Muscarinic receptor-dependent long term depression in the perirhinal cortex and recognition memory are impaired in the rTg4510 mouse model of tauopathy.

This is the final version of the article. Available from the publisher via the DOI in this record.Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tauP301L. We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory. Furthermore, we also established that PRh slices prepared from rTg4510 mice, unlike those prepared from wildtype littermates, could not support a muscarinic acetylcholine receptor-dependent form of LTD, induced by a 5 Hz stimulation protocol. In contrast, bath application of the muscarinic agonist carbachol induced a form of chemical LTD in both WT and rTg4510 slices. Finally, when rTg4510 slices were preincubated with the acetylcholinesterase inhibitor donepezil, the 5 Hz stimulation protocol was capable of inducing significant levels of LTD. These data suggest that dysfunctional cholinergic innervation of the PRh of rTg4510 mice, results in deficits in synaptic LTD which may contribute to aberrant recognition memory in this rodent model of tauopathy.SES was supported by a Medical Research Council studentship. JTB was an Alzheimer’s Research UK Senior Research Fellow. Eli Lilly & Co supplied the rTg4510 mice

Early Life Socioeconomic Circumstance and Late Life Brain Hyperintensities : A Population Based Cohort Study

Funding: Image acquisition and image analysis for this study was funded by the Alzheimer's Research Trust (now Alzheimer's Research UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments The authors would like to thank the participants of the Aberdeen 1936 Birth Cohort (ABC36), without whom this research would not have been possible.Peer reviewedPublisher PD

Joint machine learning analysis of muon spectroscopy data from different materials

Machine learning (ML) methods have proved to be a very successful tool in physical sciences, especially when applied to experimental data analysis. Artificial intelligence is particularly good at recognizing patterns in high dimensional data, where it usually outperforms humans. Here we applied a simple ML tool called principal component analysis (PCA) to study data from muon spectroscopy. The measured quantity from this experiment is an asymmetry function, which holds the information about the average intrinsic magnetic field of the sample. A change in the asymmetry function might indicate a phase transition; however, these changes can be very subtle, and existing methods of analyzing the data require knowledge about the specific physics of the material. PCA is an unsupervised ML tool, which means that no assumption about the input data is required, yet we found that it still can be successfully applied to asymmetry curves, and the indications of phase transitions can be recovered. The method was applied to a range of magnetic materials with different underlying physics. We discovered that performing PCA on all those materials simultaneously can have a positive effect on the clarity of phase transition indicators and can also improve the detection of the most important variations of asymmetry functions. For this joint PCA we introduce a simple way to track the contributions from different materials for a more meaningful analysis

A standardization approach to compare treatment safety and effectiveness outcomes between clinical trials and real‐world populations in psoriasis

Background: Patients recruited in randomized controlled trials (RCTs) for biologic therapies in psoriasis are not fully representative of the real‐world psoriasis population. Objectives: Firstly, to investigate whether patient characteristics are associated with being included in a psoriasis RCT. Secondly, to estimate the differences in the incidence of severe adverse events (SAEs) and the response rate between RCT and real‐world populations of patients on biologic therapies for psoriasis using a standardization method. Methods: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) were appended to individual participant‐level data from two RCTs assessing ustekinumab in patients with psoriasis. Baseline variables were assessed for association of being in an RCT using a multivariable logistic regression model. Propensity score weights were derived to reweigh the registry population so that variables had the distribution of the trial population. We measured the C‐statistic of the model with trial status as the dependent variable, and the risk differences in the incidence rate of SAEs in the first year and Psoriasis Area and Severity Index (PASI) after 6 months in the BADBIR cohort before and after weighting. Results: In total 6790 registry and 2021 RCT participants were included. The multivariable logistic regression model had a C‐statistic of 0.82 [95% confidence interval (CI) 0.81–0.83]. The risk differences for the incidence rate of SAEs and the proportion of patients with PASI < 1.5 were 9.27 (95% CI −3.91–22.5) per 1000 person‐years and 0.95 (95% CI −1.98–4.15), respectively. Conclusions: Our results suggest that RCTs of biologic therapies in patients with psoriasis are not fully representative of the real‐world population, but this lack of external validity does not account for the efficacy–effectiveness gap

Sputum smear negative pulmonary tuberculosis: sensitivity and specificity of diagnostic algorithm

<p>Abstract</p> <p>Background</p> <p>The diagnosis of pulmonary tuberculosis in patients with Human Immunodeficiency Virus (HIV) is complicated by the increased presence of sputum smear negative tuberculosis. Diagnosis of smear negative pulmonary tuberculosis is made by an algorithm recommended by the National Tuberculosis and Leprosy Programme that uses symptoms, signs and laboratory results.</p> <p>The objective of this study is to determine the sensitivity and specificity of the tuberculosis treatment algorithm used for the diagnosis of sputum smear negative pulmonary tuberculosis.</p> <p>Methods</p> <p>A cross-section study with prospective enrollment of patients was conducted in Dar-es-Salaam Tanzania. For patients with sputum smear negative, sputum was sent for culture. All consenting recruited patients were counseled and tested for HIV. Patients were evaluated using the National Tuberculosis and Leprosy Programme guidelines and those fulfilling the criteria of having active pulmonary tuberculosis were started on anti tuberculosis therapy. Remaining patients were provided appropriate therapy. A chest X-ray, mantoux test, and Full Blood Picture were done for each patient. The sensitivity and specificity of the recommended algorithm was calculated. Predictors of sputum culture positive were determined using multivariate analysis.</p> <p>Results</p> <p>During the study, 467 subjects were enrolled. Of those, 318 (68.1%) were HIV positive, 127 (27.2%) had sputum culture positive for Mycobacteria Tuberculosis, of whom 66 (51.9%) were correctly treated with anti-Tuberculosis drugs and 61 (48.1%) were missed and did not get anti-Tuberculosis drugs. Of the 286 subjects with sputum culture negative, 107 (37.4%) were incorrectly treated with anti-Tuberculosis drugs. The diagnostic algorithm for smear negative pulmonary tuberculosis had a sensitivity and specificity of 38.1% and 74.5% respectively. The presence of a dry cough, a high respiratory rate, a low eosinophil count, a mixed type of anaemia and presence of a cavity were found to be predictive of smear negative but culture positive pulmonary tuberculosis.</p> <p>Conclusion</p> <p>The current practices of establishing pulmonary tuberculosis diagnosis are not sensitive and specific enough to establish the diagnosis of Acid Fast Bacilli smear negative pulmonary tuberculosis and over treat people with no pulmonary tuberculosis.</p

Cold-water coral distributions in the Drake Passage area from towed camera observations – initial interpretations

This article is distributed under the terms of the Creative Commons Public Domain. The definitive version was published in PLoS One 6 (2011): e16153, doi:10.1371/journal.pone.0016153.Seamounts are unique deep-sea features that create habitats thought to have high levels of endemic fauna, productive fisheries and benthic communities vulnerable to anthropogenic impacts. Many seamounts are isolated features, occurring in the high seas, where access is limited and thus biological data scarce. There are numerous seamounts within the Drake Passage (Southern Ocean), yet high winds, frequent storms and strong currents make seafloor sampling particularly difficult. As a result, few attempts to collect biological data have been made, leading to a paucity of information on benthic habitats or fauna in this area, particularly those on primarily hard-bottom seamounts and ridges. During a research cruise in 2008 six locations were examined (two on the Antarctic margin, one on the Shackleton Fracture Zone, and three on seamounts within the Drake Passage), using a towed camera with onboard instruments to measure conductivity, temperature, depth and turbidity. Dominant fauna and bottom type were categorized from 200 randomized photos from each location. Cold-water corals were present in high numbers in habitats both on the Antarctic margin and on the current swept seamounts of the Drake Passage, though the diversity of orders varied. Though the Scleractinia (hard corals) were abundant on the sedimented margin, they were poorly represented in the primarily hard-bottom areas of the central Drake Passage. The two seamount sites and the Shackleton Fracture Zone showed high numbers of stylasterid (lace) and alcyonacean (soft) corals, as well as large numbers of sponges. Though data are preliminary, the geological and environmental variability (particularly in temperature) between sample sites may be influencing cold-water coral biogeography in this region. Each area observed also showed little similarity in faunal diversity with other sites examined for this study within all phyla counted. This manuscript highlights how little is understood of these isolated features, particularly in Polar regions.This work was funded by the National Science Foundation’s Antarctic Earth Sciences Program (ANT0636787 awarded to LFR and RGW) and a CenSeam minigrant (awarded to RGW), and RGW is supported by a SOEST Young Investigator Fellowship from the University of Hawaii at Manoa

Influence of low birth weight on C-reactive protein in asymptomatic younger adults: the bogalusa heart study

<p>Abstract</p> <p>Background</p> <p>Both low birth weight, an indicator of intrauterine growth restriction, and low grade systemic inflammation depicted by high sensitivity C-reactive protein (hs-CRP) have emerged as independent predictors of cardiovascular (CV) disease and type 2 diabetes. However, information linking low birth weight and hs-CRP in a biracial (black/white) population is scant. We assessed a cohort of 776 black and white subjects (28% black, 43% male) aged 24-43 years (mean 36.1 years) enrolled in the Bogalusa Heart Study with regard to birth weight and gestational age data were retrieved from Louisiana State Public Health Office.</p> <p>Findings</p> <p>Black subjects had significantly lower birth weight than white subjects (3.145 kg vs 3.441 kg, p < 0.0001) and higher hs-CRP level (3.29 mg/L vs 2.57 mg/L, p = 0.011). After adjusting for sex, age, body mass index (BMI), smoking status and race (for total sample), the hs-CRP level decreased across quartiles of increasing birth weight in white subjects (p = 0.001) and the combined sample (p = 0.002). Adjusting for sex, age, BMI, smoking status and race for the total sample in a multivariate regression model, low birth weight was retained as an independent predictor variable for higher hs-CRP levels in white subjects (p = 0.004) and the total sample (p = 0.007). Conversely, the area under the receiver operative curve (c statistic) analysis adjusted for race, sex, age, smoking status and BMI yielded a value of 0.777 with regard to the discriminating value of hs-CRP for predicting low birth weight.</p> <p>Conclusions</p> <p>The deleterious effect of low birth weight on systemic inflammation depicted by the hs-CRP levels in asymptomatic younger adults may potentially link fetal growth retardation, CV disease and diabetes, with important health implications.</p