Beyond Positive Affect: Discrete Positive Emotions Differentiate Major Depression from Social Anxiety Disorder.

Background: Social anxiety disorder (SAD) and major depressive disorder (MDD) are both associated with diminished global positive affect. However, little is known about which specific positive emotions are affected, and which positive emotions differentiate MDD from SAD. Methods: Four groups of adults recruited from the community were examined (N = 272): control group (no psychiatric history; n = 76), SAD without MDD group (n = 76), MDD without SAD group (n = 46), and comorbid group (diagnoses of both SAD and MDD; n = 74). Discrete positive emotions were measured with the Modified Differential Emotions Scale, which asked about the frequency of 10 different positive emotions experienced during the past week. Results: The control group had higher scores on all positive emotions compared to all three clinical groups. The SAD group had higher scores on awe, inspiration, interest, and joy compared to the MDD group, and higher scores on those emotions, as well as amusement, hope, love, pride, and contentment, than the comorbid group. MDD and comorbid groups did not differ on any positive emotions. Gratitude did not differ significantly between clinical groups. Conclusion: Adopting a discrete positive emotion approach revealed shared and distinct features across SAD, MDD, and their comorbidity. We consider possible mechanisms underlying transdiagnostic vs. disorder-specific emotion deficits. Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10355-y.

Randomized controlled trial of computerized approach/avoidance training in social anxiety disorder: Neural and symptom outcomes.

Social anxiety is associated with diminished automatic approach toward positive social cues that may limit the ability to connect with others. This diminished approach bias may be a modifiable treatment target. We evaluated the effects of an approach avoidance training procedure on positive emotions, social relationship outcomes, clinical symptoms, and neural indices of social approach and reward processing. Forty-five individuals with social anxiety disorder were randomized (parallel 1:1 randomization) to complete computerized Approach Positive training (n = 21) or Balanced training(n = 24). Sessions included a standardized social interaction task. Participants were blind to training group. Participants completed clinical outcome measures and functional magnetic resonance imaging at baseline and post intervention with an MRI-compatible AAT and the social incentive delay task (SID). Both groups displayed significant improvements of similar magnitude on the primary outcome of social connectedness (between group post-treatment d = -0.21) but not positive affect (d = -0.09), from before to after treatment, persisting through follow-up. Groups demonstrated significant improvements on additional outcomes including anxiety, depression, and anhedonia symptoms. Participants in Approach Positive AAT demonstrated increased activation in the thalamus and medial prefrontal cortex during social versus neutral- approach relative to Balanced AAT during the fMRI AAT. Participants in Balanced AAT showed increased activation in regions within an a priori-defined striatum region of interest mask during anticipation of social reward (vs. baseline) in the SID relative to Approach Positive AAT. At a neural processing level AAT may influence the valuation and motivations associated with positive social cues regulated by the mPFC and thalamus. NCT02136212, NIMH R00MH090243.

Neural Changes in Reward Processing Following Approach Avoidance Training for Depression.

Altered approach motivation is hypothesized to be critical for the maintenance of depression. Computer-administered approach-avoidance training programs to increase approach action tendencies toward positive stimuli produce beneficial outcomes. However, there have been few studies examining neural changes following approach-avoidance training. Participants with Major Depressive Disorder were randomized to an Approach Avoidance Training (AAT) manipulation intended to increase approach tendencies for positive social cues (n=13) or a control procedure (n=15). We examined changes in neural activation (primary outcome) and connectivity patterns using Group Iterative Multiple Model Estimation during a social reward anticipation task (exploratory). A laboratory-based social affiliation task was also administered following the manipulation to measure affect during anticipation of real-world social activity. Individuals in the AAT group demonstrated increased activation in reward processing regions during social reward anticipation relative to the control group from pre to post-training. Following training, connectivity patterns across reward regions were observed in the full sample and connectivity between the medial PFC and caudate was associated with anticipatory positive affect before the social interaction; preliminary evidence of differential connectivity patterns between the two groups also emerged. Results support models whereby modifying approach-oriented behavioral tendencies with computerized training leads to alterations in reward circuitry. (NCT02330744).

Computer-delivered behavioural activation and approach-avoidance training in major depression: Proof of concept and initial outcomes.

OBJECTIVES: Individuals with major depressive disorder (MDD) have problems with engaging in approach behaviour to potentially rewarding encounters, which contributes to the maintenance of depressive symptoms. Approach-avoidance training (AAT) retrains implicit approach tendencies, and behavioural activation (BA) promotes explicit approach behaviour in MDD. As a novel MDD treatment strategy, this study aimed to implement a brief, computerized version of BA integrated with implicit AAT. DESIGN: Adults with a principal diagnosis of MDD (N = 25) were randomly assigned to complete one of two versions of AAT - approach-positive faces (n = 12) or balanced approach of positive and neutral faces (n = 13) - concurrently with self-guided BA twice weekly for 2 weeks. METHODS: Outcomes included treatment completion rates; bias scores for automatic approach towards positive social cues; and symptom scales for depression, positive affect, social relationship functioning, anhedonia, and anxiety. RESULTS: Feasibility and acceptability of computerized BA + AAT were supported by moderate pre-treatment credibility and expectancy ratings and 80% treatment completion. Participants across both conditions displayed significant and large sized reductions in depression from pre- to post-assessment (Cohen's d = -1.23) that maintained three months later, as well as decreased anxiety and anhedonia and increased positive affect and social relationship functioning (medium to large effects). CONCLUSION: Results support the feasibility and potential efficacy of brief, computerized BA + AAT. Research is needed to determine whether AAT is additive to BA, and what AAT parameters best enhance treatment outcomes. PRACTITIONER POINTS: Brief, computerized behavioral activation plus approach/avoidance training (BA + AAT) may be acceptable and beneficial for some patients with moderate-to-severe major depression. Computer-delivered BA + AAT can be implemented as a largely self-guided program for MDD and could be administered remotely and/or with minimal clinician interaction. As this was a small proof of concept study, it cannot be determined which treatment components - AAT, BA, or both - contributed to positive clinical outcomes. Because BA + AAT was implemented in a research clinic, it remains unknown what treatment engagement and response would look like in community settings.

The cost-effectiveness of diagnostic cardiac imaging for stable coronary artery disease.

Early and accurate diagnosis of stable coronary artery disease (CAD) is crucial to reduce morbidity, mortality and healthcare costs. This critical appraisal of health-economic literature concerning non-invasive diagnostic cardiac imaging aims to summarize current approaches to economic evaluation of diagnostic cardiac imaging and associated procedural risks, inform cardiologists how to use economic analyses for decision-making, highlight areas where new information could strengthen the economic evaluation and shed light on cost-effective approaches to diagnose stable CAD. Economic analysis can support cardiologists' decision-making. Current economic evidence in the field does not provide sufficient information to guide the choice among different imaging modalities or strategies for each patient. Available economic analyses suggest that computed tomography coronary angiography (CTCA) is a cost-effective approach to rule out CAD prior to invasive coronary angiography in patients with low to intermediate pre-test probability of disease and that stress imaging modalities may be cost-effective at variable pre-test probabilities.

Diagnostic imaging and biopsy pathways following abnormal screen-film and digital screening mammography.

The transition from screen-film to digital mammography may have altered diagnostic evaluation of women following a positive screening examination. This study compared the use and timeliness of diagnostic imaging and biopsy for women screened with screen-film or digital mammography. Data were obtained from 35,321 positive screening mammograms on 32,087 women aged 40-89 years, from 22 breast cancer surveillance consortium facilities in 2005-2008. Diagnostic pathways were classified by their inclusion of diagnostic mammography, ultrasound, magnetic resonance imaging, and biopsy. We compared time to resolution and frequency of diagnostic pathways by patient characteristics, screening exam modality, and radiology facility. Between-facility differences were evaluated by computing the proportion of mammograms receiving follow-up with a particular pathway for each facility and examining variation in these proportions across facilities. Multinomial logistic regression adjusting for age, calendar year, and facility compared odds of follow-up with each pathway. The median time to resolution of a positive screening mammogram was 10 days. Compared to screen-film mammograms, digital mammograms were more frequently followed by only a single diagnostic mammogram (46 vs. 36 %). Pathways following digital screening mammography were also less likely to include biopsy (16 vs. 20 %). However, in adjusted analyses, most differences were not statistically significant (p = 0.857 for mammography only; p = 0.03 for biopsy). Substantial variability in diagnostic pathway frequency was seen across facilities. For instance, the frequency of evaluation with diagnostic mammography alone ranged from 23 to 55 % across facilities. Differences in evaluation of positive digital and screen-film screening mammograms were minor, and appeared to be largely attributable to substantial variation between radiology facilities. To guide health systems in their efforts to eliminate practices that do not contribute to effective care, we need further research to identify the causes of this variation and the best evidence-based approach for follow-up.

The impact of CT colonography for colorectal cancer screening on the UK NHS: costs, healthcare resources and health outcomes.

BACKGROUND: Biennial faecal occult blood testing (FOBT) for individuals aged 60-69 years is the primary screening tool for colorectal cancer (CRC) in the UK NHS, despite a large number of patients undergoing an unnecessary optical colonoscopy (OC) and evidence from modelling studies to suggest that more cost-effective technologies exist. CT colonography (CTC) is an emerging CRC screening technology with the potential to prevent CRC by detecting pre-cancerous polyps and to detect cancer at an earlier stage. OBJECTIVE: to assess the impact of introducing CTC into the UK NHS screening programme for CRC on key health outcomes as well as the NHS budget and healthcare resource capacity. METHODS: a discrete Markov model was used to reflect the natural history of CRC and the impact of three screening scenarios (biennial FOBT with and without CTC triage of patients referred to OC, and CTC every 5 years) on a range of health outcomes, including the incidence and prevalence of CRC, in a hypothetical cohort of individuals. The yearly costs, health outcomes and healthcare resource capacity requirements were estimated over a 10-year period (2009-18). RESULTS: using CTC to follow up FOBT-positive patients (scenario 2) was less costly than directing all FOBT-positive patients to OC (scenario 1); saving £776 283 over 10 years for 100 000 individuals invited for screening (year 2007 values), primarily by avoiding approximately 1700 OCs, but was estimated to require 2200 additional CT scans. Implementing a programme of 5-yearly CTC as a primary screen is expected to be more expensive than FOBT screening over the short term (driven by high screening and diagnosis costs), despite substantial savings in treatment costs for CRC over the 10-year time horizon of the model and improved health outcomes. CONCLUSIONS: adding CTC into the existing NHS Bowel Cancer Screening Programme as part of a preventive screening strategy could be less costly to the NHS over the longer term when used to triage FOBT-positive patients to appropriate follow-up. Increased demand for radiology services may be compensated for by reduced demand in endoscopy units.

Cost effectiveness of CT colonography for UK NHS colorectal cancer screening of asymptomatic adults aged 60-69 years.

BACKGROUND: Screening of populations at risk for colorectal cancer (CRC) allows the detection and successful treatment of tumours and their precursor polyps. The current UK CRC screening programme is faecal occult blood testing (FOBT), despite evidence from modelling studies to suggest that more cost-effective technologies exist. OBJECTIVE: To assess the cost effectiveness of CT colonography (CTC) for colorectal cancer screening from the perspective of the UK NHS. METHODS: A state-transition Markov model was constructed to estimate lifetime costs and health outcomes of a cohort of individuals screened at age 60-69 years using four different CRC screening technologies: FOBT, flexible sigmoidoscopy, optical colonoscopy and CTC. RESULTS: CTC screening offered every 10 years was cost saving compared with the current UK programme of biennial FOBT screening. This strategy also yielded greater health benefits (QALYs and life-years) than biennial FOBT screening. The model fit observed CRC epidemiology data well and was robust to changes in underlying parameter values. CTC remained cost effective under a range of assumptions in the univariate sensitivity analysis. However, in the probabilistic sensitivity analysis, CTC dominated FOBT in only 5.9% of simulations and was cost effective at a threshold of pound30,000 per QALY gained in 48% of simulations. CONCLUSIONS: CTC has the potential to provide a cost-effective option for CRC screening in the UK NHS and may be cost saving compared with the current programme of biennial FOBT. Further analysis is required to assess the impact of introducing CTC to the UK CRC screening programme on the NHS budget and capacity.

The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy.

We report a case of rapidly progressive frontotemporal dementia presenting at age 33 years. At autopsy there was severe atrophy of the frontal and temporal lobes. Tau-positive Pick bodies, which ultrastructurally were composed of straight filaments, were present, accompanied by severe neuronal loss and gliosis. RD3, a tau antibody specific for the three-repeat (3R) isoforms, labeled the Pick bodies. ET3, a four-repeat (4R) isoform-specific tau antibody, did not label Pick bodies, but highlighted rare astrocytes, and threads in white matter bundles in the corpus striatum. Analysis of the tau gene revealed an L266V mutation in exon 9. Analysis of brain tissue from this case revealed elevated levels of exon 10+ tau RNA and soluble 4R tau. However, both 3R and 4R isoforms were present in sarkosyl-insoluble tau fractions with a predominance of the shortest 3R isoform. The L266V mutation is associated with decreased rate and extent of tau-induced microtubule assembly, and a 3R isoform-specific increase in tau self assembly as measured by an in vitro assay. Combined, these data indicate that L266V is a pathogenic tau mutation that is associated with Pick-like pathology. In addition, the results of the RD3 and ET3 immunostains clearly explain for the first time the presence of both 3R and 4R tau isoforms in preparations of insoluble tau from some Pick's disease cases.

Evaluation of saturation labelling two-dimensional difference gel electrophoresis fluorescent dyes.

Two-dimensional difference gel electrophoresis (2-D DIGE) enables an increased confidence in detection of protein differences. However, due to the nature of the minimal labelling where only approximately 5% of a given protein is labelled, spots cannot be directly excised for mass spectrometry (MS) analysis and detection sensitivity could be further enhanced. Amersham Biosciences have developed a second set of CyDye DIGE Cy 3 and Cy5 dyes, which aim to overcome these limitations through saturation-labelling of cysteine residues. The dyes were evaluated in relation to their sensitivity and dynamic range, their useability as multiplexing reagents and the possibility of direct spot picking from saturation-labelled gels for MS analysis. The saturation-labelling dyes were superior in sensitivity to their minimal-labelling counterparts, silver stain and Sypro Ruby, however, the resulting 2-D spot pattern was significantly altered from that of unlabelled or minimal-labelled protein. The dyes were found to be useful as multiplexing reagents although preferential labelling of proteins with one dye over another was observed but was controlled for through experimental design. Protein identities were successfully obtained from material directly excised from saturation-labelled gels eliminating the need for post-stained preparative gels.