Systematic Review of miRNA as Biomarkers in Alzheimer's Disease.

Currently there are 850,000 people with Alzheimer's disease in the UK, with an estimated rise to 1.1 million by 2025. Alzheimer's disease is characterised by the accumulation of amyloid-beta plaques and hyperphosphorylated tau in the brain causing a progressive decline in cognitive impairment. Small non-coding microRNA (miRNA) sequences have been found to be deregulated in the peripheral blood of Alzheimer patients. A systematic review was conducted to extract all miRNA found to be significantly deregulated in the peripheral blood. These deregulated miRNAs were cross-referenced against the miRNAs deregulated in the brain at Braak Stage III. This resulted in a panel of 10 miRNAs (hsa-mir-107, hsa-mir-26b, hsa-mir-30e, hsa-mir-34a, hsa-mir-485, hsa-mir200c, hsa-mir-210, hsa-mir-146a, hsa-mir-34c, and hsa-mir-125b) hypothesised to be deregulated early in Alzheimer's disease, nearly 20 years before the onset of clinical symptoms. After network analysis of the 10 miRNAs, they were found to be associated with the immune system, cell cycle, gene expression, cellular response to stress, neuron growth factor signalling, wnt signalling, cellular senescence, and Rho GTPases

Resilience: Easy to use but hard to define

First conceptualized in the 1970s, resilience has become a popular term in the ecological literature, used in the title, abstract, or keywords of approximately 1% of papers identified by ISI Web of Science in the field of environmental sciences and ecology in 2011. However, many papers make only passing reference to the term and do not explain what resilience means in the context of their study system, despite there being a number of possible definitions. In an attempt to determine how resilience is being used in ecological studies, we surveyed 234 papers published between 2004 and 2011 that were identified under the topic “resilience” by ISI Web of Science. Of these, 38% used the word resilience fewer than three times (often in the abstract or keyword list), 66% did not define the term, and 71% did not provide a citation to the resilience literature. Studies that defined resilience most often discussed it as pertaining to an entire ecosystem under continuous rather than discrete disturbance. Given the complex nature of this concept, we believe that care should be taken to properly describe what is meant by the term resilience in ecological studies

Faculty-Led Virtual Level 1 Community Fieldwork during the COVID-19 Pandemic

Fieldwork is an integral portion of occupational therapy education that ensures students have the opportunity to develop basic competencies in real world practice settings. The national shortage of fieldwork placements, particularly in the area of mental health, in combination with the COVID-19 pandemic, have led to the adoption of increasingly innovative fieldwork models. This retrospective, qualitative study investigates occupational therapy assistant students’ experiences of completing a faculty-led (i.e. where faculty served as the primary fieldwork educator) and virtual (i.e., where services were offered in a virtual environment) Level I fieldwork with a community-based peer led behavioral health agency. Twenty-three students completed a confidential survey describing their experiences in Fall 2020. A secondary analysis of students’ responses was performed using principles of thematic analysis, which yielded results centered on four themes: knowledge, skills, attitudes, and structure. Subcategories highlighted growth across multiple areas including knowledge of occupational therapy’s role in mental health, interpersonal skills, and use of technology and other resources. Students’ preconceived notions of individuals with mental illness were challenged and many reported increased confidence in their abilities to work with these individuals. Both positive and constructive feedback were provided regarding the overall virtual fieldwork experience. The faculty-led virtual fieldwork model was viable in supporting occupational therapy assistant students’ skills to engage people with mental health and substance use challenges in a community setting. The potential use of this model is discussed in light of the anticipated increase of behavioral health problems for many across the lifespan post-COVID-19 pandemic

A sequential dynamic Bayesian network for pore pressure estimation with uncertainty quantification

Pore-pressure estimation is an important part of oil-well drilling, since drilling into unexpected highly pressured fluids can be costly and dangerous. However, standard estimation methods rarely account for the many sources of uncertainty, or for the multivariate nature of the system. We propose the pore pressure sequential dynamic Bayesian network (PP SDBN) as an appropriate solution to both these issues. The PP SDBN models the relationships between quantities in the pore pressure system, such as pressures, porosity, lithology and wireline log data, using conditional probability distributions based on geophysical relationships to capture our uncertainty about these variables and the relationships between them. When wireline log data is given to the PP SDBN, the probability distributions are updated, providing an estimate of pore pressure along with a probabilistic measure of uncertainty that reflects the data acquired and our understanding of the system. This is the advantage of a Bayesian approach. Our model provides a coherent statistical framework for modelling the pore pressure system. The specific geophysical relationships used can be changed to better suit a particular setting, or reflect geoscientists’ knowledge. We demonstrate the PP SDBN on an offshore well from West Africa. We also perform a sensitivity analysis, demonstrating how this can be used to better understand the working of the model and which parameters are the most influential. The dynamic nature of the model makes it suitable for real time estimation during logging while drilling. The PP SDBN models shale pore pressure in shale rich formations with mechanical compaction as the overriding source of overpressure. The PP SDBN improves on existing methods since it produces a probabilistic estimate that reflects the many sources of uncertainty present

Mapping the Corneal Sub-Basal Nerve Plexus in Orthokeratology Lens Wear Using in vivo Laser Scanning Confocal Microscopy

PURPOSE. This study was designed to map the sub-basal nerve plexus (SBNP) in the cornea of orthokeratology (OK) lens wearers. METHODS. Laser scanning confocal microscopy (LSCM) was performed in vivo on three subjects: a non-lens wearer and two OK lens wearers. Scans were performed on the right eye while the left eye fixated a moving target. A total of 575, 430, and 676 contiguous images of the SBNP were taken from the non-lens wearing and the OK lens wearing subjects, respectively, and used to construct maps of the central to midperipheral SBNP. RESULTS. In the non-lens wearing eye, nerves radiated towards a whorl-like complex centered nasally and inferiorly in an overall pattern consistent with previously reported studies. In the OK lens wearing eyes, this whorl pattern was absent, replaced by a tortuous network of nerve fibers centrally, and thicker curvilinear fibers mid-peripherally, particularly in the nasal, inferior, and temporal regions. CONCLUSIONS. This study maps the corneal SBNP in OK lens wearers and provides compelling evidence that OK lens wear alters the normal SBNP distribution observed in healthy, nonlens wearing eyes. (Invest Ophthalmol Vis Sci

RIDME distance measurements using Gd(iii) tags with a narrow central transition

Methods based on pulse electron paramagnetic resonance allow measurement of the electron-electron dipolar coupling between two spin labels. Here we compare the most popular technique, Double Electron-Electron Resonance (DEER or PELDOR), with the dead-time free 5-pulse Relaxation-Induced Dipolar Modulation Enhancement (RIDME) method for Gd(iii)-Gd(iii) distance measurements at W-band (94.9 GHz, ≈3.5 T) using Gd(iii) tags with a small zero field splitting (ZFS). Such tags are important because of their high EPR sensitivity arising from their narrow central transition. Two systems were investigated: (i) a rigid model compound with an inter-spin distance of 2.35 nm, and (ii) two mutants of a homodimeric protein, both labeled with a DOTA-based Gd(iii) chelate and characterized by an inter-spin distance of around 6 nm, one having a narrow distance distribution and the other a broad distribution. Measurements on the model compound show that RIDME is less sensitive to the complications arising from the failure of the weak coupling approximation which affect DEER measurements on systems characterized by short inter-spin distances between Gd(iii) tags having a narrow central transition. Measurements on the protein samples, which are characterized by a long inter-spin distance, emphasize the complications due to the appearance of harmonics of the dipolar interaction frequency in the RIDME traces for S > 1/2 spin systems, as well as enhanced uncertainties in the background subtraction. In both cases the sensitivity of RIDME was found to be significantly better than DEER. The effects of the experimental parameters on the RIDME trace are discussed.This research was supported by the Israeli Science Foundation (grant 334/14) and was made possible in part by the historic generosity of the Harold Perlman Family (D. G.). We also acknowledge the Australian Research Council for a Discovery grant to G. O. and B. G. (DP150100383) and a Future Fellowship to B. G. (FT130100838). D. G. holds the Erich Klieger professorial chair in Chemical Physics

Does stress perfusion imaging improve the diagnostic accuracy of late gadolinium enhanced cardiac magnetic resonance for establishing the etiology of heart failure?

Background Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) has excellent specificity, sensitivity and diagnostic accuracy for differentiating between ischemic cardiomyopathy (ICM) and non-ischemic dilated cardiomyopathy (NICM). CMR first-pass myocardial perfusion imaging (perfusion-CMR) may also play role in distinguishing heart failure of ischemic and non-ischemic origins, although the utility of additional of stress perfusion imaging in such patients is unclear. The aim of this retrospective study was to assess whether the addition of adenosine stress perfusion imaging to LGE-CMR is of incremental value for differentiating ICM and NICM in patients with severe left ventricular systolic dysfunction (LVSD) of uncertain etiology. Methods We retrospectively identified 100 consecutive adult patients (median age 69 years (IQR 59–73)) with severe LVSD (mean LV EF 26.6 ± 7.0%) referred for perfusion-CMR to establish the underlying etiology of heart failure. The cause of heart failure was first determined on examination of CMR cine and LGE images in isolation. Subsequent examination of complete adenosine stress perfusion-CMR studies (cine, LGE and perfusion images) was performed to identify whether this altered the initial diagnosis. Results On LGE-CMR, 38 patients were diagnosed with ICM, 46 with NICM and 16 with dual pathology. With perfusion-CMR, there were 39 ICM, 44 NICM and 17 dual pathology diagnoses. There was excellent agreement in diagnoses between LGE-CMR and perfusion-CMR (κ 0.968, p<0.001). The addition of adenosine stress perfusion images to LGE-CMR altered the diagnosis in only two of the 100 patients. Conclusion The addition of adenosine stress perfusion-CMR to cine and LGE-CMR provides minimal incremental diagnostic yield for determining the etiology of heart failure in patients with severe LVSD

Redefining the Expression and Function of the Inhibitor of Differentiation 1 in Mammary Gland Development

The accumulation of poorly differentiated cells is a hallmark of breast neoplasia and progression. Thus an understanding of the factors controlling mammary differentiation is critical to a proper understanding of breast tumourigenesis. The Inhibitor of Differentiation 1 (Id1) protein has well documented roles in the control of mammary epithelial differentiation and proliferation in vitro and breast cancer progression in vivo. However, it has not been determined whether Id1 expression is sufficient for the inhibition of mammary epithelial differentiation or the promotion of neoplastic transformation in vivo. We now show that Id1 is not commonly expressed by the luminal mammary epithelia, as previously reported. Generation and analysis of a transgenic mouse model of Id1 overexpression in the mammary gland reveals that Id1 is insufficient for neoplastic progression in virgin animals or to prevent terminal differentiation of the luminal epithelia during pregnancy and lactation. Together, these data demonstrate that there is no luminal cell-autonomous role for Id1 in mammary epithelial cell fate determination, ductal morphogenesis and terminal differentiation

Corneal Thickness Changes in Hyperopic Orthokeratology Measured by Optical Pachometry

PURPOSE. To investigate the time course of corneal thickness changes in overnight hyperopic orthokeratology (OK) lens wear for a 4-day lens-wearing period. METHODS. Fourteen subjects (age range, 20 -37 years) were fitted with hyperopic OK lenses in one eye only. The fellow eye acted as a non-lens wearing control. Lenses were worn overnight only for 4 nights, and changes from baseline in subjective refraction, corneal topography, and corneal thickness (Holden-Payor optical pachometer) at central and paracentral locations were measured on days 1 and 4 after overnight lens wear, at lens removal (AM), and 8 hours after lens removal (PM). RESULTS. There was a significant refractive and corneal topographic effect at all visits. The central total cornea thickened significantly at AM visits only because of significant stromal thickening consistent with the overnight lens wearing edema response, and returned to baseline at PM visits once edema resolved. The para-central epithelium significantly thinned at all AM and PM visits. This counteracted para-central stromal thickening at AM and resulted in significant thinning of the total para-central cornea at PM visits when stromal thickness had returned to baseline. CONCLUSIONS. Para-central corneal epithelial thinning explains corneal anterior surface steepening in hyperopic OK and is sufficient to account for the lens-induced refractive response. Whereas corneal thickening is an additional factor reported in myopic OK, this was not the case in hyperopic OK. Constraint of corneal surface change mechanisms to para-central corneal epithelial thinning alone in hyperopic OK may explain the reduced refractive effect compared with myopic OK. (Invest Ophthalmol Vis Sci. 2011;52:3648 -3653) DOI:10.1167/ iovs.10-6323 O rthokeratology (OK) is a procedure by which rigid contact lenses temporarily alter corneal curvature with the intention to correct ametropia after lens removal. A number of studies have shown that myopic OK lenses flatten corneal curvature during wear and provide reliable refractive correction for up to Ϫ4.50D of myopia on lens removal. 1-4 More recently, it has been shown that hyperopic OK lenses steepen corneal curvature during lens wear. 5-9 However, the refractive effect with hyperopic OK lenses is less consistent beyond ϩ1.50D of targeted refractive change. 7 Previous studies have shown that changes to corneal thickness (assuming no change in curvature of the posterior corneal surface) can account for the refractive change induced by myopic OK lenses. 1,4 Swarbrick et al. 1 suggested that OK-induced corneal curvature change represents an anterior corneal phenomenon rather than an overall bending of the cornea. Hyperopic OK lenses are designed on principles similar to those of myopic OK lenses, so it is reasonable to hypothesize that changes in corneal curvature from hyperopic OK lenses could be equally limited to the anterior corneal surface. In a previous study conducted by our group, 7 we reported that the time course of refractive and corneal topographic change in hyperopic OK is analogous to that of myopic OK, at least in the first 7 nights of lens wear. We also reported no increase in central corneal thickness using ultrasonic pachometry once corneal edema from overnight wear had resolved during the day without lens wear, despite significant retention of refractive effect at the end of the day. This led to the suggestion that, in the absence of central corneal thickening, the para-central cornea might have thinned in hyperopic OK to allow for the corneal steepening. Two previous publications have reported on the profile of corneal thickness change after hyperopic OK; both used optical coherence tomography (OCT) to measure changes to total, stromal, and epithelial thickness induced by the Paragon corneal refractive therapy lens for hyperopia (CRT; Paragon Vision Sciences, Mesa, AZ). Lu et al. 10 measured the short-term response over up to 60 minutes of lens wear and found no significant change from baseline in central epithelial thickness but did find significant para-central epithelial thinning after 30 minutes of lens wear. However, when CRT lens wear was extended to 1 night in the closed eye, Haque et al. The purpose of the present study was to gain understanding of the change in the corneal thickness profile during hyperopic OK lens wear over a longer wearing period of 4 nights. In a previously published study