Nanopore‐Based, Rapid Characterization of Individual Amyloid Particles in Solution: Concepts, Challenges, and Prospects

Aggregates of misfolded proteins are associated with several devastating neurodegenerative diseases. These so‐called amyloids are therefore explored as biomarkers for the diagnosis of dementia and other disorders, as well as for monitoring disease progression and assessment of the efficacy of therapeutic interventions. Quantification and characterization of amyloids as biomarkers is particularly demanding because the same amyloid‐forming protein can exist in different states of assembly, ranging from nanometer‐sized monomers to micrometer‐long fibrils that interchange dynamically both in vivo and in samples from body fluids ex vivo. Soluble oligomeric amyloid aggregates, in particular, are associated with neurotoxic effects, and their molecular organization, size, and shape appear to determine their toxicity. This concept article proposes that the emerging field of nanopore‐based analytics on a single molecule and single aggregate level holds the potential to account for the heterogeneity of amyloid samples and to characterize these particles—rapidly, label‐free, and in aqueous solution—with regard to their size, shape, and abundance. The article describes the concept of nanopore‐based resistive pulse sensing, reviews previous work in amyloid analysis, and discusses limitations and challenges that will need to be overcome to realize the full potential of amyloid characterization on a single‐particle level.Information about amyloid aggregation states is critical to understanding the pathological progression of many neurodegenerative diseases. Resistive pulse‐based nanopore sensing is a unique single‐molecule approach to studying these aggregation states because it can determine information about individual amyloids, oligomeric species, or fibrils in an aqueous solution without fluorescent labels or chemical modifications.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146577/1/smll201802412_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146577/2/smll201802412.pd

The origin of pine pollen grains captured from air at Calypsobyen, Svalbard

Spitsbergen is the largest island in the Svalbard Archipelago (Norway) that has been permanently populated. The harsh Arctic climate prevents development of large vascular plants such as trees. A two-year aerobiological survey was conducted within the framework of two consecutive polar expeditions (2014 and 2015) in Spitsbergen (Calypsobyen, Bellsund). The air quality was measured continuously from June/July to August using a 7-day volumetric air sampler, Tauber trap and moss specimens. Collected air samples and gravimetric pollen deposits were processed following transfer to sterile laboratory conditions and analyzed with the aid of light microscopy. Days when pine pollen grains were detected in the air were selected for further analysis. Clusters of back-trajectories, computed using the Hybrid Single Particle Lagrangian Integrated Trajectory model in combination with ArcGIS software as well as the Flextra trajectory model, showed the movement of air masses to the sampling location at Hornsund, and thus indicated the likely origin of pollen grains. The GlobCover 2009 and CORINE Land Cover 2012 datasets were employed to establish the distribution of coniferous forests in the areas of interest. Conclusions were drawn based on the analyses of the circulation of air masses, using visualization of global weather conditions forecast to supercomputers. For the first time, we have demonstrated that pine pollen grains occurring in pine-free Spitsbergen, could originate from numerous locations, including Scandinavia, Iceland, Siberia and northern Canada. Pollen grains were transported via air masses for distances exceeding ~2000 km. Both air samples and gravimetric pollen deposits revealed the same pattern of Pinus pollen distributio

Integrating pharmacokinetics and pharmacodynamics in operational research to end tuberculosis

Tuberculosis (TB) elimination requires innovative approaches. The new Global Tuberculosis Network (GTN) aims to conduct research on key unmet therapeutic and diagnostic needs in the field of TB elimination using multidisciplinary, multisectorial approaches. The TB Pharmacology section within the new GTN aims to detect and study the current knowledge gaps, test potential solutions using human pharmacokinetics informed through preclinical infection systems, and return those findings to the bedside. Moreover, this approach would allow prospective identification and validation of optimal shorter therapeutic durations with new regimens. Optimized treatment using available and repurposed drugs may have an increased impact when prioritizing a personcentered approach and acknowledge the importance of age, gender, comorbidities, and both social and programmatic environments. In this viewpoint article, we present an in-depth discussion on how TB pharmacology and the related strategies will contribute to TB elimination

Panspermia, Past and Present: Astrophysical and Biophysical Conditions for the Dissemination of Life in Space

Astronomically, there are viable mechanisms for distributing organic material throughout the Milky Way. Biologically, the destructive effects of ultraviolet light and cosmic rays means that the majority of organisms arrive broken and dead on a new world. The likelihood of conventional forms of panspermia must therefore be considered low. However, the information content of dam-aged biological molecules might serve to seed new life (necropanspermia).Comment: Accepted for publication in Space Science Review

Modeling factors influencing the demand for emergency department services in ontario: a comparison of methods

<p>Abstract</p> <p>Background</p> <p>Emergency departments are medical treatment facilities, designed to provide episodic care to patients suffering from acute injuries and illnesses as well as patients who are experiencing sporadic flare-ups of underlying chronic medical conditions which require immediate attention. Supply and demand for emergency department services varies across geographic regions and time. Some persons do not rely on the service at all whereas; others use the service on repeated occasions. Issues regarding increased wait times for services and crowding illustrate the need to investigate which factors are associated with increased frequency of emergency department utilization. The evidence from this study can help inform policy makers on the appropriate mix of supply and demand targeted health care policies necessary to ensure that patients receive appropriate health care delivery in an efficient and cost-effective manner. The purpose of this report is to assess those factors resulting in increased demand for emergency department services in Ontario. We assess how utilization rates vary according to the severity of patient presentation in the emergency department. We are specifically interested in the impact that access to primary care physicians has on the demand for emergency department services. Additionally, we wish to investigate these trends using a series of novel regression models for count outcomes which have yet to be employed in the domain of emergency medical research.</p> <p>Methods</p> <p>Data regarding the frequency of emergency department visits for the respondents of Canadian Community Health Survey (CCHS) during our study interval (2003-2005) are obtained from the National Ambulatory Care Reporting System (NACRS). Patients' emergency department utilizations were linked with information from the Canadian Community Health Survey (CCHS) which provides individual level medical, socio-demographic, psychological and behavioral information for investigating predictors of increased emergency department utilization. Six different multiple regression models for count data were fitted to assess the influence of predictors on demand for emergency department services, including: Poisson, Negative Binomial, Zero-Inflated Poisson, Zero-Inflated Negative Binomial, Hurdle Poisson, and Hurdle Negative Binomial. Comparison of competing models was assessed by the Vuong test statistic.</p> <p>Results</p> <p>The CCHS cycle 2.1 respondents were a roughly equal mix of males (50.4%) and females (49.6%). The majority (86.2%) were young-middle aged adults between the ages of 20-64, living in predominantly urban environments (85.9%), with mid-high household incomes (92.2%) and well-educated, receiving at least a high-school diploma (84.1%). Many participants reported no chronic disease (51.9%), fell into a small number (0-5) of ambulatory diagnostic groups (62.3%), and perceived their health status as good/excellent (88.1%); however, were projected to have high Resource Utilization Band levels of health resource utilization (68.2%). These factors were largely stable for CCHS cycle 3.1 respondents. Factors influencing demand for emergency department services varied according to the severity of triage scores at initial presentation. For example, although a non-significant predictor of the odds of emergency department utilization in high severity cases, access to a primary care physician was a statistically significant predictor of the likelihood of emergency department utilization (OR: 0.69; 95% CI OR: 0.63-0.75) and the rate of emergency department utilization (RR: 0.57; 95% CI RR: 0.50-0.66) in low severity cases.</p> <p>Conclusion</p> <p>Using a theoretically appropriate hurdle negative binomial regression model this unique study illustrates that access to a primary care physician is an important predictor of both the odds and rate of emergency department utilization in Ontario. Restructuring primary care services, with aims of increasing access to undersupplied populations may result in decreased emergency department utilization rates by approximately 43% for low severity triage level cases.</p

Assessment of alternative divertor configurations as an exhaust solution for DEMO

Plasma exhaust has been identified as a major challenge towards the realisation of magnetic confinement fusion. To mitigate the risk that the single null divertor (SND) with a high radiation fraction in the scrape-of-layer (SOL) adopted for ITER will not extrapolate to a DEMO reactor, the EUROfusion consortium is assessing potential benefits and engineering challenges of alternative divertor configurations. Alternative configurations that could be readily adopted in a DEMO design include the X divertor (XD), the Super-X divertor (SXD), the Snowflake divertor (SFD) and the double null divertor (DND). The flux flaring towards the divertor target of the XD is limited by the minimum grazing angle at the target set by gaps and misalignments. The characteristic increase of the target radius in the SXD is a trade-off with the increased TF coil volume, but, ultimately, also limited by forces onto coils. Engineering constraints also limit XD and SXD characteristics to the outer divertor leg with a solution for the inner leg requiring up-down symmetric configurations. Capital cost increases with respect to a SND configuration are largest for SXD and SFD, which require both significantly more poloidal field coil conductors and in the case of the SXD also more toroidal field coil conductors. Boundary models with increasing degrees of complexity have been used to predict the beneficial effect of the alternative configurations on exhaust performance. While all alternative configurations should decrease the power that must be radiated in the outer divertor, only the DND and possibly the SFD also ease the radiation requirements in the inner divertor. These decreases of the radiation requirements are however expected to be small making the ability of alternative divertors to increase divertor radiation without excessive core performance degradation their main advantage. Initial 2D fluid modeling of argon seeding in XD and SFD configurations indicate such advantages over the SND, while results for SXD and DND are still pending. Additional improvements, expected from increased turbulence in the low poloidal field region of the SFD also remain to be verified. A more precise comparison with the SND as well as absolute quantitative predictions for all configurations requires more complete physics models that are currently only being developed

Validation of Case-Finding Algorithms Derived from Administrative Data for Identifying Adults Living with Human Immunodeficiency Virus Infection

OBJECTIVE: We sought to validate a case-finding algorithm for human immunodeficiency virus (HIV) infection using administrative health databases in Ontario, Canada. METHODS: We constructed 48 case-finding algorithms using combinations of physician billing claims, hospital and emergency room separations and prescription drug claims. We determined the test characteristics of each algorithm over various time frames for identifying HIV infection, using data abstracted from the charts of 2,040 randomly selected patients receiving care at two medical practices in Toronto, Ontario as the reference standard. RESULTS: With the exception of algorithms using only a single physician claim, the specificity of all algorithms exceeded 99%. An algorithm consisting of three physician claims over a three year period had a sensitivity and specificity of 96.2% (95% CI 95.2%-97.9%) and 99.6% (95% CI 99.1%-99.8%), respectively. Application of the algorithm to the province of Ontario identified 12,179 HIV-infected patients in care for the period spanning April 1, 2007 to March 31, 2009. CONCLUSIONS: Case-finding algorithms generated from administrative data can accurately identify adults living with HIV. A relatively simple "3 claims in 3 years" definition can be used for assembling a population-based cohort and facilitating future research examining trends in health service use and outcomes among HIV-infected adults in Ontario