The effect of mTBI and PTSD symptoms on computerized cognitive performance: Results from a sample of treatment-seeking active duty US service members.

TBI and PTSD occur in a significant number of service members and can each result in considerable distress and cognitive challenges. Past research has established the individual impact of mild TBI (mTBI) and PTSD on cognitive performance; however, findings regarding the combined effects of mTBI and PTSD on cognitive performance are inconsistent. The present study examined the potentially synergistic effects of mTBI and PTSD symptoms on cognitive performance in a sample of 180 treatment-seeking active duty service members. As part of a larger clinical study, participants completed several self-report measures and an objective cognitive assessment via computer-based testing. Compared to norms, service members with mTBI-only, PTSD-symptoms-only, and comorbid TBI and PTSD performed significantly worse on cognitive tests, and there was a significant effect of group on cognitive performance, even when controlling for performance validity. Notably, individuals experiencing both mTBI and PTSD performed worse than those with either condition alone; service members with mTBI-only and those with PTSD symptoms-only did not differ. Findings further illustrate the complexity of the relationship between these two conditions, indicating comorbid mTBI and PTSD may represent a unique challenge to cognitive performance. Additional research is needed to clarify their combined impact on post-injury functioning.

Executing plans to enhance diversity across cancer centers in the United States: opportunities and challenges.

BACKGROUND: Lack of diversity in the cancer research workforce persists, which the new requirement for all National Cancer Institute (NCI)-designated cancer centers to have a Plan to Enhance Diversity (PED) seeks to address. However, it is not well understood how different cancer centers are approaching the development and execution of these plans. Our objective was to assess how cancer centers are establishing and pursuing their PED. METHODS: We conducted a cross-sectional survey of members of the Cancer Center Diversity, Equity and Inclusion Network, which includes all NCI-designated cancer centers and several emerging centers. A total of 62 cancer centers (75% of those invited), including 58 NCI-designated cancer centers (81% of those with this designation), participated and completed a questionnaire that assessed PED leadership, major challenges, implementation strategies, and approach to evaluate PED progress. RESULTS: The most common PED challenge identified is recruiting diverse faculty (68% of centers), and the most common strategy currently used to address this is reviewing and revising faculty recruitment practices (67%). The most common approach centers are using to measure PED progress is shifts in demographics (68%), and data on the demographics of faculty, leadership, and trainees are available at 79%, 81%, and 75% of centers, respectively. CONCLUSIONS: Almost all centers have established a PED leadership structure, however, there is considerable variation in the approaches used to realize PED goals and in the resources provided to support PED work. Realizing opportunities to share and implement common best practices and exemplar programs has the potential to elevate the impact of PED efforts nationally.

Effect of probiotic bacteria on the intestinal microbiota in irritable bowel syndrome.

BACKGROUND AND AIM: In irritable bowel syndrome (IBS), the gut microbiota may be altered. Probiotic bacteria appear to be therapeutically effective. We characterized the mucosa-associated microbiota, and determined the clinical and microbiological effects of orally administered probiotic bacteria, in patients with IBS. METHODS: Mucosal microbiota from rectal biopsies of IBS patients and controls were assessed on the V1 and V2 variable regions of the 16S ribosomal RNA gene amplified using 454 pyrosequencing. Clinical symptoms and changes in mucosal microbiota were assessed in IBS patients before and after 4 weeks of treatment with probiotic mix VSL#3. RESULTS: Ten IBS subjects (eight female; mean age 46 years) were included. At week 4 of probiotic therapy, six patients showed symptom improvement on global symptom assessment compared with baseline (P = 0.031). Before therapy, intestinal microbiota of IBS subjects differed significantly from that of healthy controls, with less diversity and evenness than controls (n = 9; P < 0.05), increased abundance of Bacteroidetes (P = 0.014) and Synegitestes (P = 0.017), and reduced abundance of Actinobacteria (P = 0.004). The classes Flavobacteria (P = 0.028) and Epsilonproteobacteria (P = 0.017) were less enriched in IBS. Abundance differences were largely consistent from the phylum to genus level. Probiotic treatment in IBS patients was associated with a significant reduction of the genus Bacteroides (all taxonomy levels; P < 0.05) to levels similar to that of controls. CONCLUSION: In this pilot study, global and deep molecular analysis demonstrates an altered mucosal microbiota composition in IBS. Probiotic leads to detectable changes in the microbiota. These effects of probiotic bacteria may contribute to their therapeutic benefit.

Brain-specific proteins decline in the cerebrospinal fluid of humans with Huntington disease.

We integrated five sets of proteomics data profiling the constituents of cerebrospinal fluid (CSF) derived from Huntington disease (HD)-affected and -unaffected individuals with genomics data profiling various human and mouse tissues, including the human HD brain. Based on an integrated analysis, we found that brain-specific proteins are 1.8 times more likely to be observed in CSF than in plasma, that brain-specific proteins tend to decrease in HD CSF compared with unaffected CSF, and that 81% of brain-specific proteins have quantitative changes concordant with transcriptional changes identified in different regions of HD brain. The proteins found to increase in HD CSF tend to be liver-associated. These protein changes are consistent with neurodegeneration, microgliosis, and astrocytosis known to occur in HD. We also discuss concordance between laboratories and find that ratios of individual proteins can vary greatly, but the overall trends with respect to brain or liver specificity were consistent. Concordance is highest between the two laboratories observing the largest numbers of proteins.

A Novel Intervention Platform for Service Members With Subjective Cognitive Complaints: Implementation, Patient Participation, and Satisfaction.

INTRODUCTION: Program overview of a novel cognitive training platform at Walter Reed National Military Medical Center (WRNMMC) for service members with subjective cognitive complaints: analysis of patient participation, satisfaction with the program, and perceived areas of improvement. MATERIALS AND METHOD: Retrospective review of 1,030 participants from November 2008 through May 2017. Data were obtained within an approved protocol (WRNMMC-EDO-2017-0004/# 876230). RESULTS: The program has shown growth in numbers of referrals, types of patient populations served, and patient visits. Patients report satisfaction with the program and endorse improvements in cognitive functions. CONCLUSIONS: This program model may benefit other military facilities looking to provide and assess novel therapeutic approaches.

Mismatch repair deficiency is implicated in carcinoma arising from ovarian teratoma.

Malignant transformation of benign mature ovarian teratoma can result in a wide spectrum of cancer, including a variety of carcinoma, sarcoma, or melanoma. The role of mismatch repair defects in such malignant transformation is still elusive. In view of current immunotherapy, the role of mismatch repair deficiency can have significant implications on therapeutic strategy. Thus, we aimed to investigate the possible involvement of mismatch repair deficiency in somatic-type carcinoma arising from teratoma. We examined seven cases of malignant transformation of ovarian teratoma to carcinoma from the years 2000-2017. Mismatch repair deficiency was demonstrated in two cases, one of which was a squamous carcinoma and another a sebaceous carcinoma. By immunohistochemistry and molecular studies, we detected mismatch repair protein deficiency, microsatellite instability (MSI) and MLH1 promoter methylation in the derived carcinoma, but not in the benign teratoma, indicating mismatch repair deficiency was implicated in the process of malignant transformation. Our findings expand the spectrum of genetic alterations which are known to accompany malignant changes in benign teratoma. This finding is also of potential therapeutic significance, as mismatch repair deficient tumours can often be responsive to immune checkpoint blockade because of the high mutational load. In conclusion, we report that a subset of teratoma-derived carcinoma harbours MLH1 promoter methylation which underlies DNA mismatch repair deficiency, and this subset of patients has the potential to benefit from immunotherapy.

Open-source platform for the analysis of liquid chromatography-mass spectrometry (LC-MS) data.

The analysis of protein mixtures by liquid chromatography-mass spectrometry (LCMS) requires tools for viewing and navigating LC-MS data, locating peptides in LC-MS data, and eliminating low-quality peptides. msInspect, an open source platform, can carry out these steps for single experiments and can align and normalize peptide features in comparative studies with multiple LC-MS runs. In addition, msInspect can analyze quantitative studies with and without isotopic labels to generate peptide arrays.

An App a Day Keeps the Doctor Away: Guided Education and Training via Smartphones in Subthreshold Post Traumatic Stress Disorder.

Post traumatic stress disorder (PTSD) symptoms are common in military service members (SMs), but stigma can impede treatment initiation. Smartphone applications (apps) are available anywhere, anytime, with the potential to both mitigate the impact of stigma and reduce PTSD symptom severity. We provided 144 SMs or family members, with subthreshold PTSD symptoms (PTSD Checklist [PCL] scores of 28-49), with apps promoting psychoeducation, social engagement, and relaxation and randomized them to 6 weeks of resilience enhancement (brief cognitive-behavioral session, followed by daily text messages directing app use) or a control group (daily text messages of inspirational quotes). Participants (54 percent males, 87 percent SMs) in both groups reported reductions in PTSD, anxiety, and depression symptoms during the 6-week intervention, which were sustained at 3 months, but exhibited partial rebound at 6-12 months. Our preliminary results suggest that app use, with or without specific direction, feasibly and effectively reduces symptom severity. Future studies should consider a longer intervention, enhanced compliance tracking, or boosters to sustain benefits.

Pyridostigmine, diethyltoluamide, permethrin, and stress: a double-blind, randomized, placebo-controlled trial to assess safety.

OBJECTIVE: To determine whether short-term human exposure to pyridostigmine bromide, diethyltoluamide, and permethrin, at rest or under stress, adversely affects short-term physical or neurocognitive performance. PARTICIPANTS AND METHODS: A multicenter, prospective, double-blind, placebo-controlled crossover trial exposing 64 volunteers to permethrin-impregnated uniforms, diethyltoluamide-containing skin cream, oral pyridostigmine, and corresponding placebos was performed. Each participant had 4 separate sessions, ensuring exposure to all treatments and placebos under both stress and rest conditions in random order. Outcomes Included physical performance (handgrip strength and duration, stair climbing, and pull-ups [males] or push-ups [females]), neurocognitive performance (computerized tests), and self-reported adverse effects. RESULTS: Permethrin was undetectable in the serum of all participants; pyridostigmine levels were higher Immediately after stress (41.6 ng/mL; 95% confidence Interval, 35.1-48.1 ng/mL) than rest (23.0 ng/mL; 95% confidence Interval, 19.2-26.9 ng/mL), whereas diethyltoluamide levels did not significantly differ by stress condition. Heart rate and systolic blood pressure increased significantly with stress compared with rest but did not vary with treatment vs placebo. Physical and neurocognitive outcome measures and self-reported adverse effects did not significantly differ by exposure group. CONCLUSION: Combined, correct use of pyridostigmine, diethyltoluamide, and permethrin is well tolerated and without evidence of short-term physical or neurocognitive impairment.

Initial evaluation of N,N-diethyl-m-toluamide and permethrin absorption in human volunteers under stress conditions.

OBJECTIVES: This was a pilot study to determine (1) whether it is feasible to effectively blind human subjects to the presence of the insect repellents N,N-diethyl-m-toluamide (DEET) and permethrin; (2) whether DEET affects the absorption of permethrin; and (3) whether combat videotape viewing and mental arithmetic are stressful. METHODS: Ten volunteers were exposed to DEET, permethrin, and stress (1-hour combat videotape plus mental arithmetic) in a double-blind, randomized, placebo-controlled trial. Outcome measurements included hemodynamics, plasma DEET and permethrin levels, and questionnaires to assess blinding. RESULTS: Highly sensitive serologic assays readily detected DEET but not permethrin. Staff members and subjects were effectively blinded to both. The videotape-math combination was stressful by both self-report and hemodynamic measures. CONCLUSIONS: It is possible to blind subjects with respect to DEET and permethrin. Permethrin on clothing does not enter the bloodstream at appreciable levels. Combat videotapes and mental arithmetic can be stressful.

Predictors of Neurocognitive Syndromes in Combat Veterans.

Traumatic brain injury, depression and posttraumatic stress disorder (PTSD) are neurocognitive syndromes often associated with impairment of physical and mental health, as well as functional status. These syndromes are also frequent in military service members (SMs) after combat, although their presentation is often delayed until months after their return. The objective of this prospective cohort study was the identification of independent predictors of neurocognitive syndromes upon return from deployment could facilitate early intervention to prevent disability. We completed a comprehensive baseline assessment, followed by serial evaluations at three, six, and 12 months, to assess for new-onset PTSD, depression, or postconcussive syndrome (PCS) in order to identify baseline factors most strongly associated with subsequent neurocognitive syndromes. On serial follow-up, seven participants developed at least one neurocognitive syndrome: five with PTSD, one with depression and PTSD, and one with PCS. On univariate analysis, 60 items were associated with syndrome development at p < 0.15. Decision trees and ensemble tree multivariate models yielded four common independent predictors of PTSD: right superior longitudinal fasciculus tract volume on MRI; resting state connectivity between the right amygdala and left superior temporal gyrus (BA41/42) on functional MRI; and single nucleotide polymorphisms in the genes coding for myelin basic protein as well as brain-derived neurotrophic factor. Our findings require follow-up studies with greater sample size and suggest that neuroimaging and molecular biomarkers may help distinguish those at high risk for post-deployment neurocognitive syndromes.

Improving the climate in research and scientific training environments for members of underrepresented minorities.

Despite significant efforts in recent years to increase diversity in science and academia, African Americans, Hispanics, and American Indian/Alaskan Natives remain severely underrepresented in these fields. To date, institutional social climate has received little attention as a target to improve the representation of these minority groups. In this article, we suggest that improvement in the social climate in both individual laboratories and larger institutions may lead to better recruitment and retention of minorities in science and academia. After documenting the magnitude of the underrepresentation problem, we offer a framework for a better understanding of climate, illustrate how members of majority and minority groups may perceive climate differently, and provide specific recommendations for improving the climate. The benefits of a diverse workforce in the sciences include a commitment to social justice, a broad diversity of perspectives leading to greater opportunities for scientific advancement, and a potentially enhanced focus on understanding and eliminating the health disparities among different racial and ethnic groups.

Installation and use of LabKey Server for proteomics.

LabKey Server (formerly CPAS, the Computational Proteomics Analysis System) provides a Web-based platform for mining data from liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic experiments. This open source platform supports systematic proteomic analyses and secure data management, integration, and sharing. LabKey Server incorporates several tools currently used in proteomic analysis, including the X! Tandem search engine, the ProteoWizard toolkit, and the PeptideProphet and ProteinProphet data mining tools. These tools and others are integrated into LabKey Server, which provides an extensible architecture for developing high-throughput biological applications. The LabKey Server analysis pipeline acts on data in standardized file formats, so that researchers may use LabKey Server with other search engines, including Mascot or SEQUEST, that follow a standardized format for reporting search engine results. Supported builds of LabKey Server are freely available at http://www.labkey.com/. Documentation and source code are available under the Apache License 2.0 at http://www.labkey.org.

Integrative proteomic analysis of serum and peritoneal fluids helps identify proteins that are up-regulated in serum of women with ovarian cancer.

BACKGROUND: We used intensive modern proteomics approaches to identify predictive proteins in ovary cancer. We identify up-regulated proteins in both serum and peritoneal fluid. To evaluate the overall performance of the approach we track the behavior of 20 validated markers across these experiments. METHODOLOGY: Mass spectrometry based quantitative proteomics following extensive protein fractionation was used to compare serum of women with serous ovarian cancer to healthy women and women with benign ovarian tumors. Quantitation was achieved by isotopically labeling cysteine amino acids. Label-free mass spectrometry was used to compare peritoneal fluid taken from women with serous ovarian cancer and those with benign tumors. All data were integrated and annotated based on whether the proteins have been previously validated using antibody-based assays. FINDINGS: We selected 54 quantified serum proteins and 358 peritoneal fluid proteins whose case-control differences exceeded a predefined threshold. Seventeen proteins were quantified in both materials and 14 are extracellular. Of 19 validated markers that were identified all were found in cancer peritoneal fluid and a subset of 7 were quantified in serum, with one of these proteins, IGFBP1, newly validated here. CONCLUSION: Proteome profiling applied to symptomatic ovarian cancer cases identifies a large number of up-regulated serum proteins, many of which are or have been confirmed by immunoassays. The number of currently known validated markers is highest in peritoneal fluid, but they make up a higher percentage of the proteins observed in both serum and peritoneal fluid, suggesting that the 10 additional markers in this group may be high quality candidates.

Improvement in cerebral function with treatment of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are signature illnesses of the Iraq and Afghanistan wars, but current diagnostic and therapeutic measures for these conditions are suboptimal. In our study, functional magnetic resonance imaging (fMRI) is used to try to differentiate military service members with: PTSD and mTBI, PTSD alone, mTBI alone, and neither PTSD nor mTBI. Those with PTSD are then randomized to virtual reality exposure therapy or imaginal exposure. fMRI is repeated after treatment and along with the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression (CGI) scores to compare with baseline. Twenty subjects have completed baseline fMRI scans, including four controls and one mTBI only; of 15 treated for PTSD, eight completed posttreatment scans. Most subjects have been male (93%) and Caucasian (83%), with a mean age of 34. Significant improvements are evident on fMRI scans, and corroborated by CGI scores, but CAPS scores improvements are modest. In conclusion, CGI scores and fMRI scans indicate significant improvement in PTSD in both treatment arms, though CAPS score improvements are less robust.

Software platform for rapidly creating computational tools for mass spectrometry-based proteomics.

We describe and demonstrate the proteomics computational toolkit provided in the open-source msInspect software distribution. The toolkit includes modules written in Java and in the R statistical programming language to aid the rapid development of proteomics software applications. It contains tools for processing and manipulating standard MS data files, including signal processing of LC-MS data and parsing of MS/MS search results, as well as for modeling proteomics data structures, creating charts, and other common tasks. We present this toolkit's capability to rapidly develop new computational tools by presenting an example application, Qurate, a graphical tool for manually curating isotopically labeled peptide quantitative events.

Peptide sequence confidence in accurate mass and time analysis and its use in complex proteomics experiments.

We present new algorithms and a software implementation for assigning confidence to peptide sequence assignments obtained through classic accurate mass and retention time (AMT) matching techniques, as well as methods for integrating these assignments with standard proteomics workflows. The algorithms are intended to increase the number of peptides and proteins identified (and, when applicable, quantitated by isotopic labeling) among related proteomics experiments that use high-resolution mass spectrometry instrumentation. The motivations for our extensions include the need to exploit high-resolution data to support highly complex proteomics experiments, especially those involving extensive off-line fractionation, to which recent label-free workflows might not easily generalize.

Installation and use of the Computational Proteomics Analysis System (CPAS).

The community of proteomic researchers has been generating openly available software infrastructure for systematic proteomic data analyses and data management for the past several years. The Computational Proteomics Analysis System (CPAS) integrates many of these efforts into a single Web-based platform for mining liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic experiments. CPAS incorporates several tools currently used in proteomic analysis, including the X! Tandem search engine and the PeptideProphet and ProteinProphet data mining tools. These tools and others are integrated into a single application built on the open-source LabKey platform, an extensible architecture for developing high-throughput biological applications. The CPAS analysis pipeline acts on data in standardized file formats, so that researchers may use CPAS with other search engines, including Mascot or SEQUEST, that follow a standardized procedure for reporting search engine results. All components of the CPAS toolkit are freely available at http://cpas.fhcrc.org.