Informed Consent: The Rate-Limiting Step in Acute Stroke Trials

Successful implementation of a randomized clinical trial (RCT) for neuro-vascular emergencies such as cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage is extraordinarily challenging. Besides establishing an accurate, hyper-expedited diagnosis among many mimics in a person with acute neurological deficits, informed consent must be obtained from this vulnerable group of patients who may be unable to convey their own wishes, grasp the gravity of their situation, or give a complete history or examination. We review the influences, barriers, and factors investigators encounter when providing established and putative stroke therapies, and focus on informed consent, the most important research protector of human subjects, as the rate-limiting step for enrollment into acute stroke RCTs. The informed consent process has received relatively little attention in the stroke literature, but is especially important for stroke victims with acute cognitive, aural, lingual, motor, or visual impairments. Consent by a surrogate may not accurately reflect the patient’s wishes. Further, confusion about trial methodology, negative opinions of placebo-controlled studies, and therapeutic misconception by patients or surrogates may impede trial enrollment and requires further study. Exception from informed consent offers an opportunity that is rarely if ever utilized for stroke RCTs. Ultimately, advancing the knowledge base and treatment paradigms for acute stroke is essential but autonomy, beneficence (non-malfeasance), and justice must also be carefully interwoven into any well-designed RCT

Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability.

There is increasing evidence that the lysosome is involved in the pathogenesis of a variety of neurodegenerative disorders. Thus, mechanisms that link lysosome dysfunction to the disruption of neuronal homeostasis offer opportunities to understand the molecular underpinnings of neurodegeneration and potentially identify specific therapeutic targets. Here, using a monogenic neurodegenerative disorder, NPC1 disease, we demonstrate that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns. The molecular mechanism linking alterations in lysosomal cholesterol egress to intrinsic tuning of neuronal excitability is a transcriptionally mediated upregulation of the ABCA1 transporter, whose PtdIns(4,5)P2-floppase activity decreases plasma membrane PtdIns(4,5)P2. The consequence of reduced PtdIns(4,5)P2 is a parallel decrease in a key regulator of neuronal excitability, the voltage-gated KCNQ2/3 potassium channel, which leads to hyperexcitability in NPC1 disease neurons. Thus, cholesterol efflux from lysosomes regulates PtdIns(4,5)P2 to shape the electrical and functional identity of the plasma membrane of neurons in health and disease

The Water Microbiome Through a Pilot Scale Advanced Treatment Facility for Direct Potable Reuse

Advanced treatment facilities for potable water reuse of wastewater are designed to achieve high removal levels of specific pathogens, as well as many other constituents. However, changes to the microbial community throughout treatment, storage, and distribution of this water have not been well characterized. We applied high-throughput amplicon sequencing, read-based, assembly-based, and genome-resolved metagenomics, and flow cytometry to investigate the microbial communities present in a pilot-scale advanced water treatment facility. Advanced treatment of secondary-treated wastewater consisted of ozonation, chloramination, microfiltration, reverse osmosis (RO), advanced oxidation (UV/H2O2), granular activated carbon (GAC) filtration, and chlorination. Treated water was fed into bench-scale simulated distribution systems (SDS). Cell counts and microbial diversity in bulk water decreased until GAC filtration, and the bacterial communities were significantly different following each treatment step. Bacteria grew within GAC media and contributed to a consistent microbial community in the filtrate, which included members of the Rhizobiales and Mycobacteriaceae. After chlorination, some of the GAC filtrate community was maintained within the SDS, and community shifts were associated with stagnation. Putative antibiotic resistance genes and potential opportunistic pathogens were identified before RO and after advanced oxidation, although few if any members of the wastewater microbial community passed through these treatment steps. These findings can contribute to improved design of advanced treatment trains and management of microbial communities in post-treatment steps

Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease

Oxidative stress is proposed as an important factor in osteoarthritis (OA). To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function

Diet and Foraging Behaviors of Timber Rattlesnakes, Crotalus horridus, in Eastern Virginia

During a 17-yr telemetry study, we examined the diet and ambush behavior of a population of Crotalus horridus in southeastern Virginia. Forty dietary items were identified from 37 fecal samples. We documented 722 instances of snakes in an ambush posture, 61 of which were in a vertical-tree posture, as if hunting arboreal prey at the base of a tree. The most common prey items were Eastern Gray Squirrels (Sciurus carolinensis), which accounted for 45 of all dietary items and represented an estimated 78 of total biomass consumed by C. horridus. Prey was not consumed in proportion to availability, based on small mammal surveys. Our analysis provides indirect evidence that the vertical-tree foraging behavior is adopted to target arboreal Eastern Gray Squirrels. Further, we provide support for the hypothesis that C. horridus alters ambush behavior to forage selectively for specific prey types

The interaction of class and gender in illness narratives

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2008 BSA Publications Ltd.Perspectives on gender and identity that emphasize variability of performance, local context and individual agency have displaced earlier paradigms.These are now perceived to have supported gender stereotypes and language ideologies by emphasizing gender difference and homogeneity within genders. In a secondary analysis of health and illness narratives we explore the interaction of class and gender in individuals' constructions of gendered identity. High social class men perform gender in particularly varied ways and we speculate that this variable repertoire, including the use of what was once termed `women's language', is linked to a capacity to maintain social distinction and authority. Men's performance of conventional masculinity is often threatened by both the experience of illness and being interviewed about personal experience. Lower social class women in particular demonstrate an intensification of a pre-existing informal family and support group culture, marking successful members by awarding them the accolade of being `lovely'.ESR

Diet and Foraging Behaviors of Timber Rattlesnakes, \u3ci\u3eCrotalus Horridus\u3c/i\u3e, in Eastern Virginia

During a 17-yr telemetry study, we examined the diet and ambush behavior of a population of Crotalus horridus in southeastern Virginia. Forty dietary items were identified from 37 fecal samples. We documented 722 instances of snakes in an ambush posture, 61% of which were in a vertical-tree posture, as if hunting arboreal prey at the base of a tree. The most common prey items were Eastern Gray Squirrels (Sciurus carolinensis), which accounted for 45% of all dietary items and represented an estimated 78% of total biomass consumed by C. horridus. Prey was not consumed in proportion to availability, based on small mammal surveys. Our analysis provides indirect evidence that the vertical-tree foraging behavior is adopted to target arboreal Eastern Gray Squirrels. Further, we provide support for the hypothesis that C. horridus alters ambush behavior to forage selectively for specific prey types

Measuring fast electron spectra and laser absorption in relativistic laser-solid interactions using differential bremsstrahlung photon detectors

A photon detector suitable for the measurement of bremsstrahlung spectra generated in relativistically-intense laser-solid interactions is described. The Monte Carlo techniques used to back-out the fast electron spectrum and laser energy absorbed into fast electrons are detailed. A relativistically-intense laser-solid experiment using frequency doubled laser light is used to demonstrate the effective operation of the detector. The experimental data was interpreted using the 3-spatial-dimension Monte Carlo code MCNPX (Pelowitz 2008), and the fast electron temperature found to be 125 keV

Combined collider constraints on neutralinos and charginos

Searches for supersymmetric electroweakinos have entered a crucial phase, as the integrated luminosity of the Large Hadron Collider is now high enough to compensate for their weak production cross-sections. Working in a framework where the neutralinos and charginos are the only light sparticles in the Minimal Supersymmetric Standard Model, we use gambit to perform a detailed likelihood analysis of the electroweakino sector. We focus on the impacts of recent ATLAS and CMS searches with 36 fb$^{-1}$ of 13 TeV proton-proton collision data. We also include constraints from LEP and invisible decays of the $Z$ and Higgs bosons. Under the background-only hypothesis, we show that current LHC searches do not robustly exclude any range of neutralino or chargino masses. However, a pattern of excesses in several LHC analyses points towards a possible signal, with neutralino masses of $(m_{\tilde{\chi}_1^0}, m_{\tilde{\chi}_2^0}, m_{\tilde{\chi}_3^0}, m_{\tilde{\chi}_4^0})$ = (8-155, 103-260, 130-473, 219-502) GeV and chargino masses of $(m_{\tilde{\chi}_1^{\pm}}, m_{\tilde{\chi}_2^{\pm}})$ = (104-259, 224-507) GeV at the 95% confidence level. The lightest neutralino is mostly bino, with a possible modest Higgsino or wino component. We find that this excess has a combined local significance of $3.3\sigma$, subject to a number of cautions. If one includes LHC searches for charginos and neutralinos conducted with 8 TeV proton-proton collision data, the local significance is lowered to 2.9$\sigma$. We briefly consider the implications for dark matter, finding that the correct relic density can be obtained through the Higgs-funnel and $Z$-funnel mechanisms, even assuming that all other sparticles are decoupled. All samples, gambit input files and best-fit models from this study are available on Zenodo.Comment: 38 pages, 16 figures, v3 is the version accepted by EPJ

Size matters: the value of small populations for wintering waterbirds

Protecting systematically selected areas of land is a major step towards biodiversity conservation worldwide. Indeed, the identification and designation of protected areas more often than not forms a core component of both national and international conservation policies. In this paper we provide an overview of those Special Protection Areas and Ramsar Sites that have been classified in Great Britain as of 1998/99 for a selection of wintering waterbird species, using bird count data from the Wetland Bird Survey. The performance of this network of sites is remarkable, particularly in comparison with published analyses of networks elsewhere in the world. Nevertheless, the current site-based approach, whilst having the great benefit of simplicity, is deliberately biased towards aggregating species at the expense of the more dispersed distribution species. To ensure that the network continues successfully to protect nationally and internationally important waterbird populations, efforts now need to concentrate on the derivation of species-specific representation targets and, in particular, the ways in which these can be incorporated into the site selection process. Although these analyses concern the performance of protected areas for waterbirds in Great Britain, the results have wide-ranging importance for conservation planning in general and the design of protected area networks