Comprehensive MicroRNA expression profiling identifies novel markers in follicular variant of papillary thyroid carcinoma

BACKGROUND Follicular variant of papillary thyroid carcinoma (FVPTC) shares features of papillary (PTC) and follicular (FTC) thyroid carcinomas on a clinical, morphological, and genetic level. MicroRNA (miRNA) deregulation was extensively studied in PTCs and FTCs. However, very limited information is available for FVPTC. The aim of this study was to assess miRNA expression in FVPTC with the most comprehensive miRNA array panel and to correlate it with the clinicopathological data. METHODS Forty-four papillary thyroid carcinomas (17 FVPTC, 27 classic PTC) and eight normal thyroid tissue samples were analyzed for expression of 748 miRNAs using Human Microarray Assays on the ABI 7900 platform (Life Technologies, Carlsbad, CA). In addition, an independent set of 61 tumor and normal samples was studied for expression of novel miRNA markers detected in this study. RESULTS Overall, the miRNA expression profile demonstrated similar trends between FVPTC and classic PTC. Fourteen miRNAs were deregulated in FVPTC with a fold change of more than five (up/down), including miRNAs known to be upregulated in PTC (miR-146b-3p, -146-5p, -221, -222 and miR-222-5p) and novel miRNAs (miR-375, -551b, 181-2-3p, 99b-3p). However, the levels of miRNA expression were different between these tumor types and some miRNAs were uniquely dysregulated in FVPTC allowing separation of these tumors on the unsupervised hierarchical clustering analysis. Upregulation of novel miR-375 was confirmed in a large independent set of follicular cell derived neoplasms and benign nodules and demonstrated specific upregulation for PTC. Two miRNAs (miR-181a-2-3p, miR-99b-3p) were associated with an adverse outcome in FVPTC patients by a Kaplan-Meier (p < 0.05) and multivariate Cox regression analysis (p < 0.05). CONCLUSIONS Despite high similarity in miRNA expression between FVPTC and classic PTC, several miRNAs were uniquely expressed in each tumor type, supporting their histopathologic differences. Highly upregulated miRNA identified in this study (miR-375) can serve as a novel marker of papillary thyroid carcinoma, and miR-181a-2-3p and miR-99b-3p can predict relapse-free survival in patients with FVPTC thus potentially providing important diagnostic and predictive value.

Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study

BACKGROUND Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. METHODS In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. FINDINGS Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0·011). INTERPRETATION (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. FUNDING Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

Impact of cardiac computed tomography of the interatrial septum before pulmonary vein isolation

BACKGROUND Multidetector computed tomography (MDCT) may be useful to identify patients with patent foramen ovale (PFO). The aim of this study was to analyze whether a MDCT performed before pulmonary vein isolation reliably detects a PFO that may be used for access to the left atrium. METHODS AND RESULTS In 79 consecutive patients, who were referred for catheter ablation of symptomatic paroxysmal or persistent atrial fibrillation (AF), the presence of a PFO was explored by MDCT and transesophageal echocardiography (TEE). TEE was considered as the gold standard, and quality of TEE was good in all patients. In 16 patients (20.3%), MDCT could not be used for analysis because of artifacts, mainly because of AF. On TEE, a PFO was found in 15 (23.8%) of the 63 patients with usable MDCT. MDCT detected six PFO of which four were present on TEE. This corresponded to a sensitivity of 26.7%, a specificity of 95.8%, a negative predictive value of 80.7%, and a positive predictive value of 66.7%. The receiver operating characteristics curve of MDCT for the detection of PFO was 0.613 (95% confidence interval 0.493-0.732). CONCLUSIONS MDCT may detect a PFO before pulmonary isolation. However, presence of AF may lead to artifacts on MDCT impeding a meaningful analysis. Furthermore, in this study sensitivity and positive predictive value of MDCT were low and therefore MDCT was not a reliable screening tool for detection of PFO.

Validity of the Adult ADHD Self-Report Scale (ASRS) as a screener for adult ADHD in treatment seeking substance use disorder patients

Background: To detect attention deficit hyperactivity disorder (ADHD) in treatment seeking substance use disorders (SUD) patients, a valid screening instrument is needed. Objectives: To test the performance of the Adult ADHD Self-Report Scale V 1.1(ASRS) for adult ADHD in an international sample of treatment seeking SUD patients for DSM-IV-TR; for the proposed DSM-5 criteria; in different subpopulations, at intake and 1–2 weeks after intake; using different scoring algorithms; and different externalizing disorders as external criterion (including adult ADHD, bipolar disorder, antisocial and borderline personality disorder). Methods: In 1138 treatment seeking SUD subjects, ASRS performance was determined using diagnoses based on Conner's Adult ADHD Diagnostic Interview for DSM-IV (CAADID) as gold standard. Results: The prevalence of adult ADHD was 13.0% (95% CI: 11.0–15.0%). The overall positive predictive value (PPV) of the ASRS was 0.26 (95% CI: 0.22–0.30), the negative predictive value (NPV) was 0.97 (95% CI: 0.96–0.98). The sensitivity (0.84, 95% CI: 0.76–0.88) and specificity (0.66, 95% CI: 0.63–0.69) measured at admission were similar to the sensitivity (0.88, 95% CI: 0.83–0.93) and specificity (0.67, 95% CI: 0.64–0.70) measured 2 weeks after admission. Sensitivity was similar, but specificity was significantly better in patients with alcohol compared to (illicit) drugs as the primary substance of abuse (0.76 vs. 0.56). ASRS was not a good screener for externalizing disorders other than ADHD. Conclusions: The ASRS is a sensitive screener for identifying possible ADHD cases with very few missed cases among those screening negative in this population.

A Stratified Model for Psychosis Prediction in Clinical Practice

Objective: Impaired cognition is an important dimension in psychosis and its at-risk states. Research on the value of impaired cognition for psychosis prediction in at-risk samples, however, mainly relies on study-specific sample means of neurocognitive tests, which unlike widely available general test norms are difficult to translate into clinical practice. The aim of this study was to explore the combined predictive value of at-risk criteria and neurocognitive deficits according to test norms with a risk stratification approach. Method: Potential predictors of psychosis (neurocognitive deficits and at-risk criteria) over 24 months were investigated in 97 at-risk patients. Results: The final prediction model included (1) at-risk criteria (attenuated psychotic symptoms plus subjective cognitive disturbances) and (2) a processing speed deficit (digit symbol test). The model was stratified into 4 risk classes with hazard rates between 0.0 (both predictors absent) and 1.29 (both predictors present). Conclusions: The combination of a processing speed deficit and at-risk criteria provides an optimized stratified risk assessment. Based on neurocognitive test norms, the validity of our proposed 3 risk classes could easily be examined in independent at-risk samples and, pending positive validation results, our approach could easily be applied in clinical practice in the future.

Can a novel computerized cognitive screening test provide additional information for early detection of Alzheimer's disease?

BACKGROUND: Virtual reality testing of everyday activities is a novel type of computerized assessment that measures cognitive, executive, and motor performance as a screening tool for early dementia. This study used a virtual reality day-out task (VR-DOT) environment to evaluate its predictive value in patients with mild cognitive impairment (MCI). METHODS: One hundred thirty-four patients with MCI were selected and compared with 75 healthy control subjects. Participants received an initial assessment that included VR-DOT, a neuropsychological evaluation, magnetic resonance imaging (MRI) scan, and event-related potentials (ERPs). After 12 months, participants were assessed again with MRI, ERP, VR-DOT, and neuropsychological tests. RESULTS: At the end of the study, we differentiated two subgroups of patients with MCI according to their clinical evolution from baseline to follow-up: 56 MCI progressors and 78 MCI nonprogressors. VR-DOT performance profiles correlated strongly with existing predictive biomarkers, especially the ERP and MRI biomarkers of cortical thickness. CONCLUSIONS: Compared with ERP, MRI, or neuropsychological tests alone, the VR-DOT could provide additional predictive information in a low-cost, computerized, and noninvasive way.

Association of alcohol craving and proximal outcomes of a residential treatment program for patients with alcohol use disorders

Background: Alcohol craving is an essential construct in research and treatment of alcohol use disorders (AUD). Craving is mostly investigated in association with concurrent variables or distal treatment outcomes at follow-up. Objectives: The aim of this study is to examine craving at admission and its relevance for essential proximal outcomes at discharge from AUD treatment such as positive alcohol expectancy, abstinent-related self-efficacy, and substance-related coping, as well as patients’ demographic and AUD characteristics. Methods: In total, 36 patients were recruited within an inpatient treatment AUD program. Results: An association between craving and positive alcohol expectancies at discharge was found in the regression model even when the respective expectancies, age, gender, and severity of alcohol dependence at admission were controlled for (F(2,29)1⁄432.71, p50.001). Craving explained 2.3% of the variance of change in positive alcohol expectancy. Conclusion: The results suggest a low predictive value of craving for positive alcohol expectancy. In addition, we found significant associations between the craving and the severity of AUD and alcohol consumption before admission. Future studies should include proximal outcomes related to treatment efficacy as well as distal outcomes.

The implicit achievement motive predicts match performance and the explicit motive choices for goal distances in team sports

Motivational research over the past decade has provided ample evidence for the existence of two distinct motivational systems. Implicit motives are affect-based needs and have been found to predict spontaneous behavioral trends over time. Explicit motives in contrast represent cognitively based self-attributes and are preferably linked to choices. The present research examines the differentiating and predictive value of the implicit vs. explicit achievement motives for team sports performances. German students (N = 42) completed a measure of the implicit (Operant Motive Test) and the explicit achievement motive (Achievement Motive Scale-Sport). Choosing a goal distance is significantly predicted by the explicit achievement motive measure. By contrast, repeated performances in a team tournament are significantly predicted by the indirect measure. Results are in line with findings showing that implicit and explicit motive measures are associated with different classes of behavior.

Predicting premature termination within a randomized controlled trial for binge-eating patients

Understanding the dropout rates of efficacious forms of psychotherapy for patients with binge eating disorder (BED) is an unsolved problem within this increasing population. Up until now the role of psychotherapy process characteristics as predictors of premature termination has not been investigated in the BED literature. Within a randomized controlled trial (N=78) we investigated the degree to which early psychological process characteristics, such as components of the therapeutic relationship and the experiences of mastery and motivational clarification, predicted premature termination of treatment. We statistically controlled for the influences of covariates such as rapid response of treatment, treatment group, body mass index, Axis II disorder, and patients' preexisting generalized self-efficacy at baseline. Patients' postsession reports from Sessions 1 to 5 indicated that low self-esteem in-session experiences was a stable predictor of premature termination. Its predictive value persisted after controlling for the above-mentioned covariates. Exploratory analyses further revealed low self-esteem experiences, low global alliance, and low mastery and clarification experiences as predictors in those patients who explicitly specified discontentment with therapy as reason for premature termination. These results indicate that patients' self-esteem experiences may not be an epiphenomenon of their specific psychopathology but may represent general mechanisms on which remaining or withdrawing from psychotherapeutic treatment depends. Early psychotherapy process characteristics should therefore be considered in training and evaluation of psychotherapists carrying through BED treatments.

Does Radar Technology Support the Diagnosis of Pneumothorax? PneumoScan-A Diagnostic Point-of-Care Tool

Background. A nonrecognized pneumothorax (PTX) may become a life-threatening tension PTX. A reliable point-of-care diagnostic tool could help in reduce this risk. For this purpose, we investigated the feasibility of the use of the PneumoScan, an innovative device based on micropower impulse radar (MIR). Patients and Methods. addition to a standard diagnostic protocol including clinical examination, chest X-ray (CXR), and computed tomography (CT), 24 consecutive patients with chest trauma underwent PneumoScan testing in the shock trauma room to exclude a PTX. Results. The application of the PneumoScan was simple, quick, and reliable without functional disorder. Clinical examination and CXR each revealed one and PneumoScan three out of altogether four PTXs (sensitivity 75%, specificity 100%, positive predictive value 100%, and negative predictive value 95%). The undetected PTX did not require intervention. Conclusion. The PneumoScan as a point-of-care device offers additional diagnostic value in patient management following chest trauma. Further studies with more patients have to be performed to evaluate the diagnostic accuracy of the device.

Who is likely to develop persistent low back pain? A longitudinal analysis of prognostic occupational factors

OBJECTIVE: Occupational low back pain (LBP) is considered to be the most expensive form of work disability, with the socioeconomic costs of persistent LBP exceeding the costs of acute and subacute LBP by far. This makes the early identification of patients at risk of developing persistent LBP essential, especially in working populations. The aim of the study was to evaluate both risk factors (for the development of persistent LBP) and protective factors (preventing the development of persistent LBP) in the same cohort. PARTICIPANTS: An inception cohort of 315 patients with acute to subacute or with recurrent LBP was recruited from 14 health practitioners (twelve general practitioners and two physiotherapists) across New Zealand. METHODS: Patients with persistent LBP at six-month follow-up were compared to patients with non-persistent LBP looking at occupational, psychological, biomedical and demographic/lifestyle predictors at baseline using multiple logistic regression analyses. All significant variables from the different domains were combined into a one predictor model. RESULTS: A final two-predictor model with an overall predictive value of 78% included social support at work (OR 0.67; 95%CI 0.45 to 0.99) and somatization (OR 1.08; 95%CI 1.01 to 1.15). CONCLUSIONS: Social support at work should be considered as a resource preventing the development of persistent LBP whereas somatization should be considered as a risk factor for the development of persistent LBP. Further studies are needed to determine if addressing these factors in workplace interventions for patients suffering from acute, subacute or recurrent LBP prevents subsequent development of persistent LBP.

High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality.

AIMS High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value. METHODS AND RESULTS We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7-10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18-0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61-1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59-1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts. CONCLUSION The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patients.

Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.

AIMS The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. METHODS AND RESULTS We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10(-40) and rs16899974; P = 1.5 × 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 × 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. CONCLUSIONS AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.

Alienation from school

Two studies aimed at understanding the time course of alienation from school and school factors that may influence alienation from school during early adolescence. In Study 1, 434 students from grade 5–8 participated (cross-sectional design). In Study 2, we followed 356 students from grade 6–7 (longitudinal design). The results confirm the prevalence of alienation for boys and low achievers, the gradual progression of alienation during adolescence, and the predictive value of instructional quality, positive teacher–student integration and positive student–student integration in determining academic alienation during early adolescence.

Detecting Functional Hubs of Ictogenic Networks

Quantitative EEG (qEEG) has modified our understanding of epileptic seizures, shifting our view from the traditionally accepted hyper-synchrony paradigm toward more complex models based on re-organization of functional networks. However, qEEG measurements are so far rarely considered during the clinical decision-making process. To better understand the dynamics of intracranial EEG signals, we examine a functional network derived from the quantification of information flow between intracranial EEG signals. Using transfer entropy, we analyzed 198 seizures from 27 patients undergoing pre-surgical evaluation for pharmaco-resistant epilepsy. During each seizure we considered for each network the in-, out- and total "hubs", defined respectively as the time and the EEG channels with the maximal incoming, outgoing or total (bidirectional) information flow. In the majority of cases we found that the hubs occur around the middle of seizures, and interestingly not at the beginning or end, where the most dramatic EEG signal changes are found by visual inspection. For the patients who then underwent surgery, good postoperative clinical outcome was on average associated with a higher percentage of out- or total-hubs located in the resected area (for out-hubs p = 0.01, for total-hubs p = 0.04). The location of in-hubs showed no clear predictive value. We conclude that the study of functional networks based on qEEG measurements may help to identify brain areas that are critical for seizure generation and are thus potential targets for focused therapeutic interventions.