Changes in brain functional connectivity and cognition related to white matter lesion burden in hypertensive patients from SPRINT.

PURPOSE: Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline. METHODS: Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis. RESULTS: Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN's left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition. CONCLUSION: In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance. TRIAL REGISTRATION: NCT01206062.

Genetic influences on neonatal cortical thickness and surface area.

Genetic and environmental influences on cortical thickness (CT) and surface area (SA) are thought to vary in a complex and dynamic way across the lifespan. It has been established that CT and SA are genetically distinct in older children, adolescents, and adults, and that heritability varies across cortical regions. Very little, however, is known about how genetic and environmental factors influence infant CT and SA. Using structural MRI, we performed the first assessment of genetic and environmental influences on normal variation of SA and CT in 360 twin neonates. We observed strong and significant additive genetic influences on total SA (a2 = 0.78) and small and nonsignificant genetic influences on average CT (a2 = 0.29). Moreover, we found significant genetic overlap (genetic correlation = 0.65) between these global cortical measures. Regionally, there were minimal genetic influences across the cortex for both CT and SA measures and no distinct patterns of genetic regionalization. Overall, outcomes from this study suggest a dynamic relationship between CT and SA during the neonatal period and provide novel insights into how genetic influences shape cortical structure during early development.

Back to the future: sagittal CT in the evaluation of COPD.

OBJECTIVES: To identify features of obstructive airway disease on sagittal reconstruction, compare the accuracy of findings to traditional imaging characteristics of COPD, and determine the fraction of additional cases identified using new characteristics. METHODS: The study was approved by the centre's Institutional Review Board and is HIPAA compliant. Two hundred sixteen patients with HRCT and spirometry within a 3-month window were included. Four radiologists evaluated each HRCT for traditional characteristics of COPD and new quantitative and qualitative features of obstruction on axial and sagittal reconstructions. Imaging characteristics were assessed for correlation with the spirometric diagnosis of obstructive airway disease. RESULTS: Quantitative and qualitative findings on sagittal reconstruction are highly specific for COPD (specificity >90 %). Features of hyperinflation on sagittal reconstruction are more accurate predictors of obstruction than traditional axial measures, with greater interobserver reliability (hyperinflation left hemidiaphragm: accuracy: 70.08 % ± 2.49 %; kappa: 0.511 versus traditional measures: accuracy: 62.00 % ± 5.38 %; kappa: 0.407). Sagittal reconstruction identified 27-70 % more patients with COPD than traditional axial findings (p < 0.05). CONCLUSIONS: Analysis of sagittal reconstruction enables greater accuracy and specificity in the diagnosis of obstructive airway disease compared to traditional measures on axial imaging. Use of sagittal reconstructions can help identify up to 70 % more patients with COPD than traditional imaging findings alone. KEY POINTS: • HRCT sagittal reconstruction is useful in the evaluation of obstructive lung disease. • Findings on sagittal reconstructions allow physicians to more accurately diagnose COPD. • Routine use of sagittal reconstructions increases the sensitivity for diagnosing COPD.

Match day: online search trends reflect growing interest in IR training.

Google Trends was used to characterize the relationship between the interventional radiology (IR) applicant pool and related Internet queries for "IR fellowship" from July 2006 to July 2013. Results were compared with National Residency Match Panel data by regression analysis and one-way analysis of variance. Search traffic for IR fellowship demonstrated a statistically significant linear annual increase (R(2) = 0.87; P = .0013). Total IR applicants increased by 184% (R(2) = 0.98; P = .0216). Search traffic was predictive of applicants for each match year (R(2) = 0.92; P = .0004) and programs filled (R(2) = 0.93; P = .0003). Internet queries mirror trainee professional interests, with significant increases in search traffic related to IR fellowship and strong correlation with growth in applicants.

Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection.

UNLABELLED: Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied for up to 6 months for phenotype and function of natural killer T (NKT) and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T-cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46, and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression), and interferon-gamma (IFN-γ) production. This multifunctional NK cell response appeared a month earlier than in the one healthcare worker who developed high-level viremia, and it differed from the impaired IFN-γ production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T-cell response. T-cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia. CONCLUSION: Exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T-cell response and may contribute to antiviral immunity.

Occupational exposure to hepatitis C virus: early T-cell responses in the absence of seroconversion in a longitudinal cohort study.

BACKGROUND: T-cell responses have been described in seronegative patients who test negative for hepatitis C virus (HCV) RNA despite frequent HCV exposure. However, the cross-sectional design of those studies did not clarify whether T cells were indeed induced by low-level HCV exposure without seroconversion or whether they resulted from regular acute infection with subsequent antibody loss. METHODS: Over a 10-year period, our longitudinal study recruited 72 healthcare workers with documented HCV exposure. We studied viremia and antibody and T-cell responses longitudinally for 6 months. RESULTS: All healthcare workers remained negative for HCV RNA and antibodies. However, 48% developed proliferative T-cell response and 42% developed responses in interferon-gamma enzyme-linked immunosorbent spot assays, with 29 healthy HCV-unexposed controls used to define assay cutoffs. The response prevalence was associated with the transmission risk score. T-cell responses peaked at week 4 and returned to baseline by week 12 after exposure. They predominantly targeted nonstructural HCV proteins, which are not part of the HCV particle and thus must have been synthesized in infected cells. CONCLUSIONS: Subclinical transmission of HCV occurs frequently, resulting in infection and synthesis of nonstructural proteins despite undetectable systemic viremia. T-cell responses are more sensitive indicators of this low-level HCV exposure than antibodies.

Neuroanatomical Correlates of Cognitive Dysfunction in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11.2DS), the most common chromosomal microdeletion, presents as a heterogeneous phenotype characterized by an array of anatomical, behavioral, and cognitive abnormalities. Individuals with 22q11.2DS exhibit extensive cognitive deficits, both in overall intellectual capacity and focal challenges in executive functioning, attentional control, perceptual abilities, motor skills, verbal processing, as well as socioemotional operations. Heterogeneity is an intrinsic factor of the deletion's clinical manifestation in these cognitive domains. Structural imaging has identified significant changes in volume, thickness, and surface area. These alterations are closely linked and display region-specific variations with an overall increase in abnormalities following a rostral-caudal gradient. Despite the extensive literature developing around the neurocognitive and neuroanatomical profiles associated with 22q11.2DS, comparatively little research has addressed specific structure-function relationships between aberrant morphological features and deficient cognitive processes. The current review attempts to categorize these limited findings alongside comparisons to populations with phenotypic and structural similarities in order to answer to what degree structural findings can explain the characteristic neurocognitive deficits seen in individuals with 22q11.2DS. In integrating findings from structural neuroimaging and cognitive assessments, this review seeks to characterize structural changes associated with the broad neurocognitive challenges faced by individuals with 22q11.2DS.

Pilot multimodal twin imaging study of generalized anxiety disorder.

BACKGROUND: Generalized anxiety disorder (GAD) is a common chronic condition that is relatively understudied compared to other psychiatric syndromes. Neuroimaging studies have begun to implicate particular neural structures and circuitry in its pathophysiology; however, no genetically informative research has examined the potential sources of reported brain differences. METHODS: We acquired spectroscopic, volumetric, and diffusion tensor magnetic resonance imaging data from a pilot study of 34 female subjects selected from monozygotic twin pairs based upon their affection status for GAD, and examined brain regions previously implicated in fear and anxiety for their relationship with affection status and genetic risk. RESULTS: Lifetime GAD associated with increased creatine levels in the amygdala, smaller left hippocampal volume, and lower fractional anisotropy in the uncinate fasciculus which connects amygdala and frontal cortex. In addition, GAD genetic risk predicted increases in myo-inositol in the amygdala and, possibly, glutamate/glutamine/GABA alterations in the hippocampus. The association of lifetime GAD with smaller hippocampal volume was independent of major depression and might represent a common genetic risk marker for internalizing disorders. CONCLUSIONS: These preliminary data suggest that GAD and its genetic risk factors are likely correlated with volumetric and spectroscopic changes in fear-related limbic structures and their connections with the frontal cortex.

Unruptured Arteriovenous Malformations in the Multidetector Computed Tomography Era: Frequency of Detection and Predictable Failures.

OBJECTIVES: While hemorrhage arising from ruptured arteriovenous malformations (AVMs) is usually evident on multidetector non-contrast computed tomography (NCCT), unruptured AVMs can be below the limits of detection. We performed a retrospective review of NCCT of patients with a proven diagnosis of unruptured AVM to determine if advances in CT technology have made them more apparent and what features predict their detection. MATERIAL AND METHODS: Twenty-five NCCTs met inclusion criteria of having angiography or MR proven AVM without hemorrhage, prior surgery, or other CNS disease. Demographic variables, clinical symptoms at presentation, abnormal CT imaging findings, attenuation of the superior sagittal sinus (SSS), and Spetzler-Martin grade of each AVM were recorded. We examined the relationship between AVM detection and SSS attenuation through Kruskal-Wallis test. Exploratory serial logistic principal components analysis was performed including demographics, symptoms, and CT features in the multivariate model. RESULTS: About 80% of the NCCTs showed an abnormality while 20% were normal. All those with an identifiable abnormality showed hyperdensity (80%). Logistic regression models indicate that clustered associations between several CT features, primarily calcifications, hyperdensity, and vascular prominence significantly predicted Spetzler-Martin grade (likelihood ratio 7.7, P = 0.006). SSS attenuation was significantly lower in subjects with occult AVMs when compared to those with CT abnormalities (median 47 vs. 55 HU, P < 0.04). CONCLUSION: Abnormal hyperdensity was evident in all detectable cases (80%) and multiple CT features were predictive of a higher Spetzler-Martin AVM grade. Moreover, SSS attenuation less than 50 HU was significantly correlated with a false-negative NCCT.

Radiology Performed Fluoroscopy-Guided Lumbar Punctures Decrease Volume of Diagnostic Study Interpretation - Impact on Resident Training and Potential Solutions.

OBJECTIVES: Lumbar punctures performed in radiology departments have significantly increased over the last few decades and are typically performed in academic centers by radiology trainees using fluoroscopy guidance. Performing fluoroscopy-guided lumbar punctures (FGLPs) can often constitute a large portion of a trainee's workday and the impact of performing FGLPs on the trainee's clinical productivity (i.e. dictating reports on neuroradiology cross-sectional imaging) has not been studied. The purpose of the study was to evaluate the relationship between the number of FGLPs performed and cross-sectional neuroimaging studies dictated by residents during their neuroradiology rotation (NR). MATERIAL AND METHODS: The number of FGLPs and myelograms performed and neuroimaging studies dictated by radiology residents on our neuroradiology service from July 2008 to December 2017 were retrospectively reviewed. The relationship between the number of FGLPs performed and neuroimaging studies (CT and MRI) dictated per day by residents was examined. RESULTS: Radiology residents (n = 84) performed 3437 FGLPs and myelograms and interpreted 33402 cross-sectional studies. Poisson regression demonstrated an exponential decrease in number of studies dictated daily with a rising number of FGLPs performed (P = 0.0001) and the following formula was derived: Number of expected studies dictated per day assuming no FGLPs × e-0.25 x number of FGLPs = adjusted expected studies dictated for the day. CONCLUSION: We quantified the impact performing FGLPs can have on the number of neuroimaging reports residents dictate on the NR. We described solutions to potentially decrease unnecessary FGLP referrals including establishing departmental guidelines for FGLP referrals and encouraging bedside lumbar punctures attempts before referral. We also emphasized equally distributing the FGLPs among trainees to mitigate procedural burden.

Unveiling the silent threat among us: leveraging health information technology in the search for asymptomatic COVID 19 healthcare workers.

Assuring the safety of both patients and healthcare workers (HCWs) in hospitals has been the primary focus of every healthcare organization during the COVID 19 pandemic. This article discusses the NIH Clinical Center's interdisciplinary approach to deploying an organizational Asymptomatic Staff Testing System.

Genetic and environmental contributions to neonatal brain structure: A twin study.

Twin studies have found that global brain volumes, including total intracranial volume (ICV), total gray matter, and total white matter volumes are highly heritable in adults and older children. Very little is known about genetic and environmental contributions to brain structure in very young children and whether these contributions change over the course of development. We performed structural imaging on a 3T MR scanner of 217 neonatal twins, 41 same-sex monozygotic, 50 same-sex dizygotic pairs, and 35 "single" twins-neonates with brain scans unavailable for their co-twins. Tissue segmentation and parcellation was performed, and structural equation modeling was used to estimate additive genetic, common environmental, and unique environmental effects on brain structure. Heritability of ICV (0.73) and total white matter volume (0.85) was high and similar to that described in older children and adults; the heritability of total gray matter (0.56) was somewhat lower. Heritability of lateral ventricle volume was high (0.71), whereas the heritability of cerebellar volume was low (0.17). Comparison with previous twin studies in older children and adults reveal that three general patterns of how heritability can change during postnatal brain development: (1) for global white matter volumes, heritability is comparable to reported heritability in adults, (2) for global gray matter volume and cerebellar volume, heritability increases with age, and (3) for lateral ventricle volume, heritability decreases with age. More detailed studies of the changes in the relative genetic and environmental effects on brain structure throughout early childhood development are needed.

A bivariate twin study of regional brain volumes and verbal and nonverbal intellectual skills during childhood and adolescence.

Twin studies indicate that both intelligence and brain structure are moderately to highly heritable. Recent bivariate studies of adult twins also suggest that intelligence and brain morphometry are influenced by shared genetic factors. The current study examines shared genetic and environmental factors between brain morphometry and intelligence in a sample of children and adolescents (twins, twin siblings, and singletons; n = 649, ages 4-19). To extend previous studies, brain morphometric data were parsed into subregions (lobar gray/white matter volumes, caudate nucleus, lateral ventricles) and intelligence into verbal and nonverbal skills (Wechsler Vocabulary and Block Design subtests). Phenotypic relationships between brain volumes and intelligence were small. Verbal skills shared unique environmental effects with gray matter volumes while nonverbal skills shared genetic effects with both global and regional gray and white matter. These results suggest that distinct mechanisms contribute to the small phenotypic relationships between brain volumes and verbal versus nonverbal intelligence.

Lower Respiratory Tract Infection with Human Metapneumovirus: Chest CT Imaging Features and Comparison with Other Viruses.

PURPOSE: Human metapneumovirus has been increasingly identified as a cause of lower respiratory tract infection in adults worldwide. The CT imaging features of human metapneumovirus in adults have not been characterized. The purpose of this paper is to determine the imaging features of human metapneumovirus and to compare them with features of other viruses. METHODS: Two clinicians retrospectively reviewed the medical records of 104 adults with lower respiratory tract infection due to human metapneumovirus at four hospitals in the northeast USA over 32 months. CT images were evaluated by two chest radiologists for airspace consolidation, bronchiectasis, bronchial wall thickening, ground-glass opacities, pleural effusion and tree-in-bud opacities and the dominant imaging pattern. Results for human metapneumovirus were compared with results previously reported for other viruses. RESULTS: Human metapneumovirus predominantly caused an airway-centric pattern (71-81/104, 68-77%) of infection characterized by bronchial wall thickening, tree-in-bud opacities, peri-bronchial consolidation and/or peri-bronchial ground-glass opacities. The airway-centric pattern has been previously reported with other paramyxoviridae (parainfluenza virus and respiratory syncytial virus). However, human metapneumovirus was significantly more likely (p = 0.03-0.001) to cause bronchopneumonia (46-55%) than parainfluenza virus (17%) or respiratory syncytial virus (21%). Follow-up CT in 41 (39%) patients with hMPV revealed resolution of findings in 38/41 (91%). CONCLUSION: The paramyxoviridae, including human metapneumovirus, are known to have a propensity to infect ciliated respiratory cells and we have demonstrated this leads to a propensity to cause bronchitis, bronchiolitis and bronchopneumonia on CT scans. Of these, human metapneumovirus is most likely to cause bronchopneumonia. Healthcare providers should consider human metapneumovirus as a cause of pneumonia on chest CT.

Epilepsy Lesion Localization is not Predicted by Developmental Venous Anomaly Location or its FDG-PET Metabolic Activity.

BACKGROUND AND PURPOSE: This study's purpose is to correlate location and metabolic activity of developmental venous anomalies (DVAs) in epilepsy patients to the seizure focus as determined by ictal/interictal encephaloelectrogram (EEG). METHODS: A retrospective search was performed for epilepsy patients with DVAs who underwent brain 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG-PET) and magnetic resonance imaging (MRI). MRI exams were analyzed to characterize DVA location and associated structural findings. MRI and PET images were co-registered and assessment of 18 F-FDG uptake in the DVA territory was performed. The electronic medical record was reviewed for each subject to determine seizure semiology and site of seizure focus by ictal/interictal EEG. RESULTS: Twenty-eight DVAs in 25 patients were included. Twelve DVAs demonstrated regional metabolic abnormality on 18 F-FDG-PET. There was no significant correlation between DVA site and seizure focus on EEG. DVA location was concordant with EEG seizure focus in three subjects, and all three demonstrated hypometabolism on 18 F-FDG-PET. This significance remains indeterminate, as one of these DVAs was associated with cavernoma, which could serve as the true seizure focus, and one of the patients underwent resection of the DVA without decrease in seizure frequency. Furthermore, there was no statistically significant relationship between DVA metabolic activity and DVA-EEG lobar or laterality concordance. CONCLUSIONS: In this sample, there is no significant correlation between location of DVA and seizure focus, and hypometabolism within the DVA territory is not predictive of EEG/DVA co-localization. As use of 18 F-FDG-PET for evaluation of epilepsy increases, knowledge of this poor correlation is important to avoid diagnostic confusion and potentially unnecessary surgery in epilepsy patients.

Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence.

In this report, we present the first regional quantitative analysis of age-related differences in the heritability of cortical thickness using anatomic MRI with a large pediatric sample of twins, twin siblings, and singletons (n = 600, mean age 11.1 years, range 5-19). Regions of primary sensory and motor cortex, which develop earlier, both phylogenetically and ontologically, show relatively greater genetic effects earlier in childhood. Later developing regions within the dorsal prefrontal cortex and temporal lobes conversely show increasingly prominent genetic effects with maturation. The observation that regions associated with complex cognitive processes such as language, tool use, and executive function are more heritable in adolescents than children is consistent with previous studies showing that IQ becomes increasingly heritable with maturity(Plomin et al. 1997: Psychol Sci 8:442-447). These results suggest that both the specific cortical region and the age of the population should be taken into account when using cortical thickness as an intermediate phenotype to link genes, environment, and behavior.

Efficient calculation of empirical P-values for genome-wide linkage analysis through weighted permutation.

Linkage analysis in multivariate or longitudinal context presents both statistical and computational challenges. The permutation test can be used to avoid some of the statistical challenges, but it substantially adds to the computational burden. Utilizing the distributional dependencies between p (defined as the proportion of alleles at a locus that are identical by descent (IBD) for a pairs of relatives, at a given locus) and the permutation test we report a new method of efficient permutation. In summary, the distribution of p for a sample of relatives at locus x is estimated as a weighted mixture of p drawn from a pool of 'representative' p distributions observed at other loci. This weighting scheme is then used to sample from the distribution of the permutation tests at the representative loci to obtain an empirical P-value at locus x (which is asymptotically distributed as the permutation test at loci x). This weighted mixture approach greatly reduces the number of permutation tests required for genome-wide scanning, making it suitable for use in multivariate and other computationally intensive linkage analyses. In addition, because the distribution of p is a property of the genotypic data for a given sample and is independent of the phenotypic data, the weighting scheme can be applied to any phenotype (or combination of phenotypes) collected from that sample. We demonstrate the validity of this approach through simulation.

Reduced Intercarotid Artery Distance in Syndromic and Isolated Brachycephaly.

INTRODUCTION: The morphology of the skull base can be altered in craniosynostoses. The objective of this study is to evaluate the reduced intercarotid artery distance in the lacerum segment in patients with syndromic and isolated brachycephaly. MATERIALS AND METHODS: The distances between the inner walls of the carotid canal at the lacerum segment were measured on high-resolution CT scans in children with Crouzon (25), Pfeiffer (21), Apert (26), Saethre-Chotzen (7) syndromes, isolated bicoronal synostosis (9), and compared to an age-matched control group (30). RESULTS: A significantly smaller mean distance between carotid canal walls was observed in Crouzon (11.1 ± 4.9 mm), Pfeiffer (9.6 ± 5.1 mm), Apert (12.3 ± 4.3 mm), Saethre-Chotzen (14.8 ± 3.0 mm) syndromes, and isolated bicoronal synostosis (14.9 ± 3.7 mm) as compared to the control group (19.7 ± 2.4 mm, P < 0.001, P < 0.001, P < 0.001, P = 0.005, and P = 0.002, respectively). There was no statistically significant difference in intercarotid canal distance among the Apert, Saethre-Chotzen and isolated bicoronal synostosis groups. Overall, the brachycephalic group showed reduced intercarotid canal distance comparing to controls (P < 0.001). DISCUSSION AND CONCLUSIONS: There is significant reduction of the distance between carotid canals in brachycephalic patients. This distance is more significantly altered in FGFR-related brachycephaly syndromes (especially Crouzon and Pfeiffer syndromes), than Saethre-Chotzen syndrome (TWIST1 mutation) and isolated non-syndromic bicoronal synostosis. This study highlights the importance of FGFRs in shaping the skull base. Altered vascular course of the internal carotid arteries can have important implications in planning skull base surgery in brachycephalic patients.