Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration

SummaryThe accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer’s disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo

Abundance and species diversity hotspots of tracked marine predators across the North American Arctic

Aim: Climate change is altering marine ecosystems worldwide and is most pronounced in the Arctic. Economic development is increasing leading to more disturbances and pressures on Arctic wildlife. Identifying areas that support higher levels of predator abundance and biodiversity is important for the implementation of targeted conservation measures across the Arctic. Location: Primarily Canadian Arctic marine waters but also parts of the United States, Greenland and Russia. Methods: We compiled the largest data set of existing telemetry data for marine predators in the North American Arctic consisting of 1,283 individuals from 21 species. Data were arranged into four species groups: (a) cetaceans and pinnipeds, (b) polar bears Ursus maritimus (c) seabirds, and (d) fishes to address the following objectives: (a) to identify abundance hotspots for each species group in the summer–autumn and winter–spring; (b) to identify species diversity hotspots across all species groups and extent of overlap with exclusive economic zones; and (c) to perform a gap analysis that assesses amount of overlap between species diversity hotspots with existing protected areas. Results: Abundance and species diversity hotpots during summer–autumn and winter–spring were identified in Baffin Bay, Davis Strait, Hudson Bay, Hudson Strait, Amundsen Gulf, and the Beaufort, Chukchi and Bering seas both within and across species groups. Abundance and species diversity hotpots occurred within the continental slope in summer–autumn and offshore in areas of moving pack ice in winter–spring. Gap analysis revealed that the current level of conservation protection that overlaps species diversity hotspots is low covering only 5% (77,498 km 2 ) in summer–autumn and 7% (83,202 km 2 ) in winter–spring. Main conclusions: We identified several areas of potential importance for Arctic marine predators that could provide policymakers with a starting point for conservation measures given the multitude of threats facing the Arctic. These results are relevant to multilevel and multinational governance to protect this vulnerable ecosystem in our rapidly changing world

The Democratic Biopolitics of PrEP

PrEP (Pre-Exposure Prophylaxis) is a relatively new drug-based HIV prevention technique and an important means to lower the HIV risk of gay men who are especially vulnerable to HIV. From the perspective of biopolitics, PrEP inscribes itself in a larger trend of medicalization and the rise of pharmapower. This article reconstructs and evaluates contemporary literature on biopolitical theory as it applies to PrEP, by bringing it in a dialogue with a mapping of the political debate on PrEP. As PrEP changes sexual norms and subjectification, for example condom use and its meaning for gay subjectivity, it is highly contested. The article shows that the debate on PrEP can be best described with the concepts ‘sexual-somatic ethics’ and ‘democratic biopolitics’, which I develop based on the biopolitical approach of Nikolas Rose and Paul Rabinow. In contrast, interpretations of PrEP which are following governmentality studies or Italian Theory amount to either farfetched or trivial positions on PrEP, when seen in light of the political debate. Furthermore, the article is a contribution to the scholarship on gay subjectivity, highlighting how homophobia and homonormativity haunts gay sex even in liberal environments, and how PrEP can serve as an entry point for the destigmatization of gay sexuality and transformation of gay subjectivity. ‘Biopolitical democratization’ entails making explicit how medical technology and health care relates to sexual subjectification and ethics, to strengthen the voice of (potential) PrEP users in health politics, and to renegotiate the profit and power of Big Pharma

Pharmacological Evaluation of the Long-Term Effects of Xanomeline on the M1 Muscarinic Acetylcholine Receptor

Xanomeline is a unique agonist of muscarinic receptors that possesses functional selectivity at the M1 and M4 receptor subtypes. It also exhibits wash-resistant binding to and activation of the receptor. In the present work we investigated the consequences of this type of binding of xanomeline on the binding characteristics and function of the M1 muscarinic receptor. Pretreatment of CHO cells that stably express the M1 receptor for 1 hr with increasing concentrations of xanomeline followed by washing and waiting for an additional 23 hr in control culture media transformed xanomeline-induced inhibition of [3H]NMS binding from monophasic to biphasic. The high-affinity xanomeline binding site exhibited three orders of magnitude higher affinity than in the case of xanomeline added directly to the binding assay medium containing control cells. These effects were associated with a marked decrease in maximal radioligand binding and attenuation of agonist-induced increase in PI hydrolysis and were qualitatively similar to those caused by continuous incubation of cells with xanomeline for 24 hr. Attenuation of agonist-induced PI hydrolysis by persistently-bound xanomeline developed with a time course that parallels the return of receptor activation by prebound xanomeline towards basal levels. Additional data indicated that blockade of the receptor orthosteric site or the use of a non-functional receptor mutant reversed the long-term effects of xanomeline, but not its persistent binding at an allosteric site. Furthermore, the long-term effects of xanomeline on the receptor are mainly due to receptor down-regulation rather than internalization

Respiratory syncytial, parainfluenza and influenza virus infection in young children with acute lower respiratory infection in rural Gambia.

Respiratory viral infections contribute significantly to morbidity and mortality worldwide, but representative data from sub-Saharan Africa are needed to inform vaccination strategies. We conducted population-based surveillance in rural Gambia using standardized criteria to identify and investigate children with acute lower respiratory infection (ALRI). Naso- and oropharyngeal swabs were collected. Each month from February through December 2015, specimens from 50 children aged 2-23 months were randomly selected to test for respiratory syncytial (RSV), parainfluenza (PIV) and influenza viruses. The expected number of viral-associated ALRI cases in the population was estimated using statistical simulation that accounted for the sampling design. RSV G and F proteins and influenza hemagglutinin genes were sequenced. 2385 children with ALRI were enrolled, 519 were randomly selected for viral testing. One or more viruses were detected in 303/519 children (58.4%). RSV-A was detected in 237 and RSV-B in seven. The expected incidence of ALRI associated with RSV, PIV or influenza was 140 cases (95% CI, 131-149) per 1000 person-years; RSV incidence was 112 cases (95% CI, 102-122) per 1000 person-years. Multiple strains of RSV and influenza circulated during the year. RSV circulated throughout most of the year and was associated with eight times the number of ALRI cases compared to PIV or IV. Gambian RSV viruses were closely related to viruses detected in other continents. An effective RSV vaccination strategy could have a major impact on the burden of ALRI in this setting

INTroducing A Care bundle To prevent pressure injury (INTACT) in at-risk patients: A protocol for a cluster randomised trial

Background Pressure injuries are a significant clinical and economic issue, affecting both patients and the health care system. Many pressure injuries in hospitals are facility acquired, and are largely preventable. Despite growing evidence and directives for pressure injury prevention, implementation of preventative strategies is suboptimal, and pressure injuries remain a serious problem in hospitals. Objectives This study will test the effectiveness and cost-effectiveness of a patient-centred pressure injury prevention care bundle on the development of hospital acquired pressure injury in at-risk patients. Design This is a multi-site, parallel group cluster randomised trial. The hospital is the unit of randomisation. Methods Adult medical and surgical patients admitted to the study wards of eight hospitals who are (a) deemed to be at risk of pressure injury (i.e. have reduced mobility), (b) expected to stay in hospital for ≥48 h, (c) admitted to hospital in the past 36 h; and (d) able to provide informed consent will be eligible to participate. Consenting patients will receive either the pressure injury prevention care bundle or standard care. The care bundle contains three main messages: (1) keep moving; (2) look after your skin; and (3) eat a healthy diet. Nurses will receive education about the intervention. Patients will exit the study upon development of a pressure injury, hospital discharge or 28 days, whichever comes first; transfer to another hospital or transfer to critical care and mechanically ventilated. The primary outcome is incidence of hospital acquired pressure injury. Secondary outcomes are pressure injury stage, patient participation in care and health care costs. A health economic sub-study and a process evaluation will be undertaken alongside the trial. Data will be analysed at the cluster (hospital) and patient level. Estimates of hospital acquired pressure injury incidence in each group, group differences and 95% confidence interval and p values will be reported. Discussion To our knowledge, this is the first trial of an intervention to incorporate a number of pressure injury prevention strategies into a care bundle focusing on patient participation and nurse–patient partnership. The results of this study will provide important information on the effectiveness and cost-effectiveness of this intervention in preventing pressure injuries in at-risk patients. If the results confirm the utility of the developed care bundle, it could have a significant impact on clinical practice worldwide

International pooled study on diet and bladder cancer: The bladder cancer, epidemiology and nutritional determinants (BLEND) study: Design and baseline characteristics

In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7th most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage

Organisational and student characteristics, fidelity, funding models, and unit costs of recovery colleges in 28 countries:a cross-sectional survey

Background: Recovery colleges were developed in England to support the recovery of individuals who have mental health symptoms or mental illness. They have been founded in many countries but there has been little international research on recovery colleges and no studies investigating their staffing, fidelity, or costs. We aimed to characterise recovery colleges internationally, to understand organisational and student characteristics, fidelity, and budget. Methods: In this cross-sectional study, we identified all countries in which recovery colleges exist. We repeated a cross-sectional survey done in England for recovery colleges in 28 countries. In both surveys, recovery colleges were defined as services that supported personal recovery, that were coproduced with students and staff, and where students learned collaboratively with trainers. Recovery college managers completed the survey. The survey included questions about organisational and student characteristics, fidelity to the RECOLLECT Fidelity Measure, funding models, and unit costs. Recovery colleges were grouped by country and continent and presented descriptively. We used regression models to explore continental differences in fidelity, using England as the reference group. Findings: We identified 221 recovery colleges operating across 28 countries, in five continents. Overall, 174 (79%) of 221 recovery colleges participated. Most recovery colleges scored highly on fidelity. Overall scores for fidelity (β=–2·88, 95% CI 4·44 to –1·32; p=0·0001), coproduction (odds ratio [OR] 0·10, 95% CI 0·03 to 0·33; p&lt;0·0001), and being tailored to the student (OR 0·10, 0·02 to 0·39; p=0·0010), were lower for recovery colleges in Asia than in England. No other significant differences were identified between recovery colleges in England, and those in other continents where recovery colleges were present. 133 recovery colleges provided data on annual budgets, which ranged from €0 to €2 550 000, varying extensively within and between continents. From included data, all annual budgets reported by the college added up to €30 million, providing 19 864 courses for 55 161 students. Interpretation: Recovery colleges exist in many countries. There is an international consensus on key operating principles, especially equality and a commitment to recovery, and most recovery colleges achieve moderate to high fidelity to the original model, irrespective of the income band of their country. Cultural differences need to be considered in assessing coproduction and approaches to individualising support. Funding: National Institute for Health and Care Research.</p