Association between glucocorticoid therapy and incidence of diabetes mellitus in polymyalgia rheumatica and giant cell arteritis: a systematic review and meta-analysis

Background: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are almost always treated with glucocorticoids (GCs), but long-term GC use is associated with diabetes mellitus (DM). The absolute incidence of this complication in this patient group remains unclear. Objective: To quantify the absolute risk of GC-induced DM in PMR and GCA from published literature. Methods: We identified literature from inception to February 2017 reporting diabetes following exposure to oral GC in patients with PMR and/or GCA without pre-existing diabetes. A random-effects meta-analysis was performed to summarise the findings. Results: 25 eligible publications were identified. In studies of patients with GCA, mean cumulative GC dose was almost 1.5 times higher than in studies of PMR (8.2 g vs 5.6 g), with slightly longer treatment duration and longer duration of follow-up (6.4 years vs 4.4 years). The incidence proportion (cumulative incidence) of patients who developed new-onset DM was 6% (95% CI 3% to 9%) for PMR and 13% (95% CI 9% to 17%) for GCA. Based on UK data on incidence rate of DM in the general population, the expected background incidence rate of DM over 4.4 years in patients with PMR and 6.4 years in patients with GCA (follow-up duration) would be 4.8% and 7.0%, respectively. Heterogeneity between studies was high (I2=79.1%), as there were differences in study designs, patient population, geographical locations and treatment. Little information on predictors of DM was found. Conclusion: Our meta-analysis produced plausible estimates of DM incidence in patients with PMR and GCA, but there is insufficient published data to allow precise quantification of DM risk

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity.

There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.NGB is supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.clon.2015.06.01

Concealed concern: Fathers' experience of having a child with Juvenile Idiopathic Arthritis

Despite increased research into families of chronically ill children, more needs to be known about the father’s experience. We address this issue through asking: ‘What is it like to be the father of a child with juvenile idiopathic arthritis?’ (JIA). Four members of eight families with an adolescent diagnosed with JIA, including seven fathers, were interviewed and transcripts analyzed using grounded theory. This study suggests that fathers of children with JIA experience several severe losses which are exacerbated through comparisons they make between their own situation and that of fathers of healthy children. In addition, the fathers faced several constraints which reduced their opportunities to communicate with their ill child through shared activities. Fathers appeared to conceal their distress by adopting strategies of denial and distraction however their adjustment was facilitated, to some extent, by social support. They could also develop greater acceptance of their situation over time as the care of their ill child became assimilated into family life and constraints upon their life gradually reduced through the increased maturity of their son or daughter with JIA. These findings have implications for healthcare professionals and voluntary organizations

Anomalous structure in the single particle spectrum of the fractional quantum Hall effect

The two-dimensional electron system (2DES) is a unique laboratory for the physics of interacting particles. Application of a large magnetic field produces massively degenerate quantum levels known as Landau levels. Within a Landau level the kinetic energy of the electrons is suppressed, and electron-electron interactions set the only energy scale. Coulomb interactions break the degeneracy of the Landau levels and can cause the electrons to order into complex ground states. In the high energy single particle spectrum of this system, we observe salient and unexpected structure that extends across a wide range of Landau level filling fractions. The structure appears only when the 2DES is cooled to very low temperature, indicating that it arises from delicate ground state correlations. We characterize this structure by its evolution with changing electron density and applied magnetic field. We present two possible models for understanding these observations. Some of the energies of the features agree qualitatively with what might be expected for composite Fermions, which have proven effective for interpreting other experiments in this regime. At the same time, a simple model with electrons localized on ordered lattice sites also generates structure similar to those observed in the experiment. Neither of these models alone is sufficient to explain the observations across the entire range of densities measured. The discovery of this unexpected prominent structure in the single particle spectrum of an otherwise thoroughly studied system suggests that there exist core features of the 2DES that have yet to be understood.Comment: 15 pages, 10 figure

Definitions and Standardization of a New Grading Scheme for Eyelid Contour Abnormalities after Trichiasis Surgery

Approximately 8 million individuals worldwide suffer from trichiasis, a condition characterized by in-turned lashes that rub against the eye. Trichiasis is caused by repeated or prolonged ocular infection with Chlamydia trachomatis. Surgery is available to correct in-turned lashes. In most programmatic and research settings, the primary determinant of surgical success is whether or not lashes are touching the globe post-operatively. However, other surgical outcomes such as the contour of the eyelid are also important. Yet, no standard method for evaluating and reporting this outcome has been defined. In this study, we developed and tested a grading system for evaluating the severity of eyelid contour abnormalities after surgery using photographs of eyelids six weeks post-operatively. We found good agreement across photograph graders and also between field and photograph grades. This system should be useful in helping to standardize reporting of this outcome

Imaging cytoplasmic cAMP in mouse brainstem neurons

<p>Abstract</p> <p>Background</p> <p>cAMP is an ubiquitous second messenger mediating various neuronal functions, often as a consequence of increased intracellular Ca²⁺levels. While imaging of calcium is commonly used in neuroscience applications, probing for cAMP levels has not yet been performed in living vertebrate neuronal tissue before.</p> <p>Results</p> <p>Using a strictly neuron-restricted promoter we virally transduced neurons in the organotypic brainstem slices which contained pre-Bötzinger complex, constituting the rhythm-generating part of the respiratory network. Fluorescent cAMP sensor Epac1-camps was expressed both in neuronal cell bodies and neurites, allowing us to measure intracellular distribution of cAMP, its absolute levels and time-dependent changes in response to physiological stimuli. We recorded [cAMP]_ichanges in the micromolar range after modulation of adenylate cyclase, inhibition of phosphodiesterase and activation of G-protein-coupled metabotropic receptors. [cAMP]_ilevels increased after membrane depolarisation and release of Ca²⁺from internal stores. The effects developed slowly and reached their maximum after transient [Ca²⁺]_ielevations subsided. Ca²⁺-dependent [cAMP]_itransients were suppressed after blockade of adenylate cyclase with 0.1 mM adenylate cyclase inhibitor 2'5'-dideoxyadenosine and potentiated after inhibiting phosphodiesterase with isobutylmethylxanthine and rolipram. During paired stimulations, the second depolarisation and Ca²⁺release evoked bigger cAMP responses. These effects were abolished after inhibition of protein kinase A with H-89 pointing to the important role of phosphorylation of calcium channels in the potentiation of [cAMP]_itransients.</p> <p>Conclusion</p> <p>We constructed and characterized a neuron-specific cAMP probe based on Epac1-camps. Using viral gene transfer we showed its efficient expression in organotypic brainstem preparations. Strong fluorescence, resistance to photobleaching and possibility of direct estimation of [cAMP] levels using dual wavelength measurements make the probe useful in studies of neurons and the mechanisms of their plasticity. Epac1-camps was applied to examine the crosstalk between Ca²⁺and cAMP signalling and revealed a synergism of actions of these two second messengers.</p

Can we continue research in splenectomized dogs? Mycoplasma haemocanis: Old problem - New insight

We report the appearance of a Mycoplasma haemocanis infection in laboratory dogs, which has been reported previously, yet, never before in Europe. Outbreak of the disease was triggered by a splenectomy intended to prepare the dogs for a hemorrhagic shock study. The clinical course of the dogs was dramatic including anorexia and hemolytic anemia. Treatment included allogeneic transfusion, prednisone, and oxytetracycline. Systematic follow-up (n=12, blood smears, antibody testing and specific polymerase chain reaction) gives clear evidence that persistent eradication of M. haemocanis is unlikely. We, therefore, had to abandon the intended shock study. In the absence of effective surveillance and screening for M. haemocanis, the question arises whether it is prudent to continue shock research in splenectomized dogs. Copyright (C) 2004 S. Karger AG, Basel

Sampling constrained probability distributions using Spherical Augmentation

Statistical models with constrained probability distributions are abundant in machine learning. Some examples include regression models with norm constraints (e.g., Lasso), probit, many copula models, and latent Dirichlet allocation (LDA). Bayesian inference involving probability distributions confined to constrained domains could be quite challenging for commonly used sampling algorithms. In this paper, we propose a novel augmentation technique that handles a wide range of constraints by mapping the constrained domain to a sphere in the augmented space. By moving freely on the surface of this sphere, sampling algorithms handle constraints implicitly and generate proposals that remain within boundaries when mapped back to the original space. Our proposed method, called {Spherical Augmentation}, provides a mathematically natural and computationally efficient framework for sampling from constrained probability distributions. We show the advantages of our method over state-of-the-art sampling algorithms, such as exact Hamiltonian Monte Carlo, using several examples including truncated Gaussian distributions, Bayesian Lasso, Bayesian bridge regression, reconstruction of quantized stationary Gaussian process, and LDA for topic modeling.Comment: 41 pages, 13 figure

Understanding innovators' experiences of barriers and facilitators in implementation and diffusion of healthcare service innovations: A qualitative study

This article is made available through the Brunel Open Access Publishing Fund - Copyright @ 2011 Barnett et al.Background: Healthcare service innovations are considered to play a pivotal role in improving organisational efficiency and responding effectively to healthcare needs. Nevertheless, healthcare organisations encounter major difficulties in sustaining and diffusing innovations, especially those which concern the organisation and delivery of healthcare services. The purpose of the present study was to explore how healthcare innovators of process-based initiatives perceived and made sense of factors that either facilitated or obstructed the innovation implementation and diffusion. Methods: A qualitative study was designed. Fifteen primary and secondary healthcare organisations in the UK, which had received health service awards for successfully generating and implementing service innovations, were studied. In-depth, semi structured interviews were conducted with the organisational representatives who conceived and led the development process. The data were recorded, transcribed and thematically analysed. Results: Four main themes were identified in the analysis of the data: the role of evidence, the function of inter-organisational partnerships, the influence of human-based resources, and the impact of contextual factors. "Hard" evidence operated as a proof of effectiveness, a means of dissemination and a pre-requisite for the initiation of innovation. Inter-organisational partnerships and people-based resources, such as champions, were considered an integral part of the process of developing, establishing and diffusing the innovations. Finally, contextual influences, both intra-organisational and extra-organisational were seen as critical in either impeding or facilitating innovators' efforts. Conclusions: A range of factors of different combinations and co-occurrence were pointed out by the innovators as they were reflecting on their experiences of implementing, stabilising and diffusing novel service initiatives. Even though the innovations studied were of various contents and originated from diverse organisational contexts, innovators' accounts converged to the significant role of the evidential base of success, the inter-personal and inter-organisational networks, and the inner and outer context. The innovators, operating themselves as important champions and being often willing to lead constructive efforts of implementation to different contexts, can contribute to the promulgation and spread of the novelties significantly.This research was supported financially by the Multidisciplinary Assessment of Technology Centre for Healthcare (MATCH)