BQsupports: systematic assessment of the support and novelty of new biomedical associations.

MOTIVATION: Living a Big Data era in Biomedicine, there is an unmet need to systematically assess experimental observations in the context of available information. This assessment would offer a means for a comprehensive and robust validation of biomedical data results and provide an initial estimate of the potential novelty of the findings. RESULTS: Here we present BQsupports, a web-based tool built upon the Bioteque biomedical descriptors that systematically analyzes and quantifies the current support to a given set of observations. The tool relies on over 1000 distinct types of biomedical descriptors, covering over 11 different biological and chemical entities, including genes, cell lines, diseases, and small molecules. By exploring hundreds of descriptors, BQsupports provide support scores for each observation across a wide variety of biomedical contexts. These scores are then aggregated to summarize the biomedical support of the assessed dataset as a whole. Finally, the BQsupports also suggests predictive features of the given dataset, which can be exploited in downstream machine learning applications. AVAILABILITY AND IMPLEMENTATION: The web application and underlying data are available online (https://bqsupports.irbbarcelona.org).

Insights into the identification of a molecular signature for amyotrophic lateral sclerosis exploiting integrated microRNA profiling of iPSC-derived motor neurons and exosomes.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by progressive degeneration of motor neurons (MNs). Most cases are sporadic, whereas 10% are familial. The pathological mechanisms underlying the disease are partially understood, but it is increasingly being recognized that alterations in RNA metabolism and deregulation of microRNA (miRNA) expression occur in ALS. In this study, we performed miRNA expression profile analysis of iPSC-derived MNs and related exosomes from familial patients and healthy subjects. We identified dysregulation of miR-34a, miR-335 and miR-625-3p expression in both MNs and exosomes. These miRNAs regulate genes and pathways which correlate with disease pathogenesis, suggesting that studying miRNAs deregulation can contribute to deeply investigate the molecular mechanisms underlying the disease. We also assayed the expression profile of these miRNAs in the cerebrospinal fluid (CSF) of familial (fALS) and sporadic patients (sALS) and we identified a significant dysregulation of miR-34a-3p and miR-625-3p levels in ALS compared to controls. Taken together, all these findings suggest that miRNA analysis simultaneously performed in different human biological samples could represent a promising molecular tool to understand the etiopathogenesis of ALS and to develop new potential miRNA-based strategies in this new propitious therapeutic era.

Subclinical Vascular Brain Lesions in Young Adults With Acute Ischemic Stroke.

BACKGROUND: Subclinical vascular brain lesions are highly prevalent in elderly patients with stroke. Little is known about predisposing factors and their impact on long-term outcome of patients with stroke at a young age. METHODS: We quantified magnetic resonance-defined subclinical vascular brain lesions, including lacunes and white matter hyperintensities, perivascular spaces and cerebral microbleeds, and assessed total small-vessel disease (SVD) score in patients with first-ever acute ischemic stroke aged 18 to 45 years, and followed them up, as part of the multicentre Italian Project on Stroke in Young Adults. The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. We assessed the predictive accuracy of magnetic resonance features and whether the addition of these markers improves outcome prediction over a validated clinical tool, such as the Italian Project on Stroke in Young Adults score. RESULTS: Among 591 patients (males, 53.8%; mean age, 37.5±6.4 years), 117 (19.8%) had subclinical vascular brain lesions. Family history of stroke was associated with lacunes (odds ratio, 2.24 [95% CI, 1.30-3.84]) and total SVD score (odds ratio, 2.06 [95% CI, 1.20-3.53] for score≥1), hypertension with white matter hyperintensities (odds ratio, 2.29 [95% CI, 1.22-4.32]). After a median follow-up of 36.0 months (25th-75th percentile, 38.0), lacunes and total SVD score were associated with primary end point (hazard ratio, 2.13 [95% CI, 1.17-3.90] for lacunes; hazard ratio, 2.17 [95% CI, 1.20-3.90] for total SVD score ≥1), and the secondary end point brain ischemia (hazard ratio, 2.55 [95% CI, 1.36-4.75] for lacunes; hazard ratio, 2.61 [95% CI, 1.42-4.80] for total SVD score ≥1). The predictive performances of the models, including magnetic resonance features were comparable to those of the random model. Adding individual magnetic resonance features to the Italian Project on Stroke in Young Adults score did not improve model prediction. CONCLUSIONS: Subclinical vascular brain lesions affect ≈2 in 10 young adults with ischemic stroke. Although lacunes and total SVD score are associated with thrombotic recurrence, they do not improve accuracy of outcome prediction over validated clinical predictors.

Antithrombotic therapy in the postacute phase of cervical artery dissection: the Italian Project on Stroke in Young Adults Cervical Artery Dissection.

OBJECTIVE: To explore the impact of antithrombotic therapy discontinuation in the postacute phase of cervical artery dissection (CeAD) on the mid-term outcome of these patients. METHODS: In a cohort of consecutive patients with first-ever CeAD, enrolled in the setting of the multicentre Italian Project on Stroke in Young Adults Cervical Artery Dissection, we compared postacute (beyond 6 months since the index CeAD) outcomes between patients who discontinued antithrombotic therapy and patients who continued taking antithrombotic agents during follow-up. Primary outcome was a composite of ischaemic stroke and transient ischaemic attack. Secondary outcomes were (1) Brain ischaemia ipsilateral to the dissected vessel and (2) Recurrent CeAD. Associations with the outcome of interest were assessed by the propensity score (PS) method. RESULTS: Of the 1390 patients whose data were available for the outcome analysis (median follow-up time in patients who did not experience outcome events, 36.0 months (25th-75th percentile, 62.0)), 201 (14.4%) discontinued antithrombotic treatment. Primary outcome occurred in 48 patients in the postacute phase of CeAD. In PS-matched samples (201 vs 201), the incidence of primary outcomes among patients taking antithrombotics was comparable with that among patients who discontinued antithrombotics during follow-up (5.0% vs 4.5%; p(log rank test)=0.526), and so was the incidence of the secondary outcomes ipsilateral brain ischaemia (4.5% vs 2.5%; p(log rank test)=0.132) and recurrent CeAD (1.0% vs 1.5%; p(log rank test)=0.798). CONCLUSIONS: Discontinuation of antithrombotic therapy in the postacute phase of CeAD does not appear to increase the risk of brain ischaemia during follow-up.

Clinical outcome of neurological patients with COVID-19: the impact of healthcare organization improvement between waves.

OBJECTIVE: The aim of this study is to evaluate the differences in clinical presentations and the impact of healthcare organization on outcomes of neurological COVID-19 patients admitted during the first and second pandemic waves. METHODS: In this single-center cohort study, we included all patients with SARS-CoV-2 infection admitted to a Neuro-COVID Unit. Demographic, clinical, and laboratory data were compared between patients admitted during the first and second waves of the COVID-19 pandemic. RESULTS: Two hundred twenty-three patients were included, of whom 112 and 111 were hospitalized during the first and second pandemic waves, respectively. Patients admitted during the second wave were younger and exhibited pulmonary COVID-19 severity, resulting in less oxygen support (n = 41, 36.9% vs n = 79, 70.5%, p < 0.001) and lower mortality rates (14.4% vs 31.3%, p = 0.004). The different healthcare strategies and early steroid treatment emerged as significant predictors of mortality independently from age, pre-morbid conditions and COVID-19 severity in Cox regression analyses. CONCLUSIONS: Differences in healthcare strategies during the second phase of the COVID-19 pandemic probably explain the differences in clinical outcomes independently of disease severity, underlying the importance of standardized early management of neurological patients with SARS-CoV-2 infection.

Clinical Features of Patients With Cervical Artery Dissection and Fibromuscular Dysplasia.

BACKGROUND AND PURPOSE: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. METHODS: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-). RESULTS: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis. CONCLUSIONS: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

Age-dependent effect of susceptibility factors on the risk of intracerebral haemorrhage: Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

OBJECTIVE: To investigate the age-dependent impact of traditional stroke risk factors on the occurrence of intracerebral haemorrhage (ICH). METHODS: We performed a case-control analysis, comparing consecutive patients with ICH with age-matched and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) between 2002 and 2014 by multivariable logistic regression model within subgroups stratified by age quartiles (Q1-Q4). RESULTS: We analysed 3492 patients and 3492 controls. The impact of untreated hypertension on the risk of ICH was higher in the lower than in the upper age quartile (OR 11.64, 95% CI 7.68 to 17.63 in Q1 vs OR 6.05, 95% CI 3.09 to 11.85 in Q4 with intermediate ORs in Q2 and Q3), while the opposite trend was observed for untreated hypercholesterolaemia (OR 0.63, 95% CI 0.45 to 0.97 in Q1 vs OR 0.36, 95% CI 0.26 to 0.56 in Q4 with intermediate ORs in Q2 and Q3). The effect of untreated diabetes and excessive alcohol intake was detected only in the older age group (OR 3.63, 95% CI 1.22 to 10.73, and OR 1.69, 95% CI 1.13 to 2.51, respectively). CONCLUSIONS: Our findings provide evidence of age-dependent differences in the effects of susceptibility factors on the risk of ICH.

Long-term outcome of cervical artery dissection : IPSYS CeAD: study protocol, rationale, and baseline data of an Italian multicenter research collaboration.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t1) and then annually (t2 at 1 year, t3 at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.

Use of enteroscopy for the detection of malignant and premalignant lesions of the small bowel in complicated celiac disease: a meta-analysis.

BACKGROUND AND AIMS: Enteroscopy (wireless or wired) is the reference standard for small-bowel (SB) diseases, and it has been applied to detect SB malignancies in complicated celiac disease (CD) with heterogeneous results. The aim of this meta-analysis was to obtain a diagnostic yield (DY) by pooling the data of studies that investigated the use of enteroscopy to detect SB adverse events in CD. METHODS: We performed an online search for studies estimating the DY of wireless and wired enteroscopy in predicting the presence of SB premalignant and/or malignant lesions. The DerSimonian and Laird random-effects method was used to pool the arcsine-transformed proportions of patients with the events. Three meta-analyses were performed considering the following events: the presence of a malignancy, premalignant damage (ulcerative jejunoileitis [UJ]), or the presence of a malignancy or UJ. A subgroup analysis was performed after extracting (if possible) patients with refractory CD (RCD). RESULTS: Of the 529 titles initially resulting from the search, 10 studies on capsule enteroscopy (CE) and 3 on double-balloon or push enteroscopy met the inclusion criteria. Overall, 439 and 76 patients were enrolled in these studies using CE and enteroscopy, respectively. Twelve tumors and 47 UJs were found by CE versus 8 tumors and 13 UJs detected by wired enteroscopy. For malignancies the CE yield was 1.9% (95% CI, .5%-3.8%) and wired enteroscopy yield 8.7% (95% CI, 0%-21.2%); similarly, for UJ the DYs were 8.4% (95% CI, 2.1%-17.7%) and 16.7% (95% CI, 8.7%-26.3%); for either UJ or neoplasia the DYs were 13.0% (95% CI, 5.6%-22.5%) and 27.7% (95% CI, 14.8%-42.6%). For RCD the DYs of all enteroscopic techniques were 1.8% (95% CI, 0%-7.7%) for neoplasia, 22.3% (95% CI, 8.2%-39.7%) for UJ, and 27.5% (95% CI, 13.1%-44.2%) for either. CONCLUSIONS: Enteroscopy is a powerful and efficient diagnostic tool for the detection of SB malignancies in complicated CD.

Celiac Disease and Double-Balloon Enteroscopy: What Can We Achieve?: The Experience of 2 European Tertiary Referral Centers.

BACKGROUND: Indications to double-balloon enteroscopy (DBE) are not standardized in celiac disease (CD). GOALS: To evaluate the clinical usefulness of DBE in complicated CD. STUDY: DBE findings in celiac patients with suspected small bowel (SB) complications were retrospectively evaluated in 2 tertiary referral centers (Milan and Sheffield). Demographic data of the studied cohort were compared with a database of 1000 noncomplicated CD patients. RESULTS: Twenty-four CD cases (12 males, P=0.01 vs. controls) were reviewed. Mean age at CD diagnosis (y±SD) was 37±20 versus 27±18 and at SB evaluation 47±15 versus 38±13 (P<0.01 compared with controls). Indications for DBE were refractory CD (#9), gastrointestinal symptoms (#6), severe iron-deficiency anemia (#6), and long standing poor dietary adherence (#3). Two jejunal adenocarcinomas and an ileal neuroendocrine tumor were detected in presence of iron-deficiency anemia. Three type I and 3 type II refractory CD patients showed jejunal ulcerations; 2 of type II presented small white raised patches. Patchy atrophy was observed in nonadherent patients and in 2 on a gluten-free diet for a short time. Therapy was planned in 33% of patients after DBE. No adverse events were detected at follow-up [21 mo (range, 0 to 60 mo)]. CONCLUSIONS: This is the largest international study on the outcomes of DBE in CD demonstrating its usefulness to exclude/confirm malignant or premalignant conditions, associated with even minor lesions. Studies are needed to understand the clinical relevance of the SB endoscopic features and to optimize DBE indications.

microRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts.

CD (coeliac disease) is a frequent autoimmune disorder of the small bowel, which is characterized by an immunological reaction against gluten and transglutaminase in genetically predisposed subjects. However, the molecular determinants underpinning CD pathogenesis are yet to be fully elucidated and little data are available about the involvement of miRNAs (microRNAs) in CD. In the present study, the duodenal mucosa miRNA expression was profiled in adult untreated CD presenting with a classic phenotype or iron-deficiency anaemia, treated patients with or without duodenal normalization, and non-CD subjects as controls. Deregulation of seven miRNAs (miR-31-5p, miR-192-3p, miR-194-5p, miR-551a, miR-551b-5p, miR-638 and miR-1290) was determined in a larger series of CD patients with different clinical phenotypes compared with non-CD subjects. These seven microRNAs were then analysed in duodenal fibroblasts obtained from CD patients and incubated with gliadin peptides (13- and 33-mer). The miRNA cluster miR-192/194, involved in matrix remodelling, was deregulated in CD according to the different clinical presentations, and miR-192-3p levels were modulated by gliadin peptides in vitro. In conclusion, the analysis of miRNAs deserves further consideration for its potential use in the treatment and management of CD.

Awake pronation with helmet CPAP in early COVID-19 ARDS patients: effects on respiratory effort and distribution of ventilation assessed by EIT.

Prone positioning with continuous positive airway pressure (CPAP) is widely used for respiratory support in awake patients with COVID-19-associated acute respiratory failure. We aimed to assess the respiratory mechanics and distribution of ventilation in COVID-19-associated ARDS treated by CPAP in awake prone position. We studied 16 awake COVID-19 patients with moderate-to-severe ARDS. The study protocol consisted of a randomized sequence of supine and prone position with imposed positive end-expiratory pressure (PEEP) of 5 and 10 cmH2O delivered by helmet CPAP. Respiratory mechanics and distribution of ventilation were assessed through esophageal pressure (PES) and electrical impedance tomography (EIT). At the end of each 20-min phase, arterial blood gas analysis was performed, and PES swing and EIT tracings were recorded for the calculation of the respiratory mechanics and regional ventilation. The patient's position had no significant effects on respiratory mechanics. EIT analysis did not detect differences among global indices of ventilation. A significant proportion of pixels in the sternal region of interest showed an increase in compliance from the supine to prone position and PaO2/FIO2 increased accordingly. The best improvement of both PaO2/FIO2 and sternal compliance was obtained in the prone position with PEEP 10 cmH2O. In the studied subjects, prone positioning during CPAP treatment raised oxygenation without improvement of "protective" ventilation or global ventilatory inhomogeneity indices. Prone positioning with higher PEEP significantly increased the compliance of sternal regions.

Associations of Cerebral Small Vessel Disease and Chronic Kidney Disease in Patients With Acute Intracerebral Hemorrhage: A Cross-Sectional Study.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) may be associated with the pathogenesis and phenotype of cerebral small vessel disease (SVD), which is the commonest cause of intracerebral hemorrhage (ICH). The purpose of this study was to investigate the associations of CKD with ICH neuroimaging phenotype, volume, and location, total burden of small vessel disease, and its individual components. METHODS: In 2 cohorts of consecutive patients with ICH evaluated with MRI, we investigated the frequency and severity of CKD based on established Kidney Disease Improving Global Outcomes criteria, requiring estimated glomerular filtration rate (eGFR) measurements <60 mL/min/1.732 ≥ 3 months apart to define CKD. MRI scans were rated for ICH neuroimaging phenotype (arteriolosclerosis, cerebral amyloid angiopathy, mixed location SVD, or cryptogenic ICH) and the presence of markers of SVD (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes, and enlarged perivascular spaces, defined according to the STandards for ReportIng Vascular changes on nEuroimaging criteria). We used multinomial, binomial logistic, and ordinal logistic regression models adjusted for age, sex, hypertension, and diabetes to account for possible confounding caused by shared risk factors of CKD and SVD. RESULTS: Of 875 patients (mean age 66 years, 42% female), 146 (16.7%) had CKD. After adjusting for age, sex, and comorbidities, patients with CKD had higher rates of mixed SVD than those with eGFR >60 (relative risk ratio 2.39, 95% CI 1.16-4.94, p = 0.019). Severe WMHs, deep microbleeds, and lacunes were more frequent in patients with CKD, as was a higher overall SVD burden score (odds ratio 1.83 for each point on the ordinal scale, 95% CI 1.31-2.56, p < 0.001). Patients with eGFR ≤30 had more CMBs (median 7 [interquartile range 1-23] vs 2 [0-8] for those with eGFR >30, p = 0.007). DISCUSSION: In patients with ICH, CKD was associated with SVD burden, a mixed SVD phenotype, and markers of arteriolosclerosis. Our findings indicate that CKD might independently contribute to the pathogenesis of arteriolosclerosis and mixed SVD, although we could not definitively account for the severity of shared risk factors. Longitudinal and experimental studies are, therefore, needed to investigate causal associations. Nevertheless, stroke clinicians should be aware of CKD as a potentially independent and modifiable risk factor of SVD.

Neurological disorders throughout acute SARS-CoV2 infection: A comparative study between vaccinated and non-vaccinated patients.

BACKGROUND: The role of vaccination on Covid-19 severity in neurological patients is still unknown. We aim at describing clinical characteristics and outcomes of breakthrough and unvaccinated Covid-19 patients hospitalized for neurological disorders. METHODS: Two hundred thirty-two Covid-19 patients were admitted to a neuro-Covid Unit form March 1st 2021 to February 28th 2022. Out of the total sample, 74 (32%) were full vaccinated. The prevalence, clinical characteristics, disease severity, expressed by Brescia-COVID Respiratory Severity Scale (BCRSS) and National Early Warning Score 2 (NEWS2), and final outcomes of neurological syndromes were compared between vaccinated and unvaccinated cases. Cox regression analysis was implemented in order to investigate the combined effect of predictors of mortality. RESULTS: Breakthrough vaccinated cases were older (years 72.4 ± 16.3 vs 67.0 ± 18.9 years, p = 0.029), showed higher pre-admission comorbidity score and Clinical Frailty scale score (4.46 ± 1.6 vs 3.75 ± 2.0, p = 0.008) with no differences in terms of disease progression or mortality rate (16.2% vs 15.2%), compared to full-dose vaccinated patients. Cox-regression analysis showed age and NEWS2 score as the variables with a significant relation to mortality between the two groups, independently from pre-morbid conditions and inflammatory response. CONCLUSION: This study on breakthrough COVID-19 infection could help identify vulnerable neurological patients with higher risk of poor outcomes.

CADMUS: A Novel MRI-Based Classification of Spontaneous Intracerebral Hemorrhage Associated With Cerebral Small Vessel Disease

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH. METHODS: We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses. RESULTS: The SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes. DISCUSSION: CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

TMEM16A alternative splicing coordination in breast cancer.

BACKGROUND: TMEM16A, also known as Anoctamin-1, is a calcium-activated chloride channel gene overexpressed in many tumors. The role of TMEM16A in cancer is not completely understood and no data are available regarding the potential tumorigenic properties of the multiple isoforms generated by alternative splicing (AS). METHODS: We evaluated TMEM16A AS pattern, isoforms distribution and Splicing Coordination (SC), in normal tissues and breast cancers, through a semi-quantitative PCR-assay that amplifies transcripts across three AS exons, 6b, 13 and 15. RESULTS: In breast cancer, we did not observe an association either to AS of individual exons or to specific TMEM16A isoforms, and induced expression of the most common isoforms present in tumors in the HEK293 Flp-In Tet-ON system had no effect on cellular proliferation and migration. The analysis of splicing coordination, a mechanism that regulates AS of distant exons, showed a preferential association of exon 6b and 15 in several normal tissues and tumors: isoforms that predominantly include exon 6b tend to exclude exon 15 and vice versa. Interestingly, we found an increase in SC in breast tumors compared to matched normal tissues. CONCLUSIONS: As the different TMEM16A isoforms do not affect proliferation or migration and do not associate with tumors, our results suggest that the resulting channel activities are not directly involved in cell growth and motility. Conversely, the observed increase in SC in breast tumors suggests that the maintenance of the regulatory mechanism that coordinates distant alternative spliced exons in multiple genes other than TMEM16A is necessary for cancer cell viability.

Shear-wave elastography improves the specificity of breast US: the BE1 multinational study of 939 masses.

PURPOSE: To determine whether adding shear-wave (SW) elastographic features could improve accuracy of ultrasonographic (US) assessment of breast masses. MATERIALS AND METHODS: From September 2008 to September 2010, 958 women consented to repeat standard breast US supplemented by quantitative SW elastographic examination in this prospective multicenter institutional review board-approved, HIPAA-compliant protocol. B-mode Breast Imaging Reporting and Data System (BI-RADS) features and assessments were recorded. SW elastographic evaluation (mean, maximum, and minimum elasticity of stiffest portion of mass and surrounding tissue; lesion-to-fat elasticity ratio; ratio of SW elastographic-to-B-mode lesion diameter or area; SW elastographic lesion shape and homogeneity) was performed. Qualitative color SW elastographic stiffness was assessed independently. Nine hundred thirty-nine masses were analyzable; 102 BI-RADS category 2 masses were assumed to be benign; reference standard was available for 837 category 3 or higher lesions. Considering BI-RADS category 4a or higher as test positive for malignancy, effect of SW elastographic features on area under the receiver operating characteristic curve (AUC), sensitivity, and specificity after reclassifying category 3 and 4a masses was determined. RESULTS: Median participant age was 50 years; 289 of 939 (30.8%) masses were malignant (median mass size, 12 mm). B-mode BI-RADS AUC was 0.950; eight of 303 (2.6%) BI-RADS category 3 masses, 18 of 193 (9.3%) category 4a lesions, 41 of 97 (42%) category 4b lesions, 42 of 57 (74%) category 4c lesions, and 180 of 187 (96.3%) category 5 lesions were malignant. By using visual color stiffness to selectively upgrade category 3 and lack of stiffness to downgrade category 4a masses, specificity improved from 61.1% (397 of 650) to 78.5% (510 of 650) (P<.001); AUC increased to 0.962 (P=.005). Oval shape on SW elastographic images and quantitative maximum elasticity of 80 kPa (5.2 m/sec) or less improved specificity (69.4% [451 of 650] and 77.4% [503 of 650], P<.001 for both), without significant improvement in sensitivity or AUC. CONCLUSION: Adding SW elastographic features to BI-RADS feature analysis improved specificity of breast US mass assessment without loss of sensitivity.

Spontaneous cervical artery dissection and fibromuscular dysplasia: Epidemiologic and biologic evidence of a mutual relationship.

Cervical artery dissection (CeAD) is the most common cause of ischemic stroke in young and middle-aged adults. Over the last decade, a relation between CeAD and fibromuscular dysplasia (FMD), an idiopathic, segmental, non-atherosclerotic and non-inflammatory arterial disease, has been suggested based on a number of epidemiologic observations, while preliminary data support the idea that the two conditions may share common biologic mechanisms. In this article, we review the literature on the relation between CeAD and FMD, focus on the potential pathogenetic mechanisms common to the two conditions, summarize clinical features, management and outcome, and provide support to the hypothesis that the coexistence of the two diseases in one individual might be conceptualized as a distinct non-atherosclerotic non-inflammatory arteriopathy.