Altered long-range functional connectivity in PTSD: Role of the infraslow oscillations of cortical activity amplitude envelopes.

OBJECTIVE: Coupling between the amplitude envelopes (AEs) of regional cortical activity reflects mechanisms that coordinate the excitability of large-scale cortical networks. We used resting-state MEG recordings to investigate the association between alterations in the coupling of cortical AEs and symptoms of post-traumatic stress disorder (PTSD). METHODS: Participants (n = 96) were service members with combat exposure and various levels of post-traumatic stress severity (PTSS). We assessed the correlation between PTSS and (1) coupling of broadband cortical AEs of beta band activity, (2) coupling of the low- (<0.5 Hz) and high-frequency (>0.5 Hz) components of the AEs, and (3) their time-varying patterns. RESULTS: PTSS was associated with widespread hypoconnectivity assessed from the broadband AE fluctuations, which correlated with subscores for the negative thoughts and feelings/emotional numbing (NTF/EN) and hyperarousal clusters of symptoms. Higher NTF/EN scores were also associated with smaller increases in resting-state functional connectivity (rsFC) with time during the recordings. The distinct patterns of rsFC in PTSD were primarily due to differences in the coupling of low-frequency (infraslow) fluctuations of the AEs of beta band activity. CONCLUSIONS: Our findings implicate the mechanisms underlying the regulation/coupling of infraslow oscillations in the alterations of rsFC assessed from broadband AEs and in PTSD symptomatology. SIGNIFICANCE: Altered coordination of infraslow amplitude fluctuations across large-scale cortical networks can contribute to network dysfunction and may provide a target for treatment in PTSD.

Intensive Outpatient Program Response Among Service Members With Mild Traumatic Brain Injury: Change Between Distinct Post-Concussive Symptom Subgroups.

OBJECTIVE: Among service members (SMs) with mild traumatic brain injury (mTBI) admitted to an intensive outpatient program (IOP), we identified qualitatively distinct subgroups based on post-concussive symptoms (PCSs) and characterized changes between subgroups from admission to discharge. Further, we examined whether co-morbid posttraumatic stress disorder (PTSD) influenced changes between subgroups. DESIGN: Quasi-experimental. Latent transition analysis identified distinctive subgroups of SMs and examined transitions between subgroups from admission to discharge. Logistic regression examined the effect of PTSD on transition to the Minimal subgroup (low probability of any moderate-very severe PCS) while adjusting for admission subgroup designation. SETTING: National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center. PARTICIPANTS: 1141 active duty SMs with persistent PCS despite prior treatment (N=1141). INTERVENTIONS: NICoE 4-week interdisciplinary IOP. MAIN OUTCOME MEASURE(S): Subgroups identified using Neurobehavioral Symptom Inventory items at admission and discharge. RESULTS: Model fit indices supported a 7-class solution. The 7 subgroups of SMs were distinguished by diverging patterns of probability for specific PCS. The Minimal subgroup was most prevalent at discharge (39.4%), followed by the Sleep subgroup (high probability of sleep problems, low probability of other PCS; 26.8%). 41% and 25% of SMs admitted within the Affective (ie, predominantly affective PCS) and Sleep subgroups remained within the same group at discharge, respectively. The 19% of SMs with co-morbid PTSD were less likely to transition to the Minimal subgroup (odds ratio=0.28; P<.001) and were more likely to remain in their admission subgroup at discharge (35.5% with PTSD vs 22.2% without). CONCLUSIONS: Most of SMs achieved symptom resolution after participation in the IOP, with most transitioning to subgroups characterized by reduced symptom burden. SMs admitted in the Affective and Sleep subgroups, as well as those with PTSD, were most likely to have continuing clinical needs at discharge, revealing priority targets for resource allocation and follow-up treatment.

Cognitive flexibility in post-traumatic stress disorder: Sustained interference associated with altered modulation of cortical oscillatory activity during task-switching.

Post-traumatic stress disorder (PTSD) is associated with deficits in cognitive flexibility, with evidence suggesting that these deficits may be a risk factor for the development of core PTSD symptoms. Understanding the neurophysiological substrate of this association could aid the development of effective therapies for PTSD. In this study, we investigated the relationship between post-traumatic stress severity (PTSS) in service members with combat exposure and the modulation of cortical oscillatory activity during a test of cognitive flexibility. Participants were assigned to three groups based on PTSS scores: low (well below a threshold consistent with a diagnosis of PTSD, n = 30), moderate (n = 32), and high (n = 29) symptom severity. Magnetoencephalography data were recorded while participants performed a cued rule-switching task in which two matching rules were repeated or switched across consecutive trials. Participants with high PTSS had longer reaction times for both switch and repeat trials, and showed evidence of sustained residual interference during repeat trials. During the cue-stimulus interval, participants with moderate and high PTSS showed higher relative theta power in switch trials over left dorsolateral prefrontal cortex (DLPFC). After test-stimulus onset, participants with high PTSS showed less suppression of beta band activity, which was present over multiple prefrontal, parietal, and temporal regions in switch trials, but it was confined to ventromedial prefrontal cortex in repeat trials. Higher theta band activity is a marker of effortful voluntary shifting of attention, while lower suppression of beta band activity reflects difficulties with inhibition of competing perceptual information and courses of action. These findings are consistent with a role for altered suppression of beta band activity, which can be due to less effective top-down bias signals exerted by DLPFC, in the etiology of cognitive flexibility deficits in PTSD.

Development of the Blast Ordnance and Occupational Exposure Measure for Self-Reported Lifetime Blast Exposures.

INTRODUCTION: To address the military gap in the standardized collection of lifetime blast exposures across clinical and research endeavors, researchers at the National Intrepid Center of Excellence (NICoE) completed a quality improvement project that utilized systematic, iterative focus groups that leveraged the input from various stakeholders including subject matter experts, clinical providers, and service members (SMs) to develop a comprehensive, self-report blast exposure inventory that could be completed within 5-10 minutes. This manuscript outlines the process of the development of this inventory. MATERIALS AND METHODS: This project included three phases of focus groups that occurred at the NICoE between August 2020 and March 2021 to collect feedback and input from relevant military stakeholders. The study team utilized related assessments available in the literature, together with clinical experience with the NICoE patient population, to inform the development of an initial draft inventory. Phase 1 consisted of blast injury research subject matter experts who had extensive experience researching and providing clinical care to SMs exposed to blast. Phase 2 consisted of NICoE clinicians across numerous clinical specialties. Phase 3 included current active duty patients in the NICoE intensive outpatient program. RESULTS: Following completion of the focus groups, a lifetime blast exposure inventory was developed in the form of a single page table including incoming, outgoing, training, and operational exposures and broken down by levels of weapon systems as well as breaching and explosive ordnance disposal exposures. In addition, select questions related to the first and most recent blast exposures and experience as an instructor for explosive ordnance disposal- and breaching-related training were included. CONCLUSIONS: Researchers at the NICoE developed a self-report blast exposure inventory through a quality improvement project that included active, ongoing participation and feedback of clinical experts and military SMs. The end result is a brief, single page inventory that can be administered within 5-10 minutes. Although additional research is needed to refine and validate the inventory, the project team believes that the tool begins to address a long-standing gap in the DoD in the standardized collection of lifetime blast exposures.

Post-traumatic stress disorder is associated with alterations in evoked cortical activation during visual recognition of scenes.

We recorded magnetoencephalography data during a visual recognition task in participants with combat exposure (n = 40, age: 41.2 ± 7.2 years) to investigate the relationship between the evoked brain activity, behavioral performance, and the severity of their post-traumatic stress symptoms assessed using the PTSD Check List for DSM V version (PCL-5). In an initial study session, participants were presented with a series of images of outdoor scenes and were instructed to study the images for an upcoming recognition test. In a subsequent session, the original images were shown intermixed with novel images while participants performed the recognition task. PCL-5 scores were negatively correlated with discrimination performance and with the recognition accuracy for original images. During the recognition session, higher PCL-5 scores were associated with reduced relative power of the evoked response to original images from 100 ms to 300 ms following the image onset over a distributed brain network including the bilateral inferior frontal gyri, left middle frontal gyrus, left supramarginal gyrus, right precuneus and the bilateral superior temporal gyri. These findings indicate that the lower recognition performance in participants with higher PTSD symptom severity is associated with altered cortical activity in brain regions that are known to play a role in the elaboration on visual cues that supports recollection.

Altered modulation of beta band oscillations during memory encoding is predictive of lower subsequent recognition performance in post-traumatic stress disorder.

We studied the relationship between electrophysiological markers of memory encoding, subsequent recognition performance, and severity of PTSD symptoms in service members with combat exposure (n = 40, age: 41.2 ± 7.2 years) and various levels of PTSD symptom severity assessed using the PTSD Check List for DSM V version (PCL-5). Brain activity was recorded using magnetoencephalography during a serial presentation of 86 images of outdoor scenes that were studied by participants for an upcoming recognition test. In a second session, the original images were shown intermixed with an equal number of novel images while participants performed the recognition task. Participants recognized 76.0% ± 12.1% of the original images and correctly categorized as novel 89.9% ± 7.0% of the novel images. A negative correlation was present between PCL-5 scores and discrimination performance (Spearman rs = -0.38, p = 0.016). PCL-5 scores were also negatively correlated with the recognition accuracy for original images (rs = -0.37, p = 0.02). Increases in theta and gamma power and decreases in alpha and beta power were observed over distributed brain networks during memory encoding. Higher PCL-5 scores were associated with less suppression of beta band power in bilateral ventral and medial temporal regions and in the left orbitofrontal cortex. These regions also showed positive correlations between the magnitude of suppression of beta power during encoding and subsequent recognition accuracy. These findings indicate that the lower recognition performance in participants with greater PTSD symptom severity may be due in part to ineffective encoding reflected in altered modulation of beta band oscillatory activity.

Efficacy of an Interdisciplinary Intensive Outpatient Program in Treating Combat-Related Traumatic Brain Injury and Psychological Health Conditions.

Background: Since 2000, over 413,000 US service members (SM) experienced at least one traumatic brain injury (TBI), and 40% of those with in-theater TBIs later screened positive for comorbid psychological health (PH) conditions, including post-traumatic stress disorder (PTSD), depression, and anxiety. Many SMs with these persistent symptoms fail to achieve a recovery that results in a desirable quality of life or return to full duty. Limited information exists though to guide treatment for SMs with a history of mild TBI (mTBI) and comorbid PH conditions. This report presents the methods and outcomes of an interdisciplinary intensive outpatient program (IOP) in the treatment of SMs with combat-related mTBI and PH comorbidities. The IOP combines conventional rehabilitation therapies and integrative medicine techniques with the goal of reducing morbidity in multiple neurological and behavioral health domains and enhancing military readiness. Methods: SMs (n = 1,456) with residual symptoms from mTBI and comorbid PH conditions were treated in a 4-week IOP at the National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center (WRNMMC). The IOP uses an interdisciplinary, holistic, and patient-centric rehabilitative care model. Interdisciplinary teams provide a diagnostic workup of neurological, psychiatric, and existential injuries, and from these assessments, individualized care plans are developed. Treatment response was assessed using the Neurobehavioral Symptom Inventory (NSI), PTSD Checklist-Military Version (PCL-M), Satisfaction With Life Scale (SWLS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Epworth Sleepiness Scale (ESS), and Headache Impact Test-6 (HIT-6) and administered at admission, discharge, and at 1, 3, and 6 months post-discharge. Findings: Following treatment in the IOP, the symptomatic patients had statistically significant and clinically meaningful improvements across all outcome measures. The largest effect size was seen with GAD-7 (r = 0.59), followed by PHQ-8 (r = 0.56), NSI (r = 0.55), PCL-M (r = 0.52), ESS (r = 0.50), SWLS (r = 0.49), and HIT-6 (r = 0.42). In cross-sectional follow ups, the significant improvements were sustained at 1, 3, and 6 months post-discharge. Interpretation: This report demonstrates that an interdisciplinary IOP achieves significant and sustainable symptom recovery in SMs with combat-related mTBI and comorbid PH conditions and supports the further study of this model of care in complex medical conditions.

Post-traumatic stress disorder is associated with altered modulation of prefrontal alpha band oscillations during working memory.

OBJECTIVE: To investigate the relationship between the severity of PTSD symptoms, modulation of alpha band oscillations, and behavioral performance in a working memory task. METHODS: Magnetoencephalography data were recorded in 35 participants with combat exposure and various degrees of PTSD symptom severity while they performed a modified Sternberg working memory task: briefly presented sets of two or six letters had to be held in memory and participants indicated whether subsequent probe letters were present or absent from these sets. RESULTS: PTSD scores were positively correlated with the false positive rate in the high memory load condition. Higher rates of false recognition were associated with negative probes that were seen in recent previous trials (negative probe recency effect) or were physically similar with the list letters. The relative alpha band power in the left middle frontal gyrus was negatively correlated with both PTSD scores and false positive rates. CONCLUSIONS: Reduced task specific modulation of alpha band oscillations in left middle frontal cortex may reflect alterations in the functions of pattern separation and suppression of memory traces for irrelevant or no longer relevant information in PTSD. SIGNIFICANCE: The lower amplitude of prefrontal alpha band oscillations may represent an important physiological basis for core PTSD symptoms and can provide a target for interventions to augment response to treatment.

Observational study of associations between visual imagery and measures of depression, anxiety and post-traumatic stress among active-duty military service members with traumatic brain injury at the Walter Reed National Military Medical Center.

OBJECTIVES: The study aimed tocompare recurring themes in the artistic expression of military service members (SMs) with post-traumatic stress disorder (PTSD), traumatic brain injury and psychological health (PH) conditions with measurable psychiatric diagnoses. Affective symptoms and struggles related to verbally expressing information can limit communication in individuals with symptoms of PTSD and deployment-related health conditions. Visual self-expression through art therapy is an alternative way for SMs with PTSD and other PH conditions to communicate their lived experiences. This study offers the first systematic examination of the associations between visual self-expression and standardised clinical self-report measures. DESIGN: Observational study of correlations between clinical symptoms of post-traumatic stress, depression and anxiety and visual themes in mask imagery. SETTING: The National Intrepid Center of Excellence at the Walter Reed National Military Medical Center, Bethesda, Maryland, USA. PARTICIPANTS: Active-duty military SMs (n=370) with a history of traumatic brain injury, post-traumatic stress symptoms and related PH conditions. INTERVENTION: The masks used for analysis were created by the SMs during art therapy sessions in week 1 of a 4-week integrative treatment programme. PRIMARY OUTCOMES: Associations between scores on the PTSD Checklist-Military, Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale on visual themes in depictions of aspects of individual identity (psychological injury, military symbols, military identity and visual metaphors). RESULTS: Visual and clinical data comparisons indicate that SMs who depicted psychological injury had higher scores for post-traumatic stress and depression. The depiction of military unit identity, nature metaphors, sociocultural metaphors, and cultural and historical characters was associated with lower post-traumatic stress, depression and anxiety scores. Colour-related symbolism and fragmented military symbols were associated with higher anxiety, depression and post-traumatic stress scores. CONCLUSIONS: Emergent patterns of resilience and risk embedded in the use of images created by the participants could provide valuable information for patients, clinicians and caregivers.

The Biological Basis of Chronic Traumatic Encephalopathy following Blast Injury: A Literature Review.

The United States Department of Defense Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science meeting to explore links between blast-related head injury and the development of chronic traumatic encephalopathy (CTE). Before the meeting, the planning committee examined articles published between 2005 and October 2015 and prepared this literature review, which summarized broadly CTE research and addressed questions about the pathophysiological basis of CTE and its relationship to blast- and nonblast-related head injury. It served to inform participants objectively and help focus meeting discussion on identifying knowledge gaps and priority research areas. CTE is described generally as a progressive neurodegenerative disorder affecting persons exposed to head injury. Affected individuals have been participants primarily in contact sports and military personnel, some of whom were exposed to blast. The symptomatology of CTE overlaps with Alzheimer's disease and includes neurological and cognitive deficits, psychiatric and behavioral problems, and dementia. There are no validated diagnostic criteria, and neuropathological evidence of CTE has come exclusively from autopsy examination of subjects with histories of exposure to head injury. The perivascular accumulation of hyperphosphorylated tau (p-tau) at the depths of cortical sulci is thought to be unique to CTE and has been proposed as a diagnostic requirement, although the contribution of p-tau and other reported pathologies to the development of clinical symptoms of CTE are unknown. The literature on CTE is limited and is focused predominantly on head injuries unrelated to blast exposure (e.g., football players and boxers). In addition, comparative analyses of clinical case reports has been challenging because of small case numbers, selection biases, methodological differences, and lack of matched controls, particularly for blast-exposed individuals. Consequently, the existing literature is not sufficient to determine whether the development of CTE is associated with head injury frequency (e.g., single vs. multiple exposures) or head injury type (e.g., impact, nonimpact, blast-related). Moreover, the incidence and prevalence of CTE in at-risk populations is unknown. Future research priorities should include identifying additional risk factors, pursuing population-based longitudinal studies, and developing the ability to detect and diagnose CTE in living persons using validated criteria.

Activation of dominant hemisphere association cortex during naming as a function of cognitive performance in mild traumatic brain injury: Insights into mechanisms of lexical access.

Patients with a history of mild traumatic brain injury (mTBI) and objective cognitive deficits frequently experience word finding difficulties in normal conversation. We sought to improve our understanding of this phenomenon by determining if the scores on standardized cognitive testing are correlated with measures of brain activity evoked in a word retrieval task (confrontational picture naming). The study participants (n = 57) were military service members with a history of mTBI. The General Memory Index (GMI) determined after administration of the Rivermead Behavioral Memory Test, Third Edition, was used to assign subjects to three groups: low cognitive performance (Group 1: GMI ≤ 87, n = 18), intermediate cognitive performance (Group 2: 88 ≤ GMI ≤ 99, n = 18), and high cognitive performance (Group 3: GMI ≥ 100, n = 21). Magnetoencephalography data were recorded while participants named eighty pictures of common objects. Group differences in evoked cortical activity were observed relatively early (within 200 ms from picture onset) over a distributed network of left hemisphere cortical regions including the fusiform gyrus, the entorhinal and parahippocampal cortex, the supramarginal gyrus and posterior part of the superior temporal gyrus, and the inferior frontal and rostral middle frontal gyri. Differences were also present in bilateral cingulate cortex and paracentral lobule, and in the right fusiform gyrus. All differences reflected a lower amplitude of the evoked responses for Group 1 relative to Groups 2 and 3. These findings may indicate weak afferent inputs to and within an extended cortical network including association cortex of the dominant hemisphere in patients with low cognitive performance. The association between word finding difficulties and low cognitive performance may therefore be the result of a diffuse pathophysiological process affecting distributed neuronal networks serving a wide range of cognitive processes. These findings also provide support for a parallel processing model of lexical access.

Active-duty military service members' visual representations of PTSD and TBI in masks.

Active-duty military service members have a significant risk of sustaining physical and psychological trauma resulting in traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Within an interdisciplinary treatment approach at the National Intrepid Center of Excellence, service members participated in mask making during art therapy sessions. This study presents an analysis of the mask-making experiences of service members (n = 370) with persistent symptoms from combat- and mission-related TBI, PTSD, and other concurrent mood issues. Data sources included mask images and therapist notes collected over a five-year period. The data were coded and analyzed using grounded theory methods. Findings indicated that mask making offered visual representations of the self related to individual personhood, relationships, community, and society. Imagery themes referenced the injury, relational supports/losses, identity transitions/questions, cultural metaphors, existential reflections, and conflicted sense of self. These visual insights provided an increased understanding of the experiences of service members, facilitating their recovery.

Reduced prefrontal MEG alpha-band power in mild traumatic brain injury with associated posttraumatic stress disorder symptoms.

OBJECTIVE: To determine if changes in cortical alpha-band power in patients with mild traumatic brain injury (mTBI) are associated with the severity of their post-traumatic stress disorder (PTSD) symptoms, and if injury severity and level of exposure to psychologically traumatic events are predictors of these electrophysiological changes. METHODS: Resting-state magnetoencephalographic recordings were analyzed in 32 patients with mTBI. Alpha-band power was estimated for each patient in 68 cortical regions and was compared between groups of patients with low versus high PTSD symptoms severity. RESULTS: Participants with high PTSD symptom severity showed reduced alpha-band power bilaterally in the superior and middle frontal gyri and frontal poles, and in the left inferior frontal gyrus. Alpha-band power in bilateral middle frontal gyri and frontal poles was negatively correlated with scores reflecting symptoms of emotional numbing. Loss of consciousness (LOC) associated with mTBI and level of exposure to psychologically traumatic events were predictors of decreased prefrontal alpha-band power in some of these regions. CONCLUSION: Altered prefrontal alpha-band activity, shown to be partly explained by mTBI-related LOC, is associated with PTSD symptoms severity. SIGNIFICANCE: Our findings will guide future studies addressing the electrophysiological mechanisms underlying a higher incidence of PTSD in patients with mTBI.

Biomarker discovery in serum from patients with carotid atherosclerosis.

BACKGROUND: Blood-based biomarkers of atherosclerosis have been used to identify patients at high risk for developing stroke. We hypothesized that patients with carotid artery disease would have a distinctive proteomic signature in blood as compared to a healthy control population without carotid artery disease. In order to discover protein biomarkers associated with increased atherosclerotic risk, we used two different strategies to identify biomarkers from patients with clinically defined atherosclerosis who were undergoing endarterectomy for atherosclerotic carotid artery disease. These patients were compared with healthy matched controls. METHODS: Serum was obtained from patients undergoing endarterectomy (EA; n = 38) and compared to a group of age-matched healthy controls (n = 40). Serum was fractionated using anion exchange chromatography and three different surface-enhanced laser desorption/ionization (SELDI) chip surfaces and then evaluated with mass spectrometry (MS) and two-dimensional difference gel electrophoresis (2D-DIGE). RESULTS: A random forest (RF) analysis of the SELDI-MS protein peak data distinguished these two groups with 69.2% sensitivity and 73.2% specificity. Four unique SELDI peaks (4.2, 4.4, 16.7 and 28 kDa, all p< 0.01) showed the greatest influence in the RF model. The EA patients with a history of prior clinical atherosclerotic plaque rupture manifested as either stroke or transient ischemic attack (symptomatic; n = 16) were compared to patients with carotid atherosclerosis but no clinical evidence of plaque rupture (asymptomatic; n = 22). Analysis of the SELDI spectra did not separate these two patient subgroups. A subgroup analysis using 2D-DIGE images obtained from albumin-depleted serum comparing symptomatic (n = 10) to asymptomatic EA patients (n = 10) found 4 proteins that were differentially expressed (p < 0.01) in the symptomatic patients. These proteins were identified as α(1)-antitrypsin, haptoglobin and vitamin D binding protein that were downregulated and α(2)-glycoprotein precursor that was upregulated in the symptomatic EA group. CONCLUSIONS: SELDI-MS data analysis of fractionated serum suggests that a distinct protein signature exists in patients with carotid atherosclerosis compared to age-matched healthy controls. Identification of 4 proteins in a subset of patients with symptomatic and asymptomatic carotid atherosclerosis suggests that these and other protein biomarkers may assist in identifying high-risk patients with carotid atherosclerosis.

Linkage of large-vessel carotid atherosclerotic stroke to inflammatory genes via a systematic screen.

BACKGROUND: Inflammatory cytokines including the IL-1 family, TNF-alpha and IL-6 mediate the formation of thrombosis on the luminal surface of atherosclerotic plaques. Gene polymorphisms that regulate these cytokines' expression may explain part of the variation in susceptibility to stroke in patients with carotid atherosclerosis. The aim of this study was to evaluate the role of single-nucleotide polymorphisms (SNPs) and haplotypes in inflammatory genes as they relate to symptomatic carotid atherosclerosis. METHODS: The study included 95 subjects with symptomatic (transient ischaemic attacks or stroke) and 113 subjects with asymptomatic carotid atherosclerotic disease. A panel of evenly spaced SNPs including previously reported functionally significant polymorphisms were genotyped for IL-1beta (10 SNPs), IL-1alpha (nine SNPs), IL-1RN (11 SNPs), IL-6 (seven SNPs) and TNF-alpha and TNF-beta (seven SNPs). RESULTS: Using single SNP analysis, IL-1RN rs315934 (P=0.025), IL-1RN rs315946 (P=0.042), IL-1RN rs315921 (P=0.035), IL-6 rs1180243 (P=0.018) and IL-1alpha rs2071373 (P=0.025) were associated with decreased odds of symptomatic carotid disease. Additionally, two diplotypes of the IL-1RN gene (P=0.023 and 0.0064) and one diplotype in the IL-1alpha gene (P=0.02) were associated with a protective affect from cerebral ischaemic events. Logistic analysis for interaction of the protective SNPs reveals an additive effect of all SNP pair combinations. CONCLUSION: These results suggest that genetic polymorphisms in proinflammatory genes may contribute to interindividual differences in the development of symptomatic carotid atherosclerotic disease.

A novel peak detection approach with chemical noise removal using short-time FFT for prOTOF MS data.

Peak detection is a pivotal first step in biomarker discovery from MS data and can significantly influence the results of downstream data analysis steps. We developed a novel automatic peak detection method for prOTOF MS data, which does not require a priori knowledge of protein masses. Random noise is removed by an undecimated wavelet transform and chemical noise is attenuated by an adaptive short-time discrete Fourier transform. Isotopic peaks corresponding to a single protein are combined by extracting an envelope over them. Depending on the S/N, the desired peaks in each individual spectrum are detected and those with the highest intensity among their peak clusters are recorded. The common peaks among all the spectra are identified by choosing an appropriate cut-off threshold in the complete linkage hierarchical clustering. To remove the 1 Da shifting of the peaks, the peak corresponding to the same protein is determined as the detected peak with the largest number among its neighborhood. We validated this method using a data set of serial peptide and protein calibration standards. Compared with MoverZ program, our new method detects more peaks and significantly enhances S/N of the peak after the chemical noise removal. We then successfully applied this method to a data set from prOTOF MS spectra of albumin and albumin-bound proteins from serum samples of 59 patients with carotid artery disease compared to vascular disease-free patients to detect peaks with S/N> or =2. Our method is easily implemented and is highly effective to define peaks that will be used for disease classification or to highlight potential biomarkers.

Cryptogenic emboli in patients with patent foramen ovale or atrial septal defect associated with the use of nonsteroidal anti-inflammatory drugs.

BACKGROUND: Nonaspirin, nonsteroidal anti-inflammatory drugs (NANSAIDs) have been associated with arterial thromboembolic events in the general population. Our objective was to determine the prevalence of NANSAID use in patients diagnosed with cryptogenic emboli or paradoxical embolic events from a patent foramen ovale (PFO) or atrial septal defect (ASD) compared with a control population with an incidental PFO/ASD and no history of embolic events. METHODS: We performed a retrospective case-control study of 90 age-matched patients to assess the association of NANSAIDs with cryptogenic arterial embolic events in patients with and without a history of PFO/ASD. Odds ratios (ORs) were obtained by chi2 analysis. Multivariate analysis was conducted with a logistical regression method. RESULTS: Patients with cryptogenic embolic events had a high prevalence of prescription NANSAID use regardless of the presence of a PFO/ASD and were far more likely to have a history of NANSAID use than those with an incidentally discovered PFO/ASD and no history of arterial emboli (OR 4.30, 95% confidence interval 1.14-13.07, p = 0.01). CONCLUSIONS: Many patients previously diagnosed with paradoxical emboli may be experiencing the prothrombotic effects of NANSAIDs rather than a paradoxical mechanism for their arterial embolic event.

Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group.

BACKGROUND AND PURPOSE: This guideline provides an overview of the evidence on various established and potential stroke risk factors and provides recommendations for the reduction of stroke risk. METHODS: Writing group members were nominated by the committee chair on the basis of each writer's previous work in relevant topic areas and were approved by the American Heart Association Stroke Council's Scientific Statement Oversight Committee. The writers used systematic literature reviews (covering the time period since the last review published in 2001 up to January 2005), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate recommendations based on standard American Heart Association criteria. All members of the writing group had numerous opportunities to comment in writing on the recommendations and approved the final version of this document. The guideline underwent extensive peer review before consideration and approval by the AHA Science Advisory and Coordinating Committee. RESULTS: Schemes for assessing a person's risk of a first stroke were evaluated. Risk factors or risk markers for a first stroke were classified according to their potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented or less well documented). Nonmodifiable risk factors include age, sex, low birth weight, race/ethnicity, and genetic factors. Well-documented and modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, atrial fibrillation and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, alcohol abuse, drug abuse, oral contraceptive use, sleep-disordered breathing, migraine headache, hyperhomocysteinemia, elevated lipoprotein(a), elevated lipoprotein-associated phospholipase, hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are reviewed. CONCLUSIONS: Extensive evidence is available identifying a variety of specific factors that increase the risk of a first stroke and providing strategies for reducing that risk.

Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline.

BACKGROUND AND PURPOSE: This guideline provides an overview of the evidence on various established and potential stroke risk factors and provides recommendations for the reduction of stroke risk. METHODS: Writing group members were nominated by the committee chair on the basis of each writer's previous work in relevant topic areas and were approved by the American Heart Association Stroke Council's Scientific Statement Oversight Committee. The writers used systematic literature reviews (covering the time period since the last review published in 2001 up to January 2005), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate recommendations based on standard American Heart Association criteria. All members of the writing group had numerous opportunities to comment in writing on the recommendations and approved the final version of this document. The guideline underwent extensive peer review before consideration and approval by the AHA Science Advisory and Coordinating Committee. RESULTS: Schemes for assessing a person's risk of a first stroke were evaluated. Risk factors or risk markers for a first stroke were classified according to their potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented or less well documented). Nonmodifiable risk factors include age, sex, low birth weight, race/ethnicity, and genetic factors. Well-documented and modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, atrial fibrillation and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, alcohol abuse, drug abuse, oral contraceptive use, sleep-disordered breathing, migraine headache, hyperhomocysteinemia, elevated lipoprotein(a), elevated lipoprotein-associated phospholipase, hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are reviewed. CONCLUSIONS: Extensive evidence is available identifying a variety of specific factors that increase the risk of a first stroke and providing strategies for reducing that risk.