A Scoping Survey to Inform Design of Digital Dementia Risk Reduction Interventions for Adults Concerned about their Cognitive Health

Background: Digital dementia risk reduction interventions are cost-effective and scalable. However, it is unknown how they are perceived by people already experiencing cognitive concerns or decline. Objective: To understand the current use, interest, and preferences for online learning courses and interest in learning about factors influencing brain health and dementia risk among adults ≥45. To explore potential differences between individuals experiencing cognitive concerns and those without. Methods: Adults aged 45 and older completed a survey on technology use and healthy ageing (n = 249, Mean age = 65.6, 76.3% female). The Memory Assessment Clinic-Questionnaire was used to assess subjective memory decline, and 153 participants met the study criteria for cognitive concerns (≥25). Results: Almost all participants (98.4%) reported using two or more digital devices, and 51.8% reported increasing device usage following COVID-19. Most (92.1%) were interested in learning about healthy living and memory within an online course, and over 80% indicated a high interest in learning about dementia risk factors. People with cognitive concerns were more likely to report using a 'routine or system' to aid memory than people without (82.4% versus 62.9%, p = 0.001). However, no significant difference was found in technology use, course preferences, or interest in learning about different risk factors. Conclusions: We conclude that adults 45 years and over are interested in online methods for learning about brain health and offer unique insights into adapting dementia prevention programs for cognitive concerns

MyCOACH (COnnected Advice for Cognitive Health): a digitally delivered multidomain intervention for cognitive decline and risk of dementia in adults with mild cognitive impairment or subjective cognitive decline–study protocol for a randomised controlled trial

Introduction Digital health interventions are cost-effective and easily accessible, but there is currently a lack of effective online options for dementia prevention especially for people at risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Methods and analysis MyCOACH (COnnected Advice for Cognitive Health) is a tailored online dementia risk reduction programme for adults aged ≥65 living with MCI or SCD. The MyCOACH trial aims to evaluate the programme’s effectiveness in reducing dementia risk compared with an active control over a 64-week period (N=326). Eligible participants are randomly allocated to one of two intervention arms for 12 weeks: (1) the MyCOACH intervention programme or (2) email bulletins with general healthy ageing information (active control). The MyCOACH intervention programme provides participants with information about memory impairments and dementia, memory strategies and different lifestyle factors associated with brain ageing as well as practical support including goal setting, motivational interviewing, brain training, dietary and exercise consultations, and a 26-week post-intervention booster session. Follow-up assessments are conducted for all participants at 13, 39 and 65 weeks from baseline, with the primary outcome being exposure to dementia risk factors measured using the Australian National University-Alzheimer’s Disease Risk Index. Secondary measures include cognitive function, quality of life, functional impairment, motivation to change behaviour, self-efficacy, morale and dementia literacy. Ethics and dissemination Ethical approval was obtained from the University of New South Wales Human Research Ethics Committee (HC210012, 19 February 2021). The results of the study will be disseminated in peer-reviewed journals and research conferences

Ectopic A-lattice seams destabilize microtubules

Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe

Unification of New Zealand's local vertical datums: iterative gravimetric quasigeoid computations

New Zealand uses 13 separate local vertical datums (LVDs) based on normal-orthometric-corrected precise geodetic levelling from 12 different tide-gauges. We describe their unification using a regional gravimetric quasigeoid model and GPS-levelling data on each LVD. A novel application of iterative quasigeoid computation is used, where the LVD offsets computed from earlier models are used to apply additional gravity reductions from each LVD to that model. The solution converges after only three iterations yielding LVD offsets ranging from 0.24 m to 0.58 m with an average standard deviation of 0.08 m. The so-computed LVD offsets agree, within expected data errors, with geodetically levelled height differences at common benchmarks between adjacent LVDs. This shows that iterated quasigeoid models do have a role in vertical datum unification

Endometrial cells sense and react to tissue damage during infection of the bovine endometrium via interleukin 1

Cells generate inflammatory responses to bacteria when pattern recognition receptors bind pathogen-associated molecules such as lipopolysaccharide. Cells may also respond to tissue damage by sensing damage-associated molecules. Postpartum bacterial infections of the bovine uterus cause endometritis but the risk of disease is increased by tissue trauma triggered by dystocia. Animals that suffered dystocia had increased concentrations of inflammatory mediators IL-8, IL-1β and IL-1α in vaginal mucus 3 weeks postpartum, but they also had more bacteria than normal animals. Ex vivo organ cultures of endometrium, endometrial cells and peripheral blood monocytes did not generate inflammatory responses to prototypical damage molecules, HMGB1 or hyaluronan, or to necrotic cells; although they secreted IL-6 and IL-8 in a concentration-dependent manner when treated with IL-1α. However, necrotic endometrial cells did not accumulate intracellular IL-1α or release IL-1α, except when pre-treated with lipopolysaccharide or bacteria. Endometrial cell inflammatory responses to IL-1α were dependent on the cognate receptor IL-1R1, and the receptor adaptor protein MyD88, and the inflammatory response to IL-1α was independent of the response to lipopolysaccharide. Rather than a typical damage-associated molecule, IL-1α acts to scale the inflammatory response in recognition that there is a combination of pathogen challenge followed by endometrial cell damage

Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin

Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO. We first verified that depleting cellular cholesterol with methyl-β-cyclodextrin increased the resilience of stromal cells to PLO. We then used siRNA to deplete mevalonate pathway enzyme gene expression, and used pharmaceutical inhibitors, atorvastatin, alendronate or zaragozic acid to inhibit the activity of HMGCR, FDPS and FDFT1, respectively. These approaches successfully reduced cellular cholesterol abundance, but mevalonate pathway enzymes did not affect cellular resilience equally. Inhibiting FDFT1 was most effective, with zaragozic acid reducing the impact of PLO on cell viability. The present study provides evidence that inhibiting FDFT1 increases stromal cell resilience to a cholesterol-dependent cytolysin

Angiographic correlations of patients with small vessel disease diagnosed by adenosine-stress cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging (CMR) with adenosine-stress myocardial perfusion is gaining importance for the detection and quantification of coronary artery disease (CAD). However, there is little knowledge about patients with CMR-detected ischemia, but having no relevant stenosis as seen on coronary angiography (CA). The aims of our study were to characterize these patients by CMR and CA and evaluate correlations and potential reasons for the ischemic findings. 73 patients with an indication for CA were first scanned on a 1.5T whole-body CMR-scanner including adenosine-stress first-pass perfusion. The images were analyzed by two independent investigators for myocardial perfusion which was classified as subendocardial ischemia (n = 22), no perfusion deficit (n = 27, control 1), or more than subendocardial ischemia (n = 24, control 2). All patients underwent CA, and a highly significant correlation between the classification of CMR perfusion deficit and the degree of coronary luminal narrowing was found. For quantification of coronary blood flow, corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) was evaluated for the left anterior descending (LAD), circumflex (LCX) and right coronary artery (RCA). The main result was that corrected TFC in all coronaries was significantly increased in study patients compared to both control 1 and to control 2 patients. Study patients had hypertension or diabetes more often than control 1 patients. In conclusion, patients with CMR detected subendocardial ischemia have prolonged coronary blood flow. In connection with normal resting flow values in CAD, this supports the hypothesis of underlying coronary microvascular impairment. CMR stress perfusion differentiates non-invasively between this entity and relevant CAD

Extended Field Laser Confocal Microscopy (EFLCM): Combining automated Gigapixel image capture with in silico virtual microscopy

<p>Abstract</p> <p>Background</p> <p>Confocal laser scanning microscopy has revolutionized cell biology. However, the technique has major limitations in speed and sensitivity due to the fact that a single laser beam scans the sample, allowing only a few microseconds signal collection for each pixel. This limitation has been overcome by the introduction of parallel beam illumination techniques in combination with cold CCD camera based image capture.</p> <p>Methods</p> <p>Using the combination of microlens enhanced Nipkow spinning disc confocal illumination together with fully automated image capture and large scale <it>in silico </it>image processing we have developed a system allowing the acquisition, presentation and analysis of maximum resolution confocal panorama images of several Gigapixel size. We call the method Extended Field Laser Confocal Microscopy (EFLCM).</p> <p>Results</p> <p>We show using the EFLCM technique that it is possible to create a continuous confocal multi-colour mosaic from thousands of individually captured images. EFLCM can digitize and analyze histological slides, sections of entire rodent organ and full size embryos. It can also record hundreds of thousands cultured cells at multiple wavelength in single event or time-lapse fashion on fixed slides, in live cell imaging chambers or microtiter plates.</p> <p>Conclusion</p> <p>The observer independent image capture of EFLCM allows quantitative measurements of fluorescence intensities and morphological parameters on a large number of cells. EFLCM therefore bridges the gap between the mainly illustrative fluorescence microscopy and purely quantitative flow cytometry. EFLCM can also be used as high content analysis (HCA) instrument for automated screening processes.</p

Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium

Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity