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

Cardiac cell modelling: observations from the heart of the cardiac physiome project

In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field

Geologic controls on hydraulic conductivity in a karst-influenced carbonate bedrock groundwater system in southern Ontario, Canada

A large set of hydraulic conductivity values has been integrated with the geologic characterization of a Paleozoic-age carbonate groundwater system to assess the relative influence of specific geologic features on hydraulic conductivity. Three geologic controls are investigated: (1) proximity to bedrock valleys within a regional stress field; (2) carbonate rock texture; and (3) sequence stratigraphic breaks. Results demonstrate that high hydraulic conductivity values do not correlate with a single geological feature, but are associated with various features that have been enhanced by carbonate dissolution. Predicting the spatial distribution of hydraulic conductivity in carbonate rocks requires a regional understanding of the geological history with a conceptualization of where and when waters have interacted with the rocks to dissolve and enhance porosity through geologic time. This investigation focused on a region in southern Ontario, Canada, and concludes with a map identifying the area with the greatest probability of encountering high hydraulic conductivities in the main hydrostratigraphic unit, the Gasport Formation. The map supports the selection of groundwater resource exploration targets for a local municipality. Beyond the local benefits of this work, this investigation offers an approach that can be adopted by practitioners exploring for bedrock groundwater resources or characterizing contaminant transport pathways in complex karst-influenced, carbonate bedrock groundwater systems

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium

Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.; We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.; rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.; This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways