How to design and evaluate interventions to improve outcomes for patients with multimorbidity

Multimorbidity is a major challenge for patients and healthcare providers. The limited evidence of the effectiveness of interventions for people with multimorbidity means that there is a need for much more research and trials of potential interventions. Here we present a consensus view from a group of international researchers working to improve care for people with multimorbidity to guide future studies of interventions. We suggest that there is a need for careful consideration of whom to include, how to target interventions that address specific problems and that do not add to treatment burden, and selecting outcomes that matter both to patients and the healthcare system. Innovative design of these interventions will be necessary as many will be introduced in service settings and it will be important to ensure methodological rigour, relevance to service delivery, and generalizability across healthcare systems

An Altered Immune Response, but Not Individual Cationic Antimicrobial Peptides, Is Associated with the Oral Attenuation of Ara4N-Deficient Salmonella enterica Serovar Typhimurium in Mice

Salmonella enterica serovar Typhimurium (S. Typhimurium) uses two-component regulatory systems (TCRS) to respond to stimuli in the local microenvironment. Upon infection, the Salmonella TCRSs PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB) are activated by environmental signals in the intestinal lumen and within host cells. TCRS-mediated gene expression results in lipopolysaccharide (LPS) modification and cationic antimicrobial peptide resistance. The PmrA-regulated pmrHFIJKLM operon mediates 4-amino-4-deoxy-L-arabinose (Ara4N) production and attachment to the lipid A of LPS. A ΔpmrF S. Typhimurium strain cannot produce Ara4N, exhibits increased sensitivity to cationic antimicrobial peptide (CAMP)-mediated killing, and attenuated virulence in mice upon oral infection. CAMPs are predicted to play a role in elimination of Salmonella, and may activate PhoPQ and PmrAB in vivo, which could increase bacterial resistance to host defenses. Competition experiments between wild type (WT) and ΔpmrF mutant strains of S. Typhimurium indicated that selection against this mutant first occurs within the intestinal lumen early during infection. However, CRAMP and active cryptdins alone are not responsible for elimination of Ara4N-deficient bacteria in vivo. Investigation into the early immune response to ΔpmrF showed that it differed slightly from the early immune response to WT S. Typhimurium. Further investigation into the early immune response to infection of Peyer's patches suggests a role for IL-13 in the attenution of the ΔpmrF mutant strain. Thus, prominent CAMPs present in the mouse intestine are not responsible for the selection against the ΔpmrF strain in this location, but limited alterations in innate immune induction were observed that affect bacterial survival and virulence

Kinetic modelling of dissolution dynamic nuclear polarisation 13C magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours

Dissolution dynamic nuclear polarisation (dDNP) of 13C-labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised 13C-labelled pyruvate (13C1-pyruvate) and urea (13C-urea), a nonmetabolised marker. A general mathematical model of pyruvate-lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, Kip, and the forward and reverse fractional rate constants for pyruvate-lactate signal exchange, kpl and klp. An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, Kiu. A spectral fitting procedure to blood time-course data proved superior to assuming a gamma-variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. Kiu equalled Kip, indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (kpo, klo and kuo, respectively) indicated that T1s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor-product model, using the tumour pyruvate signal time-course as the input for the corresponding lactate signal time-course, was modified to account for the observed delay between them. The corresponding fractional rate constant, kavail, most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T1 for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required

The foot in forensic human identification - a review

The identification of human remains is a process which can be attempted irrespective of the stage of decomposition in which the remains are found or the anatomical regions recovered. In recent years, the discovery of fragmented human remains has garnered significant attention from the national and international media, particularly the recovery of multiple lower limbs and feet from coastlines in North America. While cases such as these stimulate public curiosity, they present unique challenges to forensic practitioners in relation to the identification of the individual from whom the body part originated. There is a paucity of literature pertaining to the foot in forensic human identification and in particular, in relation to the assessment of the parameters represented by the biological profile. This article presents a review of the literature relating to the role of the foot in forensic human identification and highlights the areas in which greater research is required. © 2013

Diffuse inverse Compton and synchrotron emission from dark matter annihilations in galactic satellites

Annihilating dark matter particles produce roughly as much power in electrons and positrons as in gamma ray photons. The charged particles lose essentially all of their energy to inverse Compton and synchrotron processes in the galactic environment. We discuss the diffuse signature of dark matter annihilations in satellites of the Milky Way (which may be optically dark with few or no stars), providing a tail of emission trailing the satellite in its orbit. Inverse Compton processes provide X-rays and gamma rays, and synchrotron emission at radio wavelengths might be seen. We discuss the possibility of detecting these signals with current and future observations, in particular EGRET and GLAST for the gamma rays.Comment: 13 pages, 5 figure

Association between CMD signs and symptoms, oral parafunctions, race and sex, in 4–6-year-old African-American and Caucasian children

The associations between oral parafunctions, signs and symptoms of craniomandibular disorders (CMD), race, and sex were analysed in recordings from 203 4-6-year-old African-American and Caucasian children. Significant correlations were found between bruxism, nail biting, thumb sucking and most of the CMD signs and symptoms. There were also significant associations between most of the signs and symptoms and race, while significant association with sex was found only regarding headache, TMJ sounds and chewing pain. Significant associations were found between most CMD signs and TMJ sounds supporting the view that joint sound recordings have diagnostic value. There were also significant associations between the pain variables recorded by questionnaire and those recorded by palpation, which indicates that reliable data can be obtained by interviewing children as young as five. The results of this study support the concept that oral parafunctions have a significant role in the aetiology of CMD. The results also show that race and sex need to be considered when analysing the possible aetiological role of oral parafunctions in CMD. Longitudinal studies, beginning with low age groups are needed to better determine the role of childhood oral parafunctions in CMD aetiology.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75673/1/j.1365-2842.1995.tb00241.x.pd

The evolution of galaxy groups and of galaxies therein

Properties of groups of galaxies depend sensitively on the algorithm for group selection, and even the most recent catalogs of groups built from redshift-space selection should suffer from projections and infalling galaxies. The cosmo-dynamical evolution of groups from initial Hubble expansion to collapse and virialization leads to a fundamental track (FT) in virial-theorem-M/L vs crossing time. The increased rates of mergers, both direct and after dynamical friction, in groups relative to clusters, explain the higher fraction of elliptical galaxies at given local number density in X-ray selected groups, relative to clusters, even when the hierarchical evolution of groups is considered. Galaxies falling into groups and clusters should later travel outwards to typically 2 virial radii, which is somewhat less than the outermost radius where observed galaxy star formation efficiencies are enhanced relative to field galaxies of same morphological type. An ongoing analysis of the internal kinematics of X-ray selected groups suggests that the radial profiles of line of sight velocity dispersion are consistent with isotropic NFW distributions for the total mass density, with higher (lower) concentrations than LambdaCDM predictions in groups of high (low) mass. The critical mass, at M200 ~ 10^13 M_sun is consistent with possible breaks in the X-ray luminosity-temperature and Fundamental Plane relations. The internal kinematics of groups indicate that the M-T relation of groups should agree with that extrapolated from clusters with no break at the group scale. The analyses of observed velocity dispersion profiles and of the FT both suggest that low velocity dispersion groups (compact and loose, X-ray emitting or undetected) are quite contaminated by chance projections.Comment: Invited review, ESO workshop "Groups of Galaxies in the Nearby Universe", held in Santiago, Chile, 5-9 December 2005, ed. I. Saviane, V. Ivanov & J. Borissova, 16 page

Understanding Galaxy Formation and Evolution

The old dream of integrating into one the study of micro and macrocosmos is now a reality. Cosmology, astrophysics, and particle physics intersect in a scenario (but still not a theory) of cosmic structure formation and evolution called Lambda Cold Dark Matter (LCDM) model. This scenario emerged mainly to explain the origin of galaxies. In these lecture notes, I first present a review of the main galaxy properties, highlighting the questions that any theory of galaxy formation should explain. Then, the cosmological framework and the main aspects of primordial perturbation generation and evolution are pedagogically detached. Next, I focus on the ``dark side'' of galaxy formation, presenting a review on LCDM halo assembling and properties, and on the main candidates for non-baryonic dark matter. It is shown how the nature of elemental particles can influence on the features of galaxies and their systems. Finally, the complex processes of baryon dissipation inside the non-linearly evolving CDM halos, formation of disks and spheroids, and transformation of gas into stars are briefly described, remarking on the possibility of a few driving factors and parameters able to explain the main body of galaxy properties. A summary and a discussion of some of the issues and open problems of the LCDM paradigm are given in the final part of these notes.Comment: 50 pages, 10 low-resolution figures (for normal-resolution, DOWNLOAD THE PAPER (PDF, 1.9 Mb) FROM http://www.astroscu.unam.mx/~avila/avila.pdf). Lectures given at the IV Mexican School of Astrophysics, July 18-25, 2005 (submitted to the Editors on March 15, 2006

Structure, mass and stability of galactic disks

In this review I concentrate on three areas related to structure of disks in spiral galaxies. First I will review the work on structure, kinematics and dynamics of stellar disks. Next I will review the progress in the area of flaring of HI layers. These subjects are relevant for the presence of dark matter and lead to the conclusion that disk are in general not `maximal', have lower M/L ratios than previously suspected and are locally stable w.r.t. Toomre's Q criterion for local stability. I will end with a few words on `truncations' in stellar disks.Comment: Invited review at "Galaxies and their Masks" for Ken Freeman's 70-th birthday, Sossusvlei, Namibia, April 2010. A version with high-res. figures is available at http://www.astro.rug.nl/~vdkruit/jea3/homepage/Namibiachapter.pd