Development and validation of a clinical prediction model for patient-reported pain and function after primary total knee replacement surgery

To develop and validate a clinical prediction model of patient-reported pain and function after undergoing total knee replacement (TKR). We used data of 1,649 patients from the Knee Arthroplasty Trial who received primary TKR across 34 centres in the UK. The external validation included 595 patients from Southampton University Hospital, and Nuffield Orthopaedic Centre (Oxford). The outcome was the Oxford Knee Score (OKS) 12-month after TKR. Pre-operative predictors including patient characteristics and clinical factors were considered. Bootstrap backward linear regression analysis was used. Low pre-operative OKS, living in poor areas, high body mass index, and patient-reported anxiety or depression were associated with worse outcome. The clinical factors associated with worse outcome were worse pre-operative physical status, presence of other conditions affecting mobility and previous knee arthroscopy. Presence of fixed flexion deformity and an absent or damaged pre-operative anterior cruciate ligament (compared with intact) were associated with better outcome. Discrimination and calibration statistics were satisfactory. External validation predicted 21.1% of the variance of outcome. This is the first clinical prediction model for predicting self-reported pain and function 12 months after TKR to be externally validated. It will help to inform to patients regarding expectations of the outcome after knee replacement surgery

Local Optical Probe of Motion and Stress in a multilayer graphene NEMS

Nanoelectromechanical systems (NEMSs) are emerging nanoscale elements at the crossroads between mechanics, optics and electronics, with significant potential for actuation and sensing applications. The reduction of dimensions compared to their micronic counterparts brings new effects including sensitivity to very low mass, resonant frequencies in the radiofrequency range, mechanical non-linearities and observation of quantum mechanical effects. An important issue of NEMS is the understanding of fundamental physical properties conditioning dissipation mechanisms, known to limit mechanical quality factors and to induce aging due to material degradation. There is a need for detection methods tailored for these systems which allow probing motion and stress at the nanometer scale. Here, we show a non-invasive local optical probe for the quantitative measurement of motion and stress within a multilayer graphene NEMS provided by a combination of Fizeau interferences, Raman spectroscopy and electrostatically actuated mirror. Interferometry provides a calibrated measurement of the motion, resulting from an actuation ranging from a quasi-static load up to the mechanical resonance while Raman spectroscopy allows a purely spectral detection of mechanical resonance at the nanoscale. Such spectroscopic detection reveals the coupling between a strained nano-resonator and the energy of an inelastically scattered photon, and thus offers a new approach for optomechanics

Iceland is an episodic source of atmospheric ice-nucleating particles relevant for mixed-phase clouds.

Ice-nucleating particles (INPs) have the potential to remove much of the liquid water in climatically important mid- to high-latitude shallow supercooled clouds, markedly reducing their albedo. The INP sources at these latitudes are very poorly defined, but it is known that there are substantial dust sources across the high latitudes, such as Iceland. Here, we show that Icelandic dust emissions are sporadically an important source of INPs at mid to high latitudes by combining ice-nucleating active site density measurements of aircraft-collected Icelandic dust samples with a global aerosol model. Because Iceland is only one of many high-latitude dust sources, we anticipate that the combined effect of all these sources may strongly contribute to the INP population in the mid- and high-latitude northern hemisphere. This is important because these emissions are directly relevant for the cloud-phase climate feedback and because high-latitude dust emissions are expected to increase in a warmer climate

Outcomes of TB Treatment by HIV Status in National Recording Systems in Brazil, 2003–2008

BACKGROUND: Although the Brazilian national reporting system for tuberculosis cases (SINAN) has enormous potential to generate data for policy makers, formal assessments of treatment outcomes and other aspects of TB morbidity and mortality are not produced with enough depth and rigor. In particular, the effect of HIV status on these outcomes has not been fully explored, partly due to incomplete recording in the national database. METHODOLOGY/PRINCIPAL FINDINGS: In a retrospective cohort study, we assessed TB treatment outcomes, including rates of cure, default, mortality, transfer and multidrug resistant TB (MDR-TB) among a purposively chosen sample of 161,481 new cases reported in SINAN between 2003 and 2008. The study population included all new cases reported in the six States with the highest level of completeness of the HIV status field in the system. These cases were mostly male (67%), white (62%), had pulmonary TB (79%) and a suspect chest X ray (83%). Treatment outcomes were best for those HIV negative cases and worst for those known HIV positive patients (cure rate of 85.7% and 55.7% respectively). In multivariate modeling, the risk of having an unfavorable outcome (all outcomes except cure) was 3.09 times higher for those HIV positive compared with those HIV negative (95% CI 3.02-3.16). The risk of death and default also increased with HIV positivity. The group without a known HIV status showed intermediate outcomes between the groups above, suggesting that this group includes some with HIV infection. CONCLUSIONS: HIV status played an important role in TB treatment outcomes in the study period. The outcomes observed in those with known HIV were poor and need to be improved. Those in the group with unknown HIV status indicate the need for wider HIV testing among new TB cases

Ten-year patient-reported outcomes following total and minimally invasive unicompartmental knee arthroplasty: a propensity score-matched cohort analysis

Purpose For patients with medial compartment arthritis who have failed non-operative treatment, either a total knee arthroplasty (TKA) or a unicompartmental knee arthroplasty (UKA) can be undertaken. This analysis considers how the choice between UKA and TKA affects long-term patient-reported outcome measures (PROMs). Methods The Knee Arthroplasty Trial (KAT) and a cohort of patients who received a minimally invasive UKA provided data. Propensity score matching was used to identify comparable patients. Oxford Knee Score (OKS), its pain and function components, and the EuroQol 5 Domain (EQ-5D) index, estimated on the basis of OKS responses, were then compared over 10 years following surgery. Mixed-effects regressions for repeated measures were used to estimate the effect of patient characteristics and type of surgery on PROMs. Results Five-hundred and ninety UKAs were matched to the same number of TKAs. Receiving UKA rather than TKA was found to be associated with better scores for OKS, including both its pain and function components, and EQ-5D, with the differences expected to grow over time. UKA was also associated with an increased likelihood of patients achieving a successful outcome, with an increased chance of attaining minimally clinically important improvements in both OKS and EQ-5D, and an ‘excellent’ OKS. In addition, for both procedures, patients aged between 60 and 70 and better pre-operative scores were associated with better post-operative outcomes. Conclusion Minimally invasive UKAs performed on patients with the appropriate indications led to better patient-reported pain and function scores than TKAs performed on comparable patients. UKA can lead to better long-term quality of life than TKA and this should be considered alongside risk of revision when choosing between the procedures

Kinetic modelling of competition and depletion of shared miRNAs by competing endogenous RNAs

Non-conding RNAs play a key role in the post-transcriptional regulation of mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact with their target RNAs through protein-mediated, sequence-specific binding, giving rise to extended and highly heterogeneous miRNA-RNA interaction networks. Within such networks, competition to bind miRNAs can generate an effective positive coupling between their targets. Competing endogenous RNAs (ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk. Albeit potentially weak, ceRNA interactions can occur both dynamically, affecting e.g. the regulatory clock, and at stationarity, in which case ceRNA networks as a whole can be implicated in the composition of the cell's proteome. Many features of ceRNA interactions, including the conditions under which they become significant, can be unraveled by mathematical and in silico models. We review the understanding of the ceRNA effect obtained within such frameworks, focusing on the methods employed to quantify it, its role in the processing of gene expression noise, and how network topology can determine its reach.Comment: review article, 29 pages, 7 figure

Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration.

Gas1 and Boc/Cdon act as co-receptors in the vertebrate Hedgehog signalling pathway, but the nature of their interaction with the primary Ptch1/2 receptors remains unclear. Here we demonstrate, using primordial germ cell migration in mouse as a developmental model, that specific hetero-complexes of Ptch2/Gas1 and Ptch1/Boc mediate the process of Smo de-repression with different kinetics, through distinct modes of Hedgehog ligand reception. Moreover, Ptch2-mediated Hedgehog signalling induces the phosphorylation of Creb and Src proteins in parallel to Gli induction, identifying a previously unknown Ptch2-specific signal pathway. We propose that although Ptch1 and Ptch2 functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas1 may determine the outcome of Hedgehog signalling through compartmentalisation and modulation of Smo-downstream signalling. Our study identifies the existence of a divergent Hedgehog signal pathway mediated by Ptch2 and provides a mechanism for differential interpretation of Hedgehog signalling in the germ cell niche

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

The deep sea is a major sink for microplastic debris

Marine debris, mostly consisting of plastic, is a global problem, negatively impacting wildlife, tourism and shipping. However, despite the durability of plastic, and the exponential increase in its production, monitoring data show limited evidence of concomitant increasing concentrations in marine habitats. There appears to be a considerable proportion of the manufactured plastic that is unaccounted for in surveys tracking the fate of environmental plastics. Even the discovery of widespread accumulation of microscopic fragments (microplastics) in oceanic gyres and shallow water sediments is unable to explain the missing fraction. Here, we show that deep-sea sediments are a likely sink for microplastics. Microplastic, in the form of fibres, was up to four orders of magnitude more abundant (per unit volume) in deep-sea sediments from the Atlantic Ocean, Mediterranean Sea and Indian Ocean than in contaminated sea-surface waters. Our results show evidence for a large and hitherto unknown repository of microplastics. The dominance of microfibres points to a previously underreported and unsampled plastic fraction. Given the vastness of the deep sea and the prevalence of microplastics at all sites we investigated, the deep-sea floor appears to provide an answer to the question— where is all the plastic? </jats:p