A Pyrrole-Based Triazolium-Phane with Nh and Cationic Ch Donor Groups as a Receptor for Tetrahedral Oxyanions that Functions in Polar Media

The pyrrole-based triazolium-phane 1(4+)center dot 4BF(4)(-) has been prepared via the tetraalkylation of a macrocycle originally prepared via click chemistry. It displays a high selectivity for tetrahedral oxyanions relative to various test monoanions and trigonal planar anions in mixed polar organic-aqueous media. This selectivity is solvent dependent and is less pronounced in acetonitrile. Theoretical calculations were carried out in with the chloride anion in an effort to understand the influence of solvent on the intrinsic hydrogen bonding ability of the donor groups (pyrrole N-H, benzene C-H and triazolium C-H). The host-guest interactions between receptor 1(4+)center dot 4BF(4)(-) and representative tetrahedral oxyanions were further analysed by H-1 NMR spectroscopy, and the findings proved consistent with the differences in the intrinsic strength of the various H-bond donor groups inferred from the electronic structure calculations carried out in methanol, namely that (CH)(+)-anion interactions are less important in an energetic sense than neutral CH-anion interactions in polar media. Single crystal X-ray diffraction analyses of the mixed salts 1(4+)center dot HP2O73-center dot BF4- and 31(4+)center dot 4H(2)PO(4)(-)center dot 8BF(4)(-) confirmed that receptor 1(4+) can bind the pyrophosphate and phosphate anions in the solid state.Cai, Jiajia, Benjamin P. Hay, Neil J. Young, Xiaoping Yang, and Jonathan L. Sessler. "A pyrrole-based triazolium-phane with NH and cationic CH donor groups as a receptor for tetrahedral oxyanions that functions in polar media." Chemical Science 4, no. 4 (Jan., 2013): 1560-1567.Chemistr

Characterization and Comparison of Mesoporous Silica Particles for Optimized Drug Delivery

In this study we have investigated the suitability of a number of different mesoporous silica nanoparticle structures for carrying a drug cargo. We have fully characterized the nanoparticles in terms of their physical parameters; size, surface area, internal pore size and structure. These data are all required if we are to make an informed judgement on the suitability of the structure for drug delivery in vivo. With these parameters in mind, we investigated the loading/unloading profile of a model therapeutic into the pore structure of the nanoparticles. We demonstrate that the release can be controlled by capping the pores on the nanoparticles to achieve temporal control of the unloading. We have also examined the rate and mechanism of the degradation of the nanoparticles over an extended period of time. The eventual dissolution of the nanoparticles after cargo release is a desirable property for a drug delivery system

Disease Knowledge Transfer across Neurodegenerative Diseases

We introduce Disease Knowledge Transfer (DKT), a novel technique for transferring biomarker information between related neurodegenerative diseases. DKT infers robust multimodal biomarker trajectories in rare neurodegenerative diseases even when only limited, unimodal data is available, by transferring information from larger multimodal datasets from common neurodegenerative diseases. DKT is a joint-disease generative model of biomarker progressions, which exploits biomarker relationships that are shared across diseases. Our proposed method allows, for the first time, the estimation of plausible, multimodal biomarker trajectories in Posterior Cortical Atrophy (PCA), a rare neurodegenerative disease where only unimodal MRI data is available. For this we train DKT on a combined dataset containing subjects with two distinct diseases and sizes of data available: 1) a larger, multimodal typical AD (tAD) dataset from the TADPOLE Challenge, and 2) a smaller unimodal Posterior Cortical Atrophy (PCA) dataset from the Dementia Research Centre (DRC), for which only a limited number of Magnetic Resonance Imaging (MRI) scans are available. Although validation is challenging due to lack of data in PCA, we validate DKT on synthetic data and two patient datasets (TADPOLE and PCA cohorts), showing it can estimate the ground truth parameters in the simulation and predict unseen biomarkers on the two patient datasets. While we demonstrated DKT on Alzheimer's variants, we note DKT is generalisable to other forms of related neurodegenerative diseases. Source code for DKT is available online: https://github.com/mrazvan22/dkt.Comment: accepted at MICCAI 2019, 13 pages, 5 figures, 2 table

Impact and Experiences Relative to Critical Incidents and Critical Incident Stress Management

Purpose: Typically, athletic trainers (ATs) have relied on external support networks to debrief after a critical incident (CI). ATs report focusing on improving work-related processes after a CI rather than their emotional response to the CI. The purpose of this study was to identify both the short-term emotional impacts of CIs and what coping strategies ATs use to address their emotional response to CIs. Methods: We used a cross-sectional, web-based survey, distributed to a random sample of NATA members to explore the perceived effects of CIs on ATs. Participants (n=73, 36±11y) were primarily women (n=53, 72.6%), working in the college/university practice setting (n = 40, 54.8%), with 7±3y of experience. All participants experienced a CI within the previous 12 months. The data were analyzed using descriptive statistics for demographic variables and multi-analyst inductive coding for the open-ended items amongst a 4-person team. We used a modified consensual qualitative research (CQR) process to review and analyze the open-ended questions and identify domains and core ideas. Trustworthiness was established with multi-analyst triangulation and auditing. Results: Participants most commonly reported feelings of thinking too much (71%, n=52), anxiety (63%, n=46), sadness (60%, n=44), fatigue (53%, n=39), and sleep disturbance (49%, n=36) resulting from CIs. Common coping strategies used were exercise (63%, n=46), humor (44%, n=32), interacting with pets (41%, n=30), expressing oneself through crying (40%, n=29), and peer support (34%, n=25). Sixty-two participants (86%) responded to open-ended questions related to the outcomes of CIs. Four domains were identified from the open-ended responses. Those domains included 1) dissociation, 2) deteriorated emotional state, 3) disruption of daily activities, and 4) improved event or post-event processes. Conclusion: Various strategies are used by ATs to cope with CIs; however, the only ways in which ATs expressed that coping helped was with care delivery, not the emotional impact of the CI. The lack of responses relative to coping strategies that improve quality of life is potentially alarming. To build resilience and persistence, organizations should consider requiring support beyond process improvement that addresses the emotional impact of CIs

Biocompatibility and Physiological Thiolytic Degradability of Radically Made Thioester-Functional Copolymers: Opportunities for Drug Release

Being nondegradable, vinyl polymers have limited biomedical applicability. Unfortunately, backbone esters incorporated through conventional radical ring-opening methods do not undergo appreciable abiotic hydrolysis under physiologically relevant conditions. Here, PEG acrylate and di(ethylene glycol) acrylamide-based copolymers containing backbone thioesters were prepared through the radical ring-opening copolymerization of the thionolactone dibenzo[c,e]oxepin-5(7H)-thione. The thioesters degraded fully in the presence of 10 mM cysteine at pH 7.4, with the mechanism presumed to involve an irreversible S–N switch. Degradations with N-acetylcysteine and glutathione were reversible through the thiol–thioester exchange polycondensation of R–SC(═O)–polymer–SH fragments with full degradation relying on an increased thiolate/thioester ratio. Treatment with 10 mM glutathione at pH 7.2 (mimicking intracellular conditions) triggered an insoluble–soluble switch of a temperature-responsive copolymer at 37 °C and the release of encapsulated Nile Red (as a drug model) from core-degradable diblock copolymer micelles. Copolymers and their cysteinolytic degradation products were found to be noncytotoxic, making thioester backbone-functional polymers promising for drug delivery applications

The EX-FRAIL CKD Trial: a study protocol for a pilot randomised controlled trial of a home-based EXercise programme for pre-FRAIL and FRAIL, older adults with Chronic Kidney Disease

Introduction Frailty is highly prevalent in adults with chronic kidney disease (CKD) and is associated with adverse health outcomes including falls, poorer health-related quality of life (HRQOL), hospitalisation and mortality. Low physical activity and muscle wasting are important contributors to physical frailty in adults with CKD. Exercise training may improve physical function and frailty status leading to associated improvements in health outcomes, including HRQOL. The EX-FRAIL CKD trial aims to inform the design of a definitive randomised controlled trial (RCT) that investigates the effectiveness of a progressive, multi-component home-based exercise programme in pre-frail and frail older adults with CKD. Methods and Analysis The EX-FRAIL CKD trial is a two-arm parallel group pilot RCT. Participants categorised as pre-frail or frail, following Frailty Phenotype assessment, will be randomised to receive exercise or usual care. Participants randomised to the intervention arm will receive a tailored 12-week exercise programme, which includes weekly telephone calls to advise on exercise progression. Primary feasibility outcome measures include rate of recruitment, intervention adherence, outcome measure completion and participant attrition. Semi-structured interviews with a purposively selected group of participants will inform the feasibility of the randomisation procedures, outcome measures and intervention. Secondary outcome measures include physical function (walking speed and Short Physical Performance Battery), frailty status (Frailty Phenotype), fall concern (Falls Efficacy Scale-International tool), activities of daily living (Barthel Index), symptom-burden (Palliative Care Outcome Scale-Symptoms RENAL) and HRQOL (Short Form-12v2). Ethics and Dissemination Ethical approval was granted by a National Health Service (NHS) Regional Ethics Committee and the NHS Health Research Authority. The study team aim to publish findings in a peer-reviewed journal and present the results at relevant national and international conferences. A summary of findings will be provided to participants, a local kidney patient charity and the funding body

Linking global drivers of agricultural trade to on-the-ground impacts on biodiversity.

Consumption of globally traded agricultural commodities like soy and palm oil is one of the primary causes of deforestation and biodiversity loss in some of the world's most species-rich ecosystems. However, the complexity of global supply chains has confounded efforts to reduce impacts. Companies and governments with sustainability commitments struggle to understand their own sourcing patterns, while the activities of more unscrupulous actors are conveniently masked by the opacity of global trade. We combine state-of-the-art material flow, economic trade, and biodiversity impact models to produce an innovative approach for understanding the impacts of trade on biodiversity loss and the roles of remote markets and actors. We do this for the production of soy in the Brazilian Cerrado, home to more than 5% of the world´s species. Distinct sourcing patterns of consumer countries and trading companies result in substantially different impacts on endemic species. Connections between individual buyers and specific hot spots explain the disproportionate impacts of some actors on endemic species and individual threatened species, such as the particular impact of European Union consumers on the recent habitat losses for the iconic giant anteater (Myrmecophaga tridactyla). In making these linkages explicit, our approach enables commodity buyers and investors to target their efforts much more closely to improve the sustainability of their supply chains in their sourcing regions while also transforming our ability to monitor the impact of such commitments over time.UK Global Food Security programme (Project 304 BB/N02060X/1

Data-driven models of dominantly-inherited Alzheimer’s disease progression

Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease-progression modelling to characterise dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset (EYO). We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers: 163 PSEN1; 17 PSEN2; and 31 APP) and a baseline visit (age 19–66; up to four visits each, 1·1±1·9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential-equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then sub-cortical regions (approximately 24±11 years before onset); CSF p-tau (17±8 years), tau and Aβ42 changes; neurodegeneration first in the putamen and nucleus accumbens (up to 6±2 years); then cognitive decline (7±6 years), cerebral hypometabolism (4±4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than EYO: root-mean-squared error of 1·35 years versus 5·54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials

A data-driven study of Alzheimer's disease related amyloid and tau pathology progression

Amyloid-beta is thought to facilitate the spread of tau throughout the neocortex in Alzheimer's disease, though how this occurs is not well understood. This is because of the spatial discordance between amyloid-beta, which accumulates in the neocortex, and tau, which accumulates in the medial temporal lobe during aging. There is evidence that in some cases amyloid-beta-independent tau spreads beyond the medial temporal lobe where it may interact with neocortical amyloid-beta. This suggests that there may be multiple distinct spatiotemporal subtypes of Alzheimer's-related protein aggregation, with potentially different demographic and genetic risk profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post-mortem neuropathology and in vivo PET based measures from two large observational studies: the Alzheimer's Disease Neuroimaging Initiative and the Religious Orders Study and Rush Memory and Aging Project. We consistently identified 'amyloid-first' and 'tau-first' subtypes using cross-sectional information from both studies. In the amyloid-first subtype, extensive neocortical amyloid-beta precedes the spread of tau beyond the medial temporal lobe, while in the tau-first subtype mild tau accumulates in medial temporal and neocortical areas prior to interacting with amyloid-beta. As expected, we found a higher prevalence of the amyloid-first subtype among apolipoprotein E (APOE) ε4 allele carriers while the tau-first subtype was more common among APOE ε4 non-carriers. Within tau-first APOE ε4 carriers, we found an increased rate of amyloid-beta accumulation (via longitudinal amyloid PET), suggesting that this rare group may belong within the Alzheimer's disease continuum. We also found that tau-first APOE ε4 carriers had several fewer years of education than other groups, suggesting a role for modifiable risk factors in facilitating amyloid-beta-independent tau. Tau-first APOE ε4 non-carriers, in contrast, recapitulated many of the features of Primary Age-related Tauopathy. The rate of longitudinal amyloid-beta and tau accumulation (both measured via PET) within this group did not differ from normal aging, supporting the distinction of Primary Age-related Tauopathy from Alzheimer's disease. We also found reduced longitudinal subtype consistency within tau-first APOE ε4 non-carriers, suggesting additional heterogeneity within this group. Our findings support the idea that amyloid-beta and tau may begin as independent processes in spatially disconnected regions, with widespread neocortical tau resulting from the local interaction of amyloid-beta and tau. The site of this interaction may be subtype-dependent: medial temporal lobe in amyloid-first, neocortex in tau-first. These insights into the dynamics of amyloid-beta and tau may inform research and clinical trials that target these pathologies

Characterization of Ordering in A-Site Deficient Perovskite Ca1-xLa2x/3TiO3 Using STEM/EELS

The vacancy ordering behavior of an A-site deficient perovskite system, Ca1-xLa2x/3TiO3, was studied using atomic resolution scanning transmission electron microscopy (STEM) in conjunction with electron energy-loss spectroscopy (EELS), with the aim of determining the role of A-site composition changes. At low La content (x = 0.2), adopting Pbnm symmetry, there was no indication of long-range ordering. Domains, with clear boundaries, were observed in bright-field (BF) imaging, but were not immediately visible in the corresponding high-angle annular dark-field (HAADF) image. These boundaries, with the aid of displacement maps from A-site cations in the HAADF signal, are shown to be tilt boundaries. At the La-rich end of the composition (x = 0.9), adopting Cmmm symmetry, long-range ordering of vacancies and La3+ ions was observed, with alternating La-rich and La-poor layers on (001)p planes, creating a double perovskite lattice along the c axis. These highly ordered domains can be found isolated within a random distribution of vacancies/La3+, or within a large population, encompassing a large volume. In regions with a high number density of double perovskite domains, these highly ordered domains were separated by twin boundaries, with 90° or 180° lattice rotations across boundaries. The occurrence and characteristics of these ordered structures are discussed and compared with similar perovskite systems