Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)

This article introduces the new 5-level EQ-5D (EQ-5D-5L) health status measure. EQ-5D currently measures health using three levels of severity in five dimensions. A EuroQol Group task force was established to find ways of improving the instrument's sensitivity and reducing ceiling effects by increasing the number of severity levels. The study was performed in the United Kingdom and Spain. Severity labels for 5 levels in each dimension were identified using response scaling. Focus groups were used to investigate the face and content validity of the new versions, including hypothetical health states generated from those versions. Selecting labels at approximately the 25th, 50th, and 75th centiles produced two alternative 5-level versions. Focus group work showed a slight preference for the wording 'slight-moderate-severe' problems, with anchors of 'no problems' and 'unable to do' in the EQ-5D functional dimensions. Similar wording was used in the Pain/Discomfort and Anxiety/Depression dimensions. Hypothetical health states were well understood though participants stressed the need for the internal coherence of health states. A 5-level version of the EQ-5D has been developed by the EuroQol Group. Further testing is required to determine whether the new version improves sensitivity and reduces ceiling effects

Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe

Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery1,2, spreading efficiently via low-dose fecal-oral transmission3,4. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries, but is now emerging as a problem in the developing world, apparently replacing the more diverse S. flexneri in areas undergoing economic development and improvements in water quality4-6. Classical approaches have shown S. sonnei is genetically conserved and clonal7. We report here whole-genome sequencing of 132 globally-distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and has diversified into several distinct lineages with unique characteristics. Our analysis suggests the majority of this diversification occurred in Europe, followed by more recent establishment of local pathogen populations in other continents predominantly due to the pandemic spread of a single, rapidly-evolving, multidrug resistant lineage

A Shigella boydii bacteriophage which resembles Salmonella phage ViI

<p>Abstract</p> <p>Background</p> <p>Lytic bacteriophages have been applied successfully to control the growth of various foodborne pathogens. Sequencing of their genomes is considered as an important preliminary step to ensure their safety prior to food applications.</p> <p>Results</p> <p>The lytic bacteriophage, ΦSboM-AG3, targets the important foodborne pathogen, <it>Shigella</it>. It is morphologically similar to phage ViI of <it>Salmonella enterica </it>serovar Typhi and a series of phages of <it>Acinetobacter calcoaceticus </it>and <it>Rhizobium meliloti</it>. The complete genome of ΦSboM-AG3 was determined to be 158 kb and was terminally redundant and circularly permuted. Two hundred and sixteen open reading frames (ORFs) were identified and annotated, most of which displayed homology to proteins of <it>Salmonella </it>phage ViI. The genome also included four genes specifying tRNAs.</p> <p>Conclusions</p> <p>This is the first time that a Vi-specific phage for <it>Shigella </it>has been described. There is no evidence for the presence of virulence and lysogeny-associated genes. In conclusion, the genome analysis of ΦSboM-AG3 indicates that this phage can be safely used for biocontrol purposes.</p

Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates

Sporadic mitochondrial DNA mutations serve as clonal marks providing access to the identity and lineage potential of stem cells within human tissues. By combining quantitative clonal mapping with 3D reconstruction of adult human prostates, we show that multipotent basal stem cells, confined to discrete niches in juxta-urethral ducts, generate bipotent basal progenitors in directed epithelial migration streams. Basal progenitors are then dispersed throughout the entire glandular network, dividing and differentiating to replenish the loss of apoptotic luminal cells. Rare lineage-restricted luminal stem cells, and their progeny, are confined to proximal ducts and provide only minor contribution to epithelial homeostasis. In situ cell capture from clonal maps identified delta homolog 1 (DLK1) enrichment of basal stem cells, which was validated in functional spheroid assays. This study establishes significant insights into niche organization and function of prostate stem and progenitor cells, with implications for disease.This work was supported by grants from The Royal College of Surgeons of England and a Cancer Research UK Clinician Scientist Fellowship (C10169/A12173). This work was also supported by the Wellcome Trust (grant 098357/Z/12/Z to B.D.S. and grant 110326/Z/15/Z to E.H.). E.H. is funded by a Junior Research Fellowship from Trinity College, Cambridge, a Sir Henry Wellcome Fellowship from the Wellcome Trust and acknowledges the Bettencourt-Schueller Young Researcher Prize for support. L.C.G., D.M.T., and R.W.T. are supported by the Wellcome Trust Centre Strategic Award (096919/Z/11/Z). R.W.T. is also supported by the Medical Research Council (MRC) Centre for Neuromuscular Diseases (G0601943), the Lily Foundation, and the UK National Health Service (NHS) Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service. L.C.G. and D.M.T. receive support from the Newcastle University Centre for Ageing and Vitality funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the Engineering and Physical Sciences Research Council (EPSRC), the Economic and Social Research Council (ESRC), and MRC as part of the cross-council Lifelong Health and Wellbeing Initiative

Effect of an education programme for patients with osteoarthritis in primary care - a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis (OA) is a degenerative disease, considered to be one of the major public health problems. Research suggests that patient education is feasible and valuable for achieving improvements in quality of life, in function, well-being and improved coping. Since 1994, Primary Health Care in Malmö has used a patient education programme directed towards OA. The aim of this study was to evaluate the effects of this education programme for patients with OA in primary health care in terms of self-efficacy, function and self-perceived health.</p> <p>Method</p> <p>The study was a single-blind, randomized controlled trial (RCT) in which the EuroQol-5D and Arthritis self-efficacy scale were used to measure self-perceived health and self-efficacy and function was measured with Grip Ability Test for the upper extremity and five different functional tests for the lower extremity.</p> <p>Results</p> <p>We found differences between the intervention group and the control group, comparing the results at baseline and after 6 months in EuroQol-5D (p < 0.001) and in standing one leg eyes closed (p = 0.02) in favour of the intervention group. No other differences between the groups were found.</p> <p>Conclusion</p> <p>This study has shown that patient education for patients with osteoarthritis is feasible in a primary health care setting and can improve self-perceived health as well as function in some degree, but not self-efficacy. Further research to investigate the effect of exercise performance on function, as well as self-efficacy is warranted.</p> <p>Trial registration</p> <p>The trial is registered with ClinicalTrials.gov. Registration number: NCT00979914</p

Light-Induced Fos Expression in Intrinsically Photosensitive Retinal Ganglion Cells in Melanopsin Knockout (Opn4−/−) Mice

Retinal ganglion cells that express the photopigment melanopsin are intrinsically photosensitive (ipRGCs) and exhibit robust synaptically driven ON-responses to light, yet they will continue to depolarize in response to light when all synaptic input from rod and cone photoreceptors is removed. The light-evoked increase in firing of classical ganglion cells is determined by synaptic input from ON-bipolar cells in the proximal sublamina of the inner plexiform layer. OFF-bipolar cells synapse with ganglion cell dendrites in the distal sublamina of the inner plexiform layer. Of the several types of ipRGC that have been described, M1 ipRGCs send dendrites exclusively into the OFF region of the inner plexiform layer where they stratify near the border of the inner nuclear layer. We tested whether M1 ipRGCs with dendrites restricted to the OFF sublamina of the inner plexiform layer receive synaptic ON-bipolar input by examining light-induced gene expression in vivo using melanopsin knockout mice. Mice in which both copies of the melanopsin gene (opn4) have been replaced with the tau-lacZ gene (homozygous tau-lacZ+/+ knockin mice) are melanopsin knockouts (opn4−/−) but M1 ipRGCs are specifically identified by their expression of β-galactosidase. Approximately 60% of M1 ipRGCs in Opn4−/− mice exposed to 3 hrs of light expressed c-Fos; no β-galactosidase-positive RGCs expressed c-Fos in the dark. Intraocular application of L-AP4, a compound which blocks transmission of visual signals between photoreceptors and ON-bipolar cells significantly reduced light-evoked c-Fos expression in M1 ipRGCs compared to saline injected eyes (66% saline vs 27% L-AP4). The results are the first description of a light-evoked response in an ipRGC lacking melanopsin and provide in vivo confirmation of previous in vitro observations illustrating an unusual circuit in the retina in which ganglion cells sending dendrites to the OFF sublamina of the inner plexiform layer receive excitatory synaptic input from ON-bipolar cells

The impact of trained patient educators on musculoskeletal clinical skills attainment in pre-clerkship medical students

<p>Abstract</p> <p>Background</p> <p>Despite the high burden of musculoskeletal (MSK) diseases, few generalists are comfortable teaching MSK physical examination (PE) skills. Patient Partners^®in Arthritis (PP^®IA) is a standardized patient educator program that could potentially supplement current MSK PE teaching. This study aims to determine if differences exist in MSK PE skills between non-MSK specialist physician and PP^®IA taught students.</p> <p>Methods</p> <p>Pre-clerkship medical students attended 2-hour small group MSK PE teaching by either non-MSK specialist physician tutors or by PP^®IA. All students underwent an MSK OSCE and completed retrospective pre-post questionnaires regarding comfort with MSK PE and interest in MSK.</p> <p>Results</p> <p>83 students completed the OSCE (42 PP^®IA, 41 physician taught) and 82 completed the questionnaire (42 PP^®IA, 40 physician taught). There were no significant differences between groups in OSCE scores. For all questionnaire items, post-session ratings were significantly higher than pre-session ratings for both groups. In exploratory analysis PP^®IA students showed significantly greater improvement in 12 of 22 questions including three of five patient-centred learning questions.</p> <p>Conclusions</p> <p>PP^®IA MSK PE teaching is as good as non-MSK specialist physician tutor teaching when measured by a five station OSCE and provide an excellent complementary resource to address current deficits in MSK PE teaching.</p

Association Analysis of 94 Candidate Genes and Schizophrenia-Related Endophenotypes

While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research