Molecular Subtypes in Stage II-III Colon Cancer Defined by Genomic Instability: Early Recurrence-Risk Associated with a High Copy-Number Variation and Loss of RUNX3 and CDKN2A

Objective

We sought to investigate various molecular subtypes defined by genomic instability that may be related to early death and recurrence in colon cancer.

Methods

We sought to investigate various molecular subtypes defined by instability at microsatellites (MSI), changes in methylation patterns (CpG island methylator phenotype, CIMP) or copy number variation (CNV) in 8 genes. Stage II-III colon cancers (n = 64) were investigated by methylation-specific multiplex ligated probe amplification (MS-MLPA). Correlation of CNV, CIMP and MSI, with mutations in KRAS and BRAFV600E were assessed for overlap in molecular subtypes and early recurrence risk by uni- and multivariate regression.

Results

The CIMP phenotype occurred in 34% (22/64) and MSI in 27% (16/60) of the tumors, with noted CIMP/MSI overlap. Among the molecular subtypes, a high CNV phenotype had an associated odds ratio (OR) for recurrence of 3.2 (95% CI 1.1-9.3; P = 0.026). Losses of CACNA1G (OR of 2.9, 95% CI 1.4-6.0; P = 0.001), IGF2 (OR of 4.3, 95% CI 1.1-15.8; P = 0.007), CDKN2A (p16) (OR of 2.0, 95% CI 1.1-3.6; P = 0.024), and RUNX3 (OR of 3.4, 95% CI 1.3-8.7; P = 0.002) were associated with early recurrence, while MSI, CIMP, KRAS or BRAF V600E mutations were not. The CNV was significantly higher in deceased patients (CNV in 6 of 8) compared to survivors (CNV in 3 of 8). Only stage and loss of RUNX3 and CDKN2A were significant in the multivariable risk-model for early recurrence.

Conclusions

A high copy number variation phenotype is a strong predictor of early recurrence and death, and may indicate a dose-dependent relationship between genetic instability and outcome. Loss of tumor suppressors RUNX3 and CDKN2A were related to recurrence-risk and warrants further investigation.     

Predictors of Symptomatic Change and Adherence in Internet-Based Cognitive Behaviour Therapy for Social Anxiety Disorder in Routine Psychiatric Care

Objective

A central goal of health care is to improve patient outcomes. Although several studies have demonstrated the effectiveness of therapist guided internet-based cognitive behaviour therapy (ICBT) for social anxiety disorder (SAD), a significant proportion of patients do not respond to treatment. Consequently, the aim of this study was to identify individual characteristics and treatment program related factors that could help clinicians predict treatment outcomes and adherence for individuals with SAD.

Method

The sample comprised longitudinal data collected during a 4-year period of adult individuals (N = 764) treated for SAD at a public service psychiatric clinic. Weekly self-rated Liebowitz Social Anxiety Scale (LSAS-SR) scores were provided. Rates of symptomatic change during treatment and adherence levels were analysed using multilevel modelling. The following domains of prognostic variables were examined: (a) socio-demographic variables; (b) clinical characteristics; (c) family history of mental illness; and (d) treatment-related factors.

Results

Higher treatment credibility and adherence predicted a faster rate of improvement during treatment, whereas higher overall functioning level evidenced a slower rate of improvement. Treatment credibility was the strongest predictor of greater adherence. Having a family history of SAD-like symptoms was also associated with greater adherence, whereas Attention-Deficit/Hyperactivity Disorder (ADHD)-like symptoms, male gender, and family history of minor depression predicted lower adherence. Also, the amount of therapist time spent per treatment module was negatively associated with adherence.

Conclusions

Results from a large clinical sample indicate that the credibility of ICBT is the strongest prognostic factor explaining individual differences in both adherence level and symptomatic improvement. Early screening of ADHD-like symptoms may help clinicians identify patients who might need extra support or an adjusted treatment. Therapist behaviours that promote adherence may be important for treatment response, although more research is needed in order to determine what type of support would be most beneficial.     

Longitudinal Stability in Reading Comprehension Is Largely Heritable from Grades 1 to 6

Reading comprehension is a foundational academic skill and significant attention has focused on reading development. This report is the first to examine the stability and change in genetic and environmental influences on reading comprehension across Grades 1 to 6. This developmental range is particularly important because it encompasses the timespan in which most children move from learning how to read to using reading for learning. Longitudinal simplex models were fitted separately for two independent twin samples (N = 706; N = 976). Results suggested that the shared environment contributed to variance in early but not later reading. Instead, stability in reading development was largely mediated by continuous genetic influences. Thus, although reading is clearly a learned skill and the environment remains important for reading development, individual differences in reading comprehension appear to be also influenced by a core of genetic stability that persists through the developmental course of reading.     

Basketball Shot Types and Shot Success in Different Levels of Competitive Basketball

The purpose of our research was to investigate the relative frequencies of different types of basketball shots (above head, hook shot, layup, dunk, tip-in), some details about their technical execution (one-legged, two-legged, drive, cut, …), and shot success in different levels of basketball competitions. We analysed video footage and categorized 5024 basketball shots from 40 basketball games and 5 different levels of competitive basketball (National Basketball Association (NBA), Euroleague, Slovenian 1^st Division, and two Youth basketball competitions). Statistical analysis with hierarchical multinomial logistic regression models reveals that there are substantial differences between competitions. However, most differences decrease or disappear entirely after we adjust for differences in situations that arise in different competitions (shot location, player type, and attacks in transition). Differences after adjustment are mostly between the Senior and Youth competitions: more shots executed jumping or standing on one leg, more uncategorised shot types, and more dribbling or cutting to the basket in the Youth competitions, which can all be attributed to lesser technical and physical ability of developing basketball players. The two discernible differences within the Senior competitions are that, in the NBA, dunks are more frequent and hook shots are less frequent compared to European basketball, which can be attributed to better athleticism of NBA players. The effect situational variables have on shot types and shot success are found to be very similar for all competitions.     

Construct Validation of a Multidimensional Computerized Adaptive Test for Fatigue in Rheumatoid Arthritis

Objective

Multidimensional computerized adaptive testing enables precise measurements of patient-reported outcomes at an individual level across different dimensions. This study examined the construct validity of a multidimensional computerized adaptive test (CAT) for fatigue in rheumatoid arthritis (RA).

Methods

The ‘CAT Fatigue RA’ was constructed based on a previously calibrated item bank. It contains 196 items and three dimensions: ‘severity’, ‘impact’ and ‘variability’ of fatigue. The CAT was administered to 166 patients with RA. They also completed a traditional, multidimensional fatigue questionnaire (BRAF-MDQ) and the SF-36 in order to examine the CAT’s construct validity. A priori criterion for construct validity was that 75% of the correlations between the CAT dimensions and the subscales of the other questionnaires were as expected. Furthermore, comprehensive use of the item bank, measurement precision and score distribution were investigated.

Results

The a priori criterion for construct validity was supported for two of the three CAT dimensions (severity and impact but not for variability). For severity and impact, 87% of the correlations with the subscales of the well-established questionnaires were as expected but for variability, 53% of the hypothesised relations were found. Eighty-nine percent of the items were selected between one and 137 times for CAT administrations. Measurement precision was excellent for the severity and impact dimensions, with more than 90% of the CAT administrations reaching a standard error below 0.32. The variability dimension showed good measurement precision with 90% of the CAT administrations reaching a standard error below 0.44. No floor- or ceiling-effects were found for the three dimensions.

Conclusion

The CAT Fatigue RA showed good construct validity and excellent measurement precision on the dimensions severity and impact. The dimension variability had less ideal measurement characteristics, pointing to the need to recalibrate the CAT item bank with a two-dimensional model, solely consisting of severity and impact.     

Binding of the Lactococcal Drug Dependent Transcriptional Regulator LmrR to Its Ligands and Responsive Promoter Regions

The heterodimeric ABC transporter LmrCD from Lactococcus lactis is able to extrude several different toxic compounds from the cell, fulfilling a role in the intrinsic and induced drug resistance. The expression of the lmrCD genes is regulated by the multi-drug binding repressor LmrR, which also binds to its own promoter to autoregulate its own expression. Previously, we reported the crystal structure of LmrR in the presence and absence of the drugs Hoechst 33342 and daunomycin. Analysis of the mechanism how drugs control the repressor activity of LmrR is impeded by the fact that these drugs also bind to DNA. Here we identified, using X-ray crystallography and fluorescence, that riboflavin binds into the drug binding cavity of LmrR, adopting a similar binding mode as Hoechst 33342 and daunomycin. Microscale thermophoresis was employed to quantify the binding affinity of LmrR to its responsive promoter regions and to evaluate the cognate site of LmrR in the lmrCD promoter region. Riboflavin reduces the binding affinity of LmrR for the promoter regions. Our results support a model wherein drug binding to LmrR relieves the LmrR dependent repression of the lmrCD genes.     

Development of a Three-Dimensional Hand Model Using Three-Dimensional Stereophotogrammetry: Assessment of Image Reproducibility

Purpose

Using three-dimensional (3D) stereophotogrammetry precise images and reconstructions of the human body can be produced. Over the last few years, this technique is mainly being developed in the field of maxillofacial reconstructive surgery, creating fusion images with computed tomography (CT) data for precise planning and prediction of treatment outcome. Though, in hand surgery 3D stereophotogrammetry is not yet being used in clinical settings.

Methods

A total of 34 three-dimensional hand photographs were analyzed to investigate the reproducibility. For every individual, 3D photographs were captured at two different time points (baseline T0 and one week later T1). Using two different registration methods, the reproducibility of the methods was analyzed. Furthermore, the differences between 3D photos of men and women were compared in a distance map as a first clinical pilot testing our registration method.

Results

The absolute mean registration error for the complete hand was 1.46 mm. This reduced to an error of 0.56 mm isolating the region to the palm of the hand. When comparing hands of both sexes, it was seen that the male hand was larger (broader base and longer fingers) than the female hand.

Conclusions

This study shows that 3D stereophotogrammetry can produce reproducible images of the hand without harmful side effects for the patient, so proving to be a reliable method for soft tissue analysis. Its potential use in everyday practice of hand surgery needs to be further explored.     

Impact of Rural Residence on Warfarin Use and Clinical Events in Patients with Non-Valvular Atrial Fibrillation: A Canadian Population Based Study

Background and Purpose

We studied whether anticoagulant use and outcomes differed between rural versus urban Canadian non-valvular atrial fibrillation (NVAF) patients prior to the introduction of direct oral anticoagulant drugs.

Methods

Retrospective cohort study of 25,284 adult Albertans with NVAF between April 1, 1999 and December 31, 2008.

Results

Compared to urban patients, rural patients were older (p = 0.0009) and had more comorbidities but lower bleeding risk at baseline. In the first year after NVAF diagnosis, urban patients were less likely to be hospitalized (aOR 0.82, 95%CI 0.77–0.89) or have an emergency department visit for any reason (aOR 0.61, 95%CI 0.56–0.66) but warfarin dispensation rates (72.2% vs 71.8% at 365 days, p = 0.98) and clinical outcomes were similar: 7.8% died in both groups, 3.2% rural vs. 2.8% urban had a stroke or systemic embolism (SSE) (aOR 0.92, 95%CI 0.77–1.11), and 6.6% vs. 5.7% (aOR 0.93, 95%CI 0.81–1.06) had a bleed. Baseline SSE risk did not impact warfarin dispensation (73.0% in those with high vs. 72.8% in those with low CHADS₂ score, p = 0.85) but patients at higher baseline bleeding risk were less likely to be using warfarin (69.2% high vs. 73.6% low HASBLED score, p<0.0001) in the first 365 days after diagnosis. In warfarin users, bleeding was more frequent (7.5% vs 6.2%, aHR 1.51 [95%CI 1.33–1.72]) but death or SSE was less frequent (7.0% vs 18.1%, aHR 0.60 [0.54–0.66]).

Conclusion

Warfarin use and clinical event rates did not differ between rural and urban NVAF patients in a universal access publically-funded healthcare system.     

Prediction of Nociceptive Responses during Sedation by Linear and Non-Linear Measures of EEG Signals in High Frequencies

The level of sedation in patients undergoing medical procedures evolves continuously, affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to improve the prediction of nociceptive responses with linear and non-linear measures calculated from EEG signal filtered in frequency bands higher than the traditional bands. Power spectral density and auto-mutual information function was applied in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. The proposed measures exhibit better performances than the bispectral index (BIS). Values of prediction probability of P_k above 0.75 and percentages of sensitivity and specificity above 70% were achieved combining EEG measures from the traditional frequency bands and higher frequency bands.