Intensity warping for multisite MRI harmonization.

In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These "scanner effects" can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method's performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.

Amygdala Resting State Connectivity Differences between Bipolar II and Borderline Personality Disorders.

BACKGROUND: Borderline personality disorder (BPD) and bipolar II disorder (BD II) have significant clinical overlap, leaving the potential for diagnostic inaccuracies and inadequate treatment recommendations. However, few studies have probed for clinical and neurobiological differences between the two disorders. Clinically, some prior studies have linked BPD with greater impulsivity and more frequent negative affective shifts than BD II, whereas previous neuroimaging studies have highlighted both similar and distinct neural abnormalities in BPD and BD II. Notably, no prior study has specifically targeted cortico-limbic neural differences, which have been hypothesized to underlie these core clinical differences. METHODS: Individuals with BPD (n = 14) and BD II (n = 15) completed various clinical measures and a resting state functional imaging scan at 3T. Whole-brain amygdala resting state functional connectivity (RSFC) was compared between the two groups. RESULTS: Relative to the BD II group, BPD participants reported significantly higher levels of impulsivity, trait anxiety, more frequent negative affective shifts, greater interpersonally reactive affective instability, lower overall functioning, and were characterized by lower amygdala-middle frontal gyrus RSFC. Lower amygdala-middle frontal gyrus RSFC was associated with greater impulsivity, trait anxiety, affective shifts, interpersonal affective reactivity, and functional impairment. LIMITATIONS: The current study consisted of small sample sizes and lacked a control group. CONCLUSIONS: This preliminary study suggests that amygdala-frontal RSFC may distinguish BPD from BD II. These results may guide future work aimed at identifying neural markers that can help disentangle these two disorders, leading to greater diagnostic accuracy and appropriate treatment implementation.

Meiotic Genes Are Enriched in Regions of Reduced Archaic Ancestry.

About 1-6% of the genetic ancestry of modern humans today originates from admixture with archaic humans. It has recently been shown that autosomal genomic regions with a reduced proportion of Neanderthal and Denisovan ancestries (NA and DA) are significantly enriched in genes that are more expressed in testis than in other tissues. To determine whether a cellular segregation pattern would exist, we combined maps of archaic introgression with a cross-analysis of three transcriptomic datasets deciphering the transcriptional landscape of human gonadal cell types. We reveal that the regions deficient in both NA and DA contain a significant enrichment of genes transcribed in meiotic germ cells. The interbreeding of anatomically modern humans with archaic humans may have introduced archaic-derived alleles that contributed to genetic incompatibilities affecting meiosis that were subsequently purged by natural selection.

Use of Rapid Reduced Electric Field Switching to Enhance Compound Specificity for Proton Transfer Reaction-Mass Spectrometry.

The high sensitivity of proton transfer reaction-mass spectrometry (PTR-MS) makes it a suitable analytical tool for detecting trace compounds. Its specificity is primarily determined by the accuracy of identifying the m/ z of the product ions specific to a particular compound. However, specificity can be enhanced by changing the product ions (concentrations and types) through modifying the reduced electric field. For current PTR-MS systems, this is not possible for trace compounds that would only be present in the reaction chamber of a PTR-MS for a short time (seconds). For such circumstances, it is necessary to change the reduce electric field swiftly if specificity enhancements are to be achieved. In this paper we demonstrate such a novel approach, which permits any compound that may only be present in the drift tube for seconds to be thoroughly investigated. Specifically, we have developed hardware and software which permits the reaction region's voltages to be rapidly switched at a frequency of 0.1-5 Hz. We show how this technique can be used to provide a higher confidence in the identification of compounds than is possible by keeping to one reduced electric field value through illustrating the detection of explosives. Although demonstrated for homeland security applications, this new technique has applications in other analytical areas and disciplines where rapid changes in a compound's concentration can occur, for example, in the Earth's atmosphere, plant emissions and in breath. Importantly, this adaptation provides a method for improved selectivity without expensive instrumental changes or the need for high mass resolution instruments.

FLAIR* to visualize veins in white matter lesions: A new tool for the diagnosis of multiple sclerosis?

OBJECTIVE: To explore the potential of a post-processing technique combining FLAIR and T2* (FLAIR*) to distinguish between lesions caused by multiple sclerosis (MS) from cerebral small vessel disease (SVD) in a clinical setting. METHODS: FLAIR and T2* head datasets acquired at 3T of 25 people with relapsing MS (pwRMS) and ten with pwSVD were used. After post-processing, FLAIR* maps were used to determine the proportion of white matter lesions (WML) showing the 'vein in lesion' sign (VIL), a characteristic histopathological feature of MS plaques. Sensitivity and specificity of MS diagnosis were examined on the basis of >45% VIL+ and >60% VIL+ WML, and compared with current dissemination in space (DIS) MRI criteria. RESULTS: All pwRMS had >45% VIL+ WML (range 58-100%) whilst in pwSVD the proportion of VIL+ WML was significantly lower (0-64%; mean 32±20%). Sensitivity based on >45% VIL+ was 100% and specificity 80% whilst with >60% VIL+ as the criterion, sensitivity was 96% and specificity 90%. DIS criteria had 96% sensitivity and 40% specificity. CONCLUSION: FLAIR* enables VIL+ WML detection in a clinical setting, facilitating differentiation of MS from SVD based on brain MRI. KEY POINTS: • FLAIR* in a clinical setting allows visualization of veins in white matter lesions. • Significant proportions of MS lesions demonstrate a vein in lesion on MRI. • Microangiopathic lesions demonstrate a lower proportion of intralesional veins than MS lesions. • Intralesional vein-based criteria may complement current MRI criteria for MS diagnosis.

Prolonged concurrent hypotension and low bispectral index ('double low') are associated with mortality, serious complications, and prolonged hospitalization after cardiac surgery.

BACKGROUND: Low bispectral index (BIS) and low mean arterial pressure (MAP) are associated with worse outcomes after surgery. We tested the hypothesis that a combination of these risk factors, a 'double low', is associated with death and major complications after cardiac surgery. METHODS: We used data from 8239 cardiac surgical patients from two US hospitals. The primary outcomes were 30-day mortality and a composite of in-hospital mortality and morbidity. We examined whether patients who had a case-averaged double low, defined as time-weighted average BIS and MAP (calculated over an entire case) below the sample mean but not in the reference group, had increased risk of the primary outcomes compared with patients whose BIS and/or MAP were at or higher than the sample mean. We also examined whether a prolonged cumulative duration of a concurrent double low (simultaneous low MAP and BIS) increased the risk of the primary outcomes. RESULTS: Case-averaged double low was not associated with increased risk of 30-day mortality {odds ratio [OR] 1.73 [95% confidence interval (CI) 0.94-3.18] vs reference; P =0.01} or the composite of in-hospital mortality and morbidity [OR 1.47 (95% CI 0.98-2.20); P =0.01] after correction for multiple outcomes. A prolonged concurrent double low was associated with 30-day mortality [OR 1.06 (95% CI 1.01-1.11) per 10-min increase; P =0.001] and the composite of in-hospital mortality and morbidity [OR 1.04 (95% CI 1.01-1.07), P =0.004]. CONCLUSIONS: A prolonged concurrent double low, but not a case-averaged double low, was associated with higher morbidity and mortality after cardiac surgery.

Enhancement of Compound Selectivity Using a Radio Frequency Ion-Funnel Proton Transfer Reaction Mass Spectrometer: Improved Specificity for Explosive Compounds.

A key issue with any analytical system based on mass spectrometry with no initial separation of compounds is to have a high level of confidence in chemical assignment. This is particularly true for areas of security, such as airports, and recent terrorist attacks have highlighted the need for reliable analytical instrumentation. Proton transfer reaction mass spectrometry is a useful technology for these purposes because the chances of false positives are small owing to the use of a mass spectrometric analysis. However, the detection of an ion at a given m/z for an explosive does not guarantee that that explosive is present. There is still some ambiguity associated with any chemical assignment owing to the presence of isobaric compounds and, depending on mass resolution, ions with the same nominal m/z. In this article we describe how for the first time the use of a radio frequency ion-funnel (RFIF) in the reaction region (drift tube) of a proton transfer reaction-time-of-flight-mass spectrometer (PTR-ToF-MS) can be used to enhance specificity by manipulating the ion-molecule chemistry through collisional induced processes. Results for trinitrotoluene, dinitrotoluenes, and nitrotoluenes are presented to demonstrate the advantages of this new RFIF-PTR-ToF-MS for analytical chemical purposes.

Rates of psychotropic medication use reported by borderline patients and axis II comparison subjects over 16 years of prospective follow-up.

The purpose of this study was to assess the classes and types of psychotropic medication reported by borderline patients and axis II comparison subjects over 16 years of prospective follow-up. Medication use was assessed at baseline using a semistructured interview of proven reliability and validity as well as its follow-up analog at 8 contiguous 2-year follow-up periods. A significantly higher percentage of borderline patients than axis II comparison subjects reported taking an antidepressant, an anxiolytic, an antipsychotic, and a mood stabilizer over time. They also reported more commonly taking 7 of the 10 more specific types of medication studied (ie, all but tricyclic antidepressants, monoamine oxidase inhibitor antidepressants, and atypical antipsychotics). The rates over time of taking antipsychotics and mood stabilizers were stable, whereas there was a significant decline in the rates of antidepressants and anxiolytics from baseline to 8-year follow-up (but not from 8- to 16-year follow-up) reported by those in both study groups. In terms of specific medications, rates of atypical antidepressants and anticonvulsants were the most stable. In contrast, nonbenzodiazepine anxiolytics declined the most steadily over time, whereas rates of atypical antipsychotics increased significantly over the 16 years of prospective follow-up. Taken together, the results of this study suggest that a substantial percentage of borderline patients continue to use the major classes of medication over time. They also suggest that the declining rates of use tend to stabilize less than a decade after index admission.

Intraoperative arterial blood pressure lability is associated with improved 30 day survival.

BACKGROUND: Arterial blood pressure lability, defined as rapid changes in arterial blood pressure, occurs commonly during anaesthesia. It is believed that hypertensive patients exhibit more lability during surgery and that lability is associated with poorer outcomes. Neither association has been rigorously tested. We hypothesized that hypertensive patients have more blood pressure lability and that increased lability is associated with increased 30 day mortality. METHODS: This was a retrospective single-centre study of surgical patients from July 2008 to December 2012. Intraoperative data were extracted from the electronic anaesthesia record. Lability was calculated as the modulus of the percentage change in mean arterial pressure between consecutive 5 min intervals. The number of episodes of lability >10% was tabulated. Multivariate logistic regression was performed to determine the association between lability and 30 day mortality using derivation and validation cohorts. RESULTS: Inclusion criteria were met by 52 919 subjects. Of the derivation cohort, 53% of subjects were hypertensive and 42% used an antihypertensive medication. The median number of episodes of lability >10% was 9 (interquartile range 5-14) per patient. Hypertensive subjects demonstrated more lability than normotensive patients, 10 (5-15) compared with 8 (5-12), P<0.0001. In subjects taking no antihypertensive medication, lability >10% was associated with decreased 30 day mortality, odds ratio (OR) per episode 0.95 [95% confidence interval (CI) 0.92-0.97], P<0.0001. This result was confirmed in the validation cohort, OR 0.96 (95% CI 0.93-0.99), P=0.01, and in hypertensive patients taking no antihypertensive medication, OR 0.96 (95% CI 0.93-0.99), P=0.002. Use of any antihypertensive medication class reduced this effect. CONCLUSIONS: Intraoperative arterial blood pressure lability occurs more often in hypertensive patients. Contrary to common belief, increased lability was associated with decreased 30 day mortality.

Predissociation dynamics of lithium iodide.

The predissociation dynamics of lithium iodide (LiI) in the first excited A-state is investigated for molecules in the gas phase and embedded in helium nanodroplets, using femtosecond pump-probe photoionization spectroscopy. In the gas phase, the transient Li(+) and LiI(+) ion signals feature damped oscillations due to the excitation and decay of a vibrational wave packet. Based on high-level ab initio calculations of the electronic structure of LiI and simulations of the wave packet dynamics, the exponential signal decay is found to result from predissociation predominantly at the lowest avoided X-A potential curve crossing, for which we infer a coupling constant VXA = 650(20) cm(-1). The lack of a pump-probe delay dependence for the case of LiI embedded in helium nanodroplets indicates fast droplet-induced relaxation of the vibrational excitation.

Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings.

BACKGROUND: Two human herpesviruses, human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), have been repeatedly linked to multiple sclerosis (MS). OBJECTIVE: The aim of this study was to investigate HHV-6 and EBV reactive oligoclonal bands (OCBs), and viral DNA in the intrathecal compartment in MS. METHODS: The reactivity of OCBs in cerebrospinal fluid (CSF) for EBV and HHV-6 antigens and stability of virus reactive OCBs over time were studied in a well-characterized MS patient cohort. Associations between virus reactive OCBs and viral DNA in CSF (and any clinical and/or radiological findings) were investigated. RESULTS: Of patients with MS, 38% had OCBs reactive to either one of the viruses studied, compared to none in the patients with other inflammatory neurological diseases (p=0.005). The banding pattern of virus reactive OCBs remained the same over time. Furthermore, MS patients with viral DNA in CSF had more contrast enhancing lesions (CELs). CONCLUSION: The stable presence of herpesvirus reactive OCBs in CSF further strengthens the association of MS with these viruses. The finding that herpesviruses might be linked to the appearance of active lesions warrants investigation of new therapeutic strategies to treat these viruses in MS.

Rapid, high-resolution, whole-brain, susceptibility-based MRI of multiple sclerosis.

BACKGROUND: Susceptibility-based MRI offers a unique opportunity to study neurological diseases such as multiple sclerosis (MS). In this work, we assessed a three-dimensional segmented echo-planar-imaging (3D-EPI) sequence to rapidly acquire high-resolution T2 -weighted and phase contrast images of the whole brain. We also assessed if these images could depict important features of MS at clinical field strength, and we tested the effect of a gadolinium-based contrast agent (GBCA) on these images. MATERIALS AND METHODS: The 3D-EPI acquisition was performed on four healthy volunteers and 15 MS cases on a 3T scanner. The 3D sagittal images of the whole brain were acquired with a voxel size of 0.55 × 0.55 × 0.55 mm(3) in less than 4 minutes. For the MS cases, the 3D-EPI acquisition was performed before, during, and after intravenous GBCA injection. RESULTS: Both T2-weighted and phase-contrast images from the 3D-EPI acquisition were sensitive to the presence of lesions, parenchymal veins, and tissue iron. Conspicuity of the veins was enhanced when images were obtained during injection of GBCA. CONCLUSIONS: We propose this rapid imaging sequence for investigating, in a clinical setting, the spatiotemporal relationship between small parenchymal veins, iron deposition, and lesions in MS patient brains.

Prediction of time-to-attainment of recovery for borderline patients followed prospectively for 16 years.

OBJECTIVE: The purpose of this study was to determine the most clinically relevant baseline predictors of time-to-recovery from borderline personality disorder. METHOD: Two hundred and ninety in-patients meeting rigorous criteria for borderline personality disorder were assessed during their index admission using a series of semistructured interviews and self-report measures. Recovery status, which was defined as concurrent symptomatic remission and good social and full-time vocational functioning, was reassessed at eight contiguous 2-year time periods. Survival analytic methods (Cox regression), which controlled for overall baseline severity, were used to estimate hazard ratios and their confidence intervals. RESULTS: All told, 60% of the borderline patients studied achieved a 2-year recovery. In bivariate analyses, seventeen variables were found to be significant predictors of earlier time-to-recovery. Six of these predictors remained significant in multivariate analyses: no prior psychiatric hospitalizations, higher IQ, good full-time vocational record in 2 years prior to index admission, absence of an anxious cluster personality disorder, high extraversion, and high agreeableness. CONCLUSION: Taken together, the results of this study suggest that prediction of time-to-recovery for borderline patients is multifactorial in nature, involving factors related to lack of chronicity, competence, and more adaptive aspects of temperament.

Reported Personality Traits and Histories of Childhood Maltreatment in Borderline Personality Disorder and Bipolar 2 Disorder: A Comparative Study.

This study compared borderline personality disorder (BPD) and bipolar 2 disorder (BP 2 disorder) with respect to reported childhood trauma and Five-Factor personality traits using the Childhood Trauma Questionnaire (CTQ) and the NEO Five-Factor Inventory (NEO-FFI). Participants were 50 men and women, aged 18-45, with DSM-5-diagnosed BPD and 50 men and women in the same age group with DSM-5-diagnosed BP 2 disorder. Participants could not meet criteria for both BPD and BP 2 disorder. Borderline participants had significantly higher scores on the neuroticism subscale and significantly lower scores on the agreeableness subscale of the NEO-FFI. After correction for multiple comparisons, there were no between-group differences on CTQ scores. Study results suggest that BPD and BP 2 disorder differ primarily with respect to underlying temperament/genetic architecture and that environmental factors have only a limited role in the differential etiologies of the two disorders.

Influence of increased left ventricular myocardial mass on early and late mortality after cardiac surgery.

BACKGROUND: Increased left ventricular mass (LVM) is a well-recognized predictor of cardiovascular morbidity and mortality in epidemiological studies, but its impact on mortality after cardiac surgery is poorly defined. We hypothesized that patients with increased LVM index (LVMI) were more likely to have greater 30 day and 1 yr mortality. METHODS: With IRB approval, intraoperative transoesophageal echocardiography images of 844 cardiac surgical patients were reviewed. LVMI was calculated using the American Society of Echocardiography recommended formula. Outcome variables studied were 30 day and 1 yr mortality. RESULTS: Mortality within 30 days occurred in 28 patients (3.3%) and within 1 yr in 91 patients (10.8%). An almost linear relationship was found between increasing LVMI and the risk of mortality within 30 days of cardiac surgery. The odds ratio (OR) of dying within 30 days of surgery was 1.15 (95% confidence interval 1.01-1.31) per 20 g m(-2) increase in LVMI. This finding remained statistically significant in multivariate analysis controlling for the effects of age, weight, gender, surgery type, LV function, and functional status [OR=1.36 (1.11-1.66) per 20 g m(-2) increase]. Increased LVMI was not found to be a statistically significant predictor of 1 yr mortality. CONCLUSIONS: Increased LVMI, but not LV systolic function as measured by the fractional area of contraction (FAC) was identified as a strong independent predictor of perioperative mortality after adult cardiac surgery. The relationship between LVMI and risk of 30 day mortality was nearly linear. Furthermore, decreased FAC, and not LVMI, was a strong independent predictor of 1 yr mortality.

Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse.

Single-nucleotide polymorphisms (SNPs) have been the focus of much attention in human genetics because they are extremely abundant and well-suited for automated large-scale genotyping. Human SNPs, however, are less informative than other types of genetic markers (such as simple-sequence length polymorphisms or microsatellites) and thus more loci are required for mapping traits. SNPs offer similar advantages for experimental genetic organisms such as the mouse, but they entail no loss of informativeness because bi-allelic markers are fully informative in analysing crosses between inbred strains. Here we report a large-scale analysis of SNPs in the mouse genome. We characterized the rate of nucleotide polymorphism in eight mouse strains and identified a collection of 2,848 SNPs located in 1,755 sequence-tagged sites (STSs) using high-density oligonucleotide arrays. Three-quarters of these SNPs have been mapped on the mouse genome, providing a first-generation SNP map of the mouse. We have also developed a multiplex genotyping procedure by which a genome scan can be performed with only six genotyping reactions per animal.

Predictors of suicide attempts in patients with borderline personality disorder over 16 years of prospective follow-up.

BACKGROUND: It is clinically important to understand the factors that increase the likelihood of the frequent and recurrent suicide attempts seen in those with borderline personality disorder (BPD). Although several studies have examined this subject in a cross-sectional manner, the aim of this study was to determine the most clinically relevant baseline and time-varying predictors of suicide attempts over 16 years of prospective follow-up among patients with BPD. METHOD: Two-hundred and ninety in-patients meeting Revised Diagnostic Interview for Borderlines (DIB-R) and DSM-III-R criteria for BPD were assessed during their index admission using a series of semistructured interviews and self-report measures. These subjects were then reassessed using the same instruments every 2 years. The generalized estimating equations (GEE) approach was used to model the odds of suicide attempts in longitudinal analyses, controlling for assessment period, yielding an odds ratio (OR) and 95% confidence interval (CI) for each predictor. RESULTS: Nineteen variables were found to be significant bivariate predictors of suicide attempts. Eight of these, seven of which were time-varying, remained significant in multivariate analyses: diagnosis of major depressive disorder (MDD), substance use disorder (SUD), post-traumatic stress disorder (PTSD), presence of self-harm, adult sexual assault, having a caretaker who has completed suicide, affective instability, and more severe dissociation. CONCLUSIONS: The results of this study suggest that prediction of suicide attempts among borderline patients is complex, involving co-occurring disorders, co-occurring symptoms of BPD (self-harm, affective reactivity and dissociation), adult adversity, and a family history of completed suicide.

Affective lability in bipolar disorder and borderline personality disorder.

BACKGROUND: The boundaries between the affective instability in bipolar disorder and borderline personality disorder have not been clearly defined. Using self-report measures, previous research has suggested that the affective lability of patients with bipolar disorder and borderline personality disorder may have different characteristics. METHODS: We assessed the mood states of 29 subjects meeting Revised Diagnostic Interview for Borderlines and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for BPD and 25 subjects meeting DSM-IV criteria for bipolar II disorder or cyclothymia using the Affective Lability Scale (ALS), the Affect Intensity Measure (AIM), and a newly developed clinician-administered instrument, the Affective Lability Interview for Borderline Personality Disorder (ALI-BPD). The ALI-BPD measures frequency and intensity of shifts in 8 affective dimensions. Subjects in the borderline group could not meet criteria for bipolar disorder; subjects in the bipolar/cyclothymia group could not meet criteria for BPD. RESULTS: Patients in the bipolar group had significantly higher scores on the euthymia-elation subscale of the ALS; patients in the BPD group had significantly higher scores on the anxiety-depression subscale of the ALS. Patients with bipolar disorder had significantly higher total AIM scores and significantly higher score on the AIM positive emotion subscale. In terms of frequency, patients in the borderline group reported the following: (1) significantly less frequent affective shifts between euthymia-elation and depression-elation on the ALI-BPD and (2) significantly more frequent shifts between euthymia-anger, anxiety-depression, and depression-anxiety. In terms of intensity, borderline patients reported the following: (1) significantly less intense shifts between euthymia-elation and depression-elation on the ALI-BPD and (2) significantly more intense shifts between euthymia-anxiety, euthymia-anger, anxiety-depression, and depression-anxiety. CONCLUSION: The affective lability of patients with borderline and bipolar II/cyclothymic can be differentiated with respect to frequency and intensity using both self-report and clinician-administered measures.

Implementation of a standards-based anaesthesia record compliant with the health level 7 (HL7) clinical document architecture (CDA).

With the increasing use of anaesthesia information management systems (AIMS) there is the opportunity for different institutions to aggregate and share information both nationally and internationally. Potential uses of such aggregated data include outcomes research, benchmarking and improvement in clinical practice and patient safety. However, these goals can only be achieved if data contained in records from different sources are truly comparable and there is semantic inter-operability. This paper describes the development of a standard terminology for anaesthesia and also a Domain Analysis Model and implementation guide to facilitate a standard representation of AIMS records as extensible markup language documents that are compliant with the Health Level 7 Version 3 clinical document architecture. A representation of vital signs that is compliant with the International Standards Organization 11073 standard is also discussed.