Misidentification subtype of alzheimer's disease psychosis predicts a faster cognitive decline

The presence of psychosis is associated with more rapid decline in Alzheimer's disease (AD), but the impact of paranoid (persecutory delusions) and misidentification (misperceptions and/or hallucinations) subtypes of psychosis on the speed of decline in AD is still unclear. Here we analysed data on Alzheimer's Disease Neuroimaging Initiative (ADNI)2 participants with late mild cognitive impairment or AD and we described individual trajectories of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) scores using a semi-mechanistic, logistic model, with a mixed effects based approach, which accounted for drop-out, and adjusted for baseline Mini Mental State Examination scores. The covariate model included psychosis subtypes, age, gender, education, medications and Apo-e ε4 genotype. We found that ADAS-cog rate of increase was doubled in misidentification (βr,misid_subtype =0.63, p=0.031) and mixed (both subtypes) ((βr,mixed_subtype =0.70, p=0.003) compared to non-psychotic (or paranoid) subjects suggesting that the misidentification subtype may represent a distinct AD sub-phenotype associated with an accelerated pathological process. This article is protected by copyright. All rights reserved

Susceptibility of Larvae of Galleria mellonella to Infection by Asperillus fumigatus is Dependent upon Stage of Conidial Germination

The ability of conidia of the human pathogenic fungus Aspergillus fumigatus to kill larvae of the insect Galleria mellonella was investigated. Conidia at different stages of the germination process displayed variations in their virulence as measured using the Galleria infection model. Non-germinating (ârestingâ) conidia were avirulent except when an inoculation density of 1 à 107 conidia per insect was used. Conidia that had been induced to commence the germination process by pre-culturing in growth medium for 3 h were capable of killing larvae at densities of 1 à 106 and 1 à 107 per insect. An inoculation density of 1 à 105 conidia per insect remained avirulent. Conidia in the outgrowth phase of germination (characterised as the formation of a germ tube) were the most virulent and were capable of killing 100% of larvae after 5 or 24 h when 1 à 107 or 1 à 106 conidia, that had been allowed to germinate for 24 h, were used. Examination of the response of insect haemocytes to conidia at different stages of the germination process established that haemocytes could engulf non-germinating conidia and those in the early stages of the germination process but that conidia, which had reached the outgrowth stages of germination were not phagocytosed. The results presented here indicate that haemocytes of G. mellonella are capable of phagocytosing A. fumigatus conidia less than 3.0 μm in diameter but that conidia greater than this are too large to be engulfed. The virulence of A. fumigatus in G. mellonella larvae can be ascertained within 60â90 h if infection densities of 1 à 106 or 1 à 107 activated conidia (pre-incubated for 2â3 h) per insect are employed

Susceptibility of Larvae of Galleria mellonella to Infection by Asperillus fumigatus is Dependent upon Stage of Conidial Germination

The ability of conidia of the human pathogenic fungus Aspergillus fumigatus to kill larvae of the insect Galleria mellonella was investigated. Conidia at different stages of the germination process displayed variations in their virulence as measured using the Galleria infection model. Non-germinating (ârestingâ) conidia were avirulent except when an inoculation density of 1 à 107 conidia per insect was used. Conidia that had been induced to commence the germination process by pre-culturing in growth medium for 3 h were capable of killing larvae at densities of 1 à 106 and 1 à 107 per insect. An inoculation density of 1 à 105 conidia per insect remained avirulent. Conidia in the outgrowth phase of germination (characterised as the formation of a germ tube) were the most virulent and were capable of killing 100% of larvae after 5 or 24 h when 1 à 107 or 1 à 106 conidia, that had been allowed to germinate for 24 h, were used. Examination of the response of insect haemocytes to conidia at different stages of the germination process established that haemocytes could engulf non-germinating conidia and those in the early stages of the germination process but that conidia, which had reached the outgrowth stages of germination were not phagocytosed. The results presented here indicate that haemocytes of G. mellonella are capable of phagocytosing A. fumigatus conidia less than 3.0 μm in diameter but that conidia greater than this are too large to be engulfed. The virulence of A. fumigatus in G. mellonella larvae can be ascertained within 60â90 h if infection densities of 1 à 106 or 1 à 107 activated conidia (pre-incubated for 2â3 h) per insect are employed

Translocation of proteins homologous to human neutrophil p47phox and p67phox to the cell membrane in activated hemocytes of Galleria mellonella

Activation of the superoxide forming respiratory burst oxidase of human neutrophils, crucial in host defence, requires the cytosolic proteins p47phox and p67phox which translocate to the plasma membrane upon cell stimulation and activate flavocytochrome b558, the redox centre of this enzyme system. We have previously demonstrated the presence of proteins (67 and 47 kDa) in hemocytes of the insect Galleria mellonella homologous to proteins of the superoxide-forming NADPH oxidase complex of neutrophils. The work presented here illustrates for the first time translocation of homologous hemocyte proteins, 67 and 47 kDa from the cytosol to the plasma membrane upon phorbol 12-myristate 13 acetate (PMA)activation. In hemocytes, gliotoxin (GT), the fungal secondary metabolite significantly suppressed PMA-induced superoxide generation in a concentration dependent manner and reduced translocation to basel nonstimulated levels. Primarily these results correlate translocation of hemocyte 47 and 67 kDa proteins with PMA induced oxidase activity. Collectively results presented here, demonstrate further cellular and functional similarities between phagocytes of insects and mammals and further justify the use of insects in place of mammals for modelling the innate immune response to microbial pathogens

Using a meta-ethnographic approach to explore the nature of facilitation and teaching approaches employed in interprofessional education.

BACKGROUND: Interprofessional facilitators and teachers are regarded as central to the effective delivery of interprofessional education (IPE). As the IPE literature continues to expand, most studies have focused on reporting learner outcomes, with little attention paid to IPE facilitation. However, a number of studies have recently emerged reporting on this phenomenon. AIM: To present a synthesis of qualitative evidence on the facilitation of IPE, using a meta-ethnographic approach. METHODS: Electronic databases and journals were searched for the past 10 years. Of the 2164 abstracts initially found, 94 full papers were reviewed and subsequently 12 papers were included. Teams of two reviewers independently completed each step in the review process. The quality of these papers was assessed using a modified critical appraisal checklist. RESULTS: Seven key concepts embedded in the included studies were synthesized into three main factors which provided an insight into the nature of IPE facilitation. Specifically, the synthesis found that IPE facilitation is influenced by "contextual characteristics"; "facilitator experiences"; and the "use of different facilitation strategies". CONCLUSIONS: IPE facilitation is a complex activity affected by contextual, experiential and pedagogical factors. Further research is needed to explore the effects of these factors on the delivery of IPE

Guiding safer risperidone prescribing in Alzheimer's disease with therapeutic drug monitoring

Previous analysis of pharmacokinetic data on risperidone-treated patients with dementia predicted that 20% had concentration-to-dose (C/D) ratios of the active moiety (risperidone and 9-hydroxy(OH)-risperidone) above 14 ng/mL per mg/day, which were in turn associated with a greater risk of extrapyramidal side effects. This study aimed to further explore risperidone pharmacokinetics in a second dataset. Nonlinear mixed effects modelling, using a Bayesian approach, was applied to data from a randomized controlled trial of risperidone in people with dementia. Covariates included age and glomerular filtration rate (GFR). Age had a significant effect on risperidone clearance (β = −1.5) and GFR on 9-OH-risperidone clearance (β = 0.2). The model predicted that 26.2% (95% confidence interval 18.6-32.6%) had C/D ratios above 14 ng/mL per mg/day. These findings confirm the importance of age-related risperidone dose adjustments and argue strongly for therapeutic drug monitoring in the initial stages of treatment to identify those at greatest risk of toxicity

All the Lab's a Stage: the Use of Drama to Promote Engagement in Higher Education Science

Communicating science can be challenging at any educational level. We used informal and experiential learning to engage groups of potential University applicants in one project that involved staging a play in one of the teaching laboratories at the University of Worcester whilst a second project designed a play in house and took this to schools. In the first project the plot centred on stem cell research. School pupils and students from FE Colleges were offered complementary sessions including a lecture exploring the science behind stem cell research, a discussion on ethical aspects involved and a practical using university facilities. We ascertained attitudes to Higher Education in the students participating before and after the event. We found an enhanced view of the science and a highly significant change in attitude to attending University for students taking vocational subjects at FE level. The second project was aimed at exploring attitudes to ethics and animal welfare among a cohort of 15 – 18 year olds. Students engaged with the issues in the drama to a high degree. Our conclusions are that drama is an excellent way to inform potential students about higher education and HE level science in particular. Additionally we demonstrated the importance of events taking place at HE institutions in order to maximise change in attitudes to HE

Innovative Technologies for Human Exploration: Opportunities for Partnerships and Leveraging Novel Technologies External to NASA

Human spaceflight organizations have ambitious goals for expanding human presence throughout the solar system. To meet these goals, spaceflight organizations have to overcome complex technical challenges for human missions to Mars, Near Earth Asteroids, and other distant celestial bodies. Resolving these challenges requires considerable resources and technological innovations, such as advancements in human health and countermeasures for space environments; self-sustaining habitats; advanced power and propulsion systems; and information technologies. Today, government space agencies seek cooperative endeavors to reduce cost burdens, improve human exploration capabilities, and foster knowledge sharing among human spaceflight organizations. This paper looks at potential opportunities for partnerships and spin-ins from economic sectors outside the space industry. It highlights innovative technologies and breakthrough concepts that could have significant impacts on space exploration and identifies organizations throughout the broader economy that specialize in these technologies

A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status

Aims: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and Ndesmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status, and body weight. Methods: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993–2017. Results: There were 17,787 measurements from 5960 patients (4315 male) aged 18 to 86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h-1 between 20 and 80 years. Model based dose predictions to attain a pre-dose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in a nonsmoking White male weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between age 20 and 80 years. Conclusion: The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain a pre-dose plasma clozapine concentration of 0.35 mg L-1. The analysis was however limited by the absence of data on clinical outcome and further studies are required to determine optimal pre-dose concentrations specifically in those aged over 65 years

Increased seed consumption by biological control weevil tempers positive CO\u3csub\u3e2\u3c/sub\u3e effect on invasive plant (\u3ci\u3eCentaurea diffusa\u3c/i\u3e) fitness

Predicted increases in atmospheric CO2 and temperature may benefit some invasive plants, increasing the need for effective invasive plant management. Biological control can be an effective means of managing invasive plants, but the anticipated range in responses of plant–insect interactions to climate change make it difficult to predict how effective biological control will be in the future. Field experiments that manipulate climate within biological control systems could improve predictive power, but are challenging to implement and therefore rare to date. Here, we show that free air CO2 enrichment in the field increased the fitness of Centaurea diffusa Lam., a problematic invader in much of the western United States. However, CO2 enrichment also increased the impact of the biological control agent Larinus minutus (Coleoptera: Curculionidae) on C. diffusa fitness. C. diffusa plants flowered earlier and seed heads developed faster with both elevated CO2 and increased temperature. Natural dispersal of L. minutus into the experimental plots provided a unique opportunity to examine weevil preference for and effects on C. diffusa grown under the different climate change treatments. Elevated CO2 increased both the proportion of seed heads infested by L. minutus and, correspondingly, the amount of seed removed by weevils. Warming had no detectable effect on weevil utilization of plants. Higher weevil densities on elevated CO2 plants reduced, but did not eliminate, the positive effects of CO2 on C. diffusa fitness. Correlations between plant development time and weevil infestation suggest that climate change increased weevil infestation by hastening plant phenology. Phenological mismatches are anticipated with climate change in many plant–insect systems, but in the case of L. minutus and C. diffusa in mixed-grass prairie, a better phenological match may make the biological control agent more effective as CO2 levels rise