS: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were finally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan-Meier method. Immune response were assessed in blood samples obtained before each vaccines. RESULTS: -methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse effects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7-16) and median OS was 23.4 months (95% CI 16-33.1). Increase in post-vaccination tumor specific immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correlation between immune response and survival was found. CONCLUSIONS: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival benefit of this therapeutic approach. Trial registration This phase-II trial was registered as EudraCT: 2009-009879-35 and ClinicalTrials.gov Identifier: NCT01006044 retrospectively registered.

Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Agonists of the nociceptin/orphanin FQ peptide (NOP) receptor have been shown to modulate the antinociceptive and reinforcing effects of MOP agonists. We report the discovery and development of a bifunctional NOP/MOP receptor agonist, AT-121, which has partial agonist activity at both NOP and MOP receptors. AT-121 suppressed oxycodone's reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. Our results in nonhuman primates suggest that bifunctional NOP/MOP agonists with the appropriate balance of NOP and MOP agonist activity may provide a dual therapeutic action for safe and effective pain relief and treating prescription opioid abuse.

Fat-containing tumors are the most common soft-tissue tumors encountered clinically. The vast majority of fat-containing soft-tissue masses are benign. Lipomas are the most common benign fat-containing masses and demonstrate a characteristic appearance at magnetic resonance (MR) imaging. Less common benign soft-tissue masses include lipoblastoma, angiolipoma, spindle cell lipoma/pleomorphic lipoma, myolipoma, chondroid lipoma, lipomatosis of nerve, lipomatosis, hibernoma, and fat necrosis. Well-differentiated liposarcomas (WDLPSs)/atypical lipomatous tumors (ALTs) are locally aggressive soft-tissue masses that do not metastasize. Biologically more aggressive liposarcomas include myxoid, pleomorphic, and dedifferentiated liposarcomas. At MR imaging, lipomas typically resemble subcutaneous fat but may contain a few thin septa. The presence of thick, irregular, enhancing septa and nonfatty soft-tissue mass components suggests liposarcoma rather than lipoma. However, benign lipomatous lesions and WDLPS/ALT often have overlapping MR imaging findings. Distinguishing WDLPS/ALT from a benign lipomatous lesion or from fat necrosis at imaging can be challenging and often requires histologic evaluation. We present the spectrum of fat-containing masses, using the World Health Organization classification of adipocytic tumors, with an emphasis on commonly encountered lesions, characteristic MR imaging findings associated with specific tumors, and overlapping MR imaging findings of certain tumors that may require histologic sampling. We also briefly discuss the role of molecular markers in proper characterization and classification of fat-containing soft-tissue masses. (©)RSNA, 2016.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

OBJECTIVE: Use diffusion tensor imaging to investigate white matter alterations associated with blast exposure with or without acute symptoms of traumatic brain injury (TBI). PARTICIPANTS: Forty-five veterans of the recent military conflicts included 23 exposed to primary blast without TBI symptoms, 6 having primary blast with mild TBI, and 16 unexposed to blast. DESIGN: Cross-sectional case-control study. MAIN MEASURES: Neuropsychological testing and diffusion tensor imaging metrics that quantified the number of voxel clusters with altered fractional anisotropy (FA) radial diffusivity, and axial diffusivity, regardless of their spatial location. RESULTS: Significantly lower FA and higher radial diffusivity were observed in veterans exposed to primary blast with and without mild TBI relative to blast-unexposed veterans. Voxel clusters of lower FA were spatially dispersed and heterogeneous across affected individuals. CONCLUSION: These results suggest that lack of clear TBI symptoms following primary blast exposure may not accurately reflect the extent of brain injury. If confirmed, our findings would argue for supplementing the established approach of making diagnoses based purely on clinical history and observable acute symptoms with novel neuroimaging-based diagnostic criteria that "look below the surface" for pathology.

The present study examined the structural validity of the 25-item Connor-Davidson Resilience Scale (CD-RISC) in a large sample of U.S. veterans with military service since September 11, 2001. Participants (N = 1,981) completed the 25-item CD-RISC, a structured clinical interview and a self-report questionnaire assessing psychiatric symptoms. The study sample was randomly divided into two subsamples: an initial sample (Sample 1: n = 990) and a replication sample (Sample 2: n = 991). Findings derived from exploratory factor analysis (EFA) did not support the five-factor analytic structure as initially suggested in Connor and Davidson's instrument validation study. Although parallel analyses indicated a two-factor structural model, we tested one to six factor solutions for best model fit using confirmatory factor analysis. Results supported a two-factor model of resilience, composed of adaptability- (8 items) and self-efficacy-themed (6 items) items; however, only the adaptability-themed factor was found to be consistent with our view of resilience-a factor of protection against the development of psychopathology following trauma exposure. The adaptability-themed factor may be a useful measure of resilience for post-9/11 U.S. military veterans.

Trichomonas vaginalis (TV) infection is the most prevalent curable sexually transmitted infection in the United States and worldwide. Most TV infections are asymptomatic, and the accurate diagnosis of this infection has been limited by lack of sufficiently sensitive and specific diagnostic tests, particularly for men. To provide updates for the 2010 Centers for Disease Control and Prevention's Sexually Transmitted Diseases Treatment Guidelines, a PubMed search was conducted of all TV literature published from 9 January 2004 through 24 September 2008. Approximately 175 pertinent abstracts and articles were reviewed and discussed with national experts. This article describes advances in TV diagnostics which have led to an improved understanding of the epidemiology of this pathogen, as well as potential biologic and epidemiological interactions between TV and human immunodeficiency virus (HIV). New data on treatment outcomes, metronidazole-resistant TV, management of nitroimidazole-allergic patients, frequency of recurrent TV infection following treatment, and screening considerations for TV in certain populations are also presented.

The Internet has emerged as an important tool for the delivery of health promotion and disease prevention interventions. Our community-based participatory research (CBPR) partnership developed and piloted CyBER/testing, a culturally congruent intervention designed to promote HIV testing among men who have sex with men (MSM) within existing Internet chat rooms. Using a quasi-experimental, single-group study design, cross-sectional data were collected from chat room participants, known as "chatters," at pretest (n = 346) and posttest (n = 315). Extant profile data also were collected to describe the demographics of the online population. The intervention significantly increased self-reported HIV testing among chatters overall, increasing rates from 44.5% at pretest to nearly 60% at posttest (p < .001). Furthermore, chatters who reported having both male and female sexual partners had nearly 6 times the odds of reporting HIV testing at posttest. Findings suggest that chat room-based HIV testing intervention may increase testing among MSM who may be difficult to reach in traditional physical spaces.

The optimal vascular access for elderly patients remains a challenge due to the difficulty balancing the benefits and risks in a population with increased comorbidity and decreased survival. Age is commonly associated with failure to mature in fistula and decreased rates of primary and secondary patency in both fistula and grafts. In the elderly, at 1 and 2 years, primary patency rates range from 43% to 74% and from 29% to 67%, respectively. Secondary patency rates at 1 and 2 years range from 56% to 82% and 44% to 67%, respectively. Cumulative fistula survival is no better than grafts survival when primary failures are included. Several observational studies consistently demonstrate a lower adjusted mortality among those using a fistula compared with a catheter; however, catheter use in the elderly is increasing in most countries with the exception of Japan. Both guidelines and quality initiatives do not acknowledge the trade-offs involved in managing the elderly patients with multiple chronic conditions and limited life expectancy or the value that patients place on achieving these outcomes. The framework for choice of vascular access presented in this article considers: (1) likelihood of disease progression before death, (2) patient life expectancy, (3) risks and benefits by vascular access type, and (4) patient preference. Future studies evaluating the timing and type of vascular access with careful assessments of complications, functionality, cost benefit, and patients' preference will provide relevant information to individualize and optimize care to improve morbidity, mortality, and quality of life in the elderly patient.

Up to 40% of lung cancer patients develop brain metastasis, and the median survival of these patients remains less than 6 months. Smoking is associated with lung cancer. However, how smoking impacts the development of brain metastasis remains elusive. We examined 281 lung cancer patients with distant metastasis and found that smokers exhibited a significantly high incidence of brain metastasis. We found that nicotine enhanced brain metastasis, while a depletion of microglia suppressed this effect in vivo. Nicotine skewed the polarity of microglia to the M2 phenotype, thereby increasing the secretion of IGF-1 and CCL20, which promoted tumor progression and stemness. Importantly, nicotine enhanced the expression of SIRPα in microglia and restricted their phagocytic ability. We also identified a compound, parthenolide, that suppressed brain metastasis by blocking M2 polarization. Our results indicate that nicotine promotes brain metastasis by skewing the polarity of M2 microglia, which enhances metastatic tumor growth. Our results also highlight a potential risk of using nicotine for tobacco cessation.