Jumping to Conclusions, a Lack of Belief Flexibility and Delusional Conviction in Psychosis: A Longitudinal Investigation of the Structure, Frequency, and Relatedness of Reasoning Biases

Two reasoning biases, jumping to conclusions (JTC) and belief inflexibility, have been found to be associated with delusions. We examined these biases and their relationship with delusional conviction in a longitudinal cohort of people with schizophrenia-spectrum psychosis. We hypothesized that JTC, lack of belief flexibility, and delusional conviction would form distinct factors, and that JTC and lack of belief flexibility would predict less change in delusional conviction over time. Two hundred seventy-three patients with delusions were assessed over twelve months of a treatment trial (Garety et al., 2008). Forty-one percent of the sample had 100% conviction in their delusions, 50% showed a JTC bias, and 50%–75% showed a lack of belief flexibility. Delusional conviction, JTC, and belief flexibility formed distinct factors although conviction was negatively correlated with belief flexibility. Conviction declined slightly over the year in this established psychosis group, whereas the reasoning biases were stable. There was little evidence that reasoning predicted the slight decline in conviction. The degree to which people believe their delusions, their ability to think that they may be mistaken and to consider alternative explanations, and their hastiness in decision making are three distinct processes although belief flexibility and conviction are related. In this established psychosis sample, reasoning biases changed little in response to medication or psychological therapy. Required now is examination of these processes in psychosis groups where there is greater change in delusion conviction, as well as tests of the effects on delusions when these reasoning biases are specifically targeted

Problematic placebos in physical therapy trials

The placebo controlled, randomised controlled trial is widely recognised as the gold standard design for providing evidence in health care. Yet controversies surrounding placebos persist, which include issues regarding ethics, legality, mechanisms, and even whether there should be such a thing as placebo at all. Here, we intend to highlight some of the difficulties in the design and use of placebo controls within physical therapy trials. Unlike placebo tablets, which can be constructed simply by removing the active or‘characteristic’ingredient, physical therapy treatments are often more complex, with many active features that cannot be easily separated. Based on the challenges of isolating the characteristic feature(s) of treatments, we explore the problem with constructing placebos in trials of physical therapies, drawing on philosophy of science as a basis for defining what a placebo is and is not. After pointing out common problems, we outline potential solutions using alternative designs that allow trials to remain rigorous, while at the same time avoiding the pitfalls introduced when using inadequate placebos

Jumping to the wrong conclusions? An investigation of the mechanisms of reasoning errors in delusions

Understanding how people with delusions arrive at false conclusions is central to the refinement of cognitive behavioural interventions. Making hasty decisions based on limited data ('jumping to conclusions', JTC) is one potential causal mechanism, but reasoning errors may also result from other processes. In this study, we investigated the correlates of reasoning errors under differing task conditions in 204 participants with schizophrenia spectrum psychosis who completed three probabilistic reasoning tasks. Psychotic symptoms, affect, and IQ were also evaluated. We found that hasty decision makers were more likely to draw false conclusions, but only 37% of their reasoning errors were consistent with the limited data they had gathered. The remainder directly contradicted all the presented evidence. Reasoning errors showed task-dependent associations with IQ affect, and psychotic symptoms. We conclude that limited data-gathering contributes to false conclusions but is not the only mechanism involved. Delusions may also be maintained by a tendency to disregard evidence. Low IQ and emotional biases may contribute to reasoning errors in more complex situations. Cognitive strategies to reduce reasoning errors should therefore extend beyond encouragement to gather more data, and incorporate interventions focused directly on these difficulties

CK1ε Is Required for Breast Cancers Dependent on β-Catenin Activity

Background: Aberrant $\beta$-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate $\beta$-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active $\beta$-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized $\beta$-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1$\varepsilon$) as required specifically for the proliferation of breast cancer cells with activated $\beta$-catenin and confirm its role as a positive regulator of $\beta$-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated $\beta$-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/$\beta$-catenin signaling. We also find that expression of CK1$\varepsilon$ is able to promote oncogenic transformation of human cells in a $\beta$-catenin-dependent manner. Conclusions/Significance: These studies identify CK1$\varepsilon$ as a critical contributor to activated $\beta$-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active $\beta$-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors

Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells

An alternative to therapeutic targeting of oncogenes is to perform “synthetic lethality” screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with “undruggable” genetic alterations.National Institutes of Health (U.S.) (grant R33 CA128625)National Institutes of Health (U.S.) (grant NIH U54 CA112962)National Institutes of Health (U.S.) (grant P01 CA095616)National Institutes of Health (U.S.) (grant P01 CA66996)Starr Cancer ConsortiumDoris Duke Charitable FoundationMPN Research FoundationDeutsche Forschungsgemeinschaft (grant SCHO 1215/1-1)Deutsche Forschungsgemeinschaft (grant FR 2113/1-1)Brain Science FoundationLeukemia & Lymphoma Society of Americ

Advanced Fluorescence Microscopy Techniques-FRAP, FLIP, FLAP, FRET and FLIM

Fluorescence microscopy provides an efficient and unique approach to study fixed and living cells because of its versatility, specificity, and high sensitivity. Fluorescence microscopes can both detect the fluorescence emitted from labeled molecules in biological samples as images or photometric data from which intensities and emission spectra can be deduced. By exploiting the characteristics of fluorescence, various techniques have been developed that enable the visualization and analysis of complex dynamic events in cells, organelles, and sub-organelle components within the biological specimen. The techniques described here are fluorescence recovery after photobleaching (FRAP), the related fluorescence loss in photobleaching (FLIP), fluorescence localization after photobleaching (FLAP), Forster or fluorescence resonance energy transfer (FRET) and the different ways how to measure FRET, such as acceptor bleaching, sensitized emission, polarization anisotropy, and fluorescence lifetime imaging microscopy (FLIM). First, a brief introduction into the mechanisms underlying fluorescence as a physical phenomenon and fluorescence, confocal, and multiphoton microscopy is given. Subsequently, these advanced microscopy techniques are introduced in more detail, with a description of how these techniques are performed, what needs to be considered, and what practical advantages they can bring to cell biological research

Neuropsychological functioning and jumping to conclusions in delusions

Background: It has been consistently demonstrated that delusions are related to jumping to conclusions (JTC), a data-gathering bias and potential candidate endophenotype of psychosis. Recent research suggests that JTC may be a marker of treatment response. However, we know little about the factors contributing to the occurrence of this reasoning bias. This study investigated the relationship between JTC and hypothesised deficits in working memory, employing standard well-validated neuropsychological tests, in people with current delusions. Method: One hundred and twenty six people with schizophrenia spectrum psychosis and current delusions were assessed for current symptoms, and tested for JTC. We compared performance on tests of working memory in those with the reasoning bias and those without. Results: As expected, 30–40% of this sample of people with current delusions showed the JTC bias. There were no differences in premorbid IQ between those with and without the JTC reasoning bias. However, the performance of the JTC group was significantly worse on tests of working memory. Conclusions: The JTC data-gathering bias is associated with impairments in working memory. New non-pharmacological interventions for people with delusions, designed to improve data gathering, may benefit from incorporating strategies to overcome deficits in working memory

Rural-urban disparities in child nutrition in Bangladesh and Nepal

Background The persistence of rural-urban disparities in child nutrition outcomes in developing countries alongside rapid urbanisation and increasing incidence of child malnutrition in urban areas raises an important health policy question - whether fundamentally different nutrition policies and interventions are required in rural and urban areas. Addressing this question requires an enhanced understanding of the main drivers of rural-urban disparities in child nutrition outcomes especially for the vulnerable segments of the population. This study applies recently developed statistical methods to quantify the contribution of different socio-economic determinants to rural-urban differences in child nutrition outcomes in two South Asian countries – Bangladesh and Nepal. Methods Using DHS data sets for Bangladesh and Nepal, we apply quantile regression-based counterfactual decomposition methods to quantify the contribution of (1) the differences in levels of socio-economic determinants (covariate effects) and (2) the differences in the strength of association between socio-economic determinants and child nutrition outcomes (co-efficient effects) to the observed rural-urban disparities in child HAZ scores. The methodology employed in the study allows the covariate and coefficient effects to vary across entire distribution of child nutrition outcomes. This is particularly useful in providing specific insights into factors influencing rural-urban disparities at the lower tails of child HAZ score distributions. It also helps assess the importance of individual determinants and how they vary across the distribution of HAZ scores. Results There are no fundamental differences in the characteristics that determine child nutrition outcomes in urban and rural areas. Differences in the levels of a limited number of socio-economic characteristics – maternal education, spouse’s education and the wealth index (incorporating household asset ownership and access to drinking water and sanitation) contribute a major share of rural-urban disparities in the lowest quantiles of child nutrition outcomes. Differences in the strength of association between socio-economic characteristics and child nutrition outcomes account for less than a quarter of rural-urban disparities at the lower end of the HAZ score distribution. Conclusions Public health interventions aimed at overcoming rural-urban disparities in child nutrition outcomes need to focus principally on bridging gaps in socio-economic endowments of rural and urban households and improving the quality of rural infrastructure. Improving child nutrition outcomes in developing countries does not call for fundamentally different approaches to public health interventions in rural and urban areas

SlowMo, a digital therapy targeting reasoning in paranoia, versus treatment as usual in the treatment of people who fear harm from others: study protocol for a randomised controlled trial

Background: Paranoia is one of the most common symptoms of schizophrenia-spectrum disorders, and is associated with significant distress and disruption to the person’s life. Developing more effective and accessible psychological interventions for paranoia is a clinical priority. Our research team has approached this challenge in two main ways: firstly, by adopting an interventionist causal approach to increase effectiveness and secondly, by incorporating user-centred inclusive design methods to enhance accessibility and usability. Our resultant new digital intervention, SlowMo, intensively targets a reasoning style associated with paranoia, fast thinking, characterised by jumping to conclusions and belief inflexibility. It consists of an easy-to-use, enjoyable and memorable digital interface. An interactive web-based app facilitates delivery of face-to-face meetings which is then synchronised with an innovative mobile app for use in daily life. Methods/Design: We aim to test the clinical efficacy of SlowMo over 24 weeks to determine the mechanisms through which it reduces paranoia, and to identify participant characteristics that moderate its effectiveness. In a parallel-group randomised controlled trial, with 1:1 allocation, 360 participants with distressing persecutory beliefs will be independently randomised to receive either the SlowMo intervention added to treatment as usual (TAU) or TAU, using randomly varying permuted blocks, stratified by paranoia severity and site. Research workers will be blind to therapy allocation. The primary outcome is paranoia severity over 24 weeks; our hypothesised mechanism of change is reasoning; moderators include negative symptoms and working memory; and secondary outcomes include wellbeing, quality of life, and service use. The accessibility, usability and acceptability of the digital platform will be assessed. Discussion: SlowMo has been developed as the first blended digital therapy to target fears of harm from others through an inclusive design approach. In addition to testing its efficacy, this trial will add to our understanding of psychological mechanisms in paranoia. The study will examine the usability and adherence of a novel digital therapy, including an app for self-management, in a large sample of people affected by severe mental health difficulties

Antidepressant-Warfarin Interaction and Associated Gastrointestinal Bleeding Risk in a Case-Control Study

Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users.Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those ≥18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]).Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk