441 research outputs found
Benchmarking clinical management of spinal and non-spinal disorders using quality of life: results from the EPI3-LASER survey in primary care
Concerns have been raised regarding sub-optimal utilization of analgesics and psychotropic drugs in the treatment of patients with chronic musculoskeletal disorders (MSDs) and their associated co-morbidities. The objective of this study was to describe drug prescriptions for the management of spinal and non-spinal MSDs contrasted against a standardized measure of quality of life. A representative population sample of 1,756 MSDs patients [38.5% with spinal disorder (SD) and 61.5% with non-spinal MSDs (NS-MSD)] was drawn from the EPI3-LASER survey of 825 general practitioners (GPs) in France. Physicians recorded their diagnoses and prescriptions on that day. Patients provided information on socio-demographics, lifestyle and quality of life using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than 12 weeks duration of the current episode. Chronic SD and NS-MSD patients were prescribed less analgesics and non-steroidal anti-inflammatory drugs than their non-chronic counterpart [odds ratios (OR) and 95% confidence intervals (CI), respectively: 0.4, 0.2–0.7 and 0.5, 0.3–0.6]. They also had more anxio-depressive co-morbidities reported by their physicians (SD: 16.1 vs.7.4%; NS-MSD: 21.6 vs. 9.5%) who prescribed more antidepressants and anxiolytics with a difference that was statistically significant only for spinal disorder patients (OR, 95% CI: 2.0, 1.1–3.6). Psychotropic drugs were more often prescribed in patients in the lower quartile of SF-12 mental score and prescriptions of analgesics in the lower quartile of SF-12 physical score (P < 0.001). In conclusion, anxiety and depressive disorders were commonly reported by GPs among chronic MSD patients. Their prescriptions of psychotropic and analgesic drugs were consistent with patients’ self-rated mental and physical health
A critical appraisal of guidelines for the management of knee osteoarthritis using Appraisal of Guidelines Research and Evaluation criteria
Clinical practice guidelines have been elaborated to summarize evidence related to the management of knee osteoarthritis and to facilitate uptake of evidence-based knowledge by clinicians. The objectives of the present review were summarizing the recommendations of existing guidelines on knee osteoarthritis, and assessing the quality of the guidelines using a standardized and validated instrument – the Appraisal of Guidelines Research and Evaluation (AGREE) tool. Internet medical literature databases from 2001 to 2006 were searched for guidelines, with six guidelines being identified. Thirteen clinician researchers participated in the review. Each reviewer was trained in the AGREE instrument. The guidelines were distributed to four groups of three or four reviewers, each group reviewing one guideline with the exception of one group that reviewed two guidelines. One independent evaluator reviewed all guidelines. All guidelines effectively addressed only a minority of AGREE domains. Clarity/presentation was effectively addressed in three out of six guidelines, scope/purpose and rigour of development in two guidelines, editorial independence in one guideline, and stakeholder involvement and applicability in none. The clinical management recommendation tended to be similar among guidelines, although interventions addressed varied. Acetaminophen was recommended for initial pain treatment, combined with exercise and education. Nonsteroidal anti-inflammatory drugs were recommended if acetaminophen failed to control pain, but cautiously because of gastrointestinal risks. Surgery was recommended in the presence of persistent pain and disability. Education and activity management interventions were superficially addressed in most guidelines. Guideline creators should use the AGREE criteria when developing guidelines. Innovative and effective methods of knowledge translation to health professionals are needed
Novel Insights into the Bovine Polled Phenotype and Horn Ontogenesis in Bovidae
Despite massive research efforts, the molecular etiology of bovine polledness and the developmental pathways involved in horn ontogenesis are still poorly understood. In a recent article, we provided evidence for the existence of at least two different alleles at the Polled locus and identified candidate mutations for each of them. None of these mutations was located in known coding or regulatory regions, thus adding to the complexity of understanding the molecular basis of polledness. We confirm previous results here and exhaustively identify the causative mutation for the Celtic allele (PC) and four candidate mutations for the Friesian allele (PF). We describe a previously unreported eyelash-and-eyelid phenotype associated with regular polledness, and present unique histological and gene expression data on bovine horn bud differentiation in fetuses affected by three different horn defect syndromes, as well as in wild-type controls. We propose the ectopic expression of a lincRNA in PC/p horn buds as a probable cause of horn bud agenesis. In addition, we provide evidence for an involvement of OLIG2, FOXL2 and RXFP2 in horn bud differentiation, and draw a first link between bovine, ovine and caprine Polled loci. Our results represent a first and important step in understanding the genetic pathways and key process involved in horn bud differentiation in Bovidae
An Epigenetic Switch Involving Overlapping Fur and DNA Methylation Optimizes Expression of a Type VI Secretion Gene Cluster
Type VI secretion systems (T6SS) are macromolecular machines of the cell envelope of Gram-negative bacteria responsible for bacterial killing and/or virulence towards different host cells. Here, we characterized the regulatory mechanism underlying expression of the enteroagregative Escherichia coli sci1 T6SS gene cluster. We identified Fur as the main regulator of the sci1 cluster. A detailed analysis of the promoter region showed the presence of three GATC motifs, which are target of the DNA adenine methylase Dam. Using a combination of reporter fusion, gel shift, and in vivo and in vitro Dam methylation assays, we dissected the regulatory role of Fur and Dam-dependent methylation. We showed that the sci1 gene cluster expression is under the control of an epigenetic switch depending on methylation: fur binding prevents methylation of a GATC motif, whereas methylation at this specific site decreases the affinity of Fur for its binding box. A model is proposed in which the sci1 promoter is regulated by iron availability, adenine methylation, and DNA replication
Comparative genomics of Pseudomonas fluorescens subclade III strains from human lungs
Abstract
Background
While the taxonomy and genomics of environmental strains from the P. fluorescens species-complex has been reported, little is known about P. fluorescens strains from clinical samples. In this report, we provide the first genomic analysis of P. fluorescens strains in which human vs. environmental isolates are compared.
Results
Seven P. fluorescens strains were isolated from respiratory samples from cystic fibrosis (CF) patients. The clinical strains could grow at a higher temperature (>34 °C) than has been reported for environmental strains. Draft genomes were generated for all of the clinical strains, and multi-locus sequence analysis placed them within subclade III of the P. fluorescens species-complex. All strains encoded type- II, −III, −IV, and -VI secretion systems, as well as the widespread colonization island (WCI). This is the first description of a WCI in P. fluorescens strains. All strains also encoded a complete I2/PfiT locus and showed evidence of horizontal gene transfer. The clinical strains were found to differ from the environmental strains in the number of genes involved in metal resistance, which may be a possible adaptation to chronic antibiotic exposure in the CF lung.
Conclusions
This is the largest comparative genomics analysis of P. fluorescens subclade III strains to date and includes the first clinical isolates. At a global level, the clinical P. fluorescens subclade III strains were largely indistinguishable from environmental P. fluorescens subclade III strains, supporting the idea that identifying strains as ‘environmental’ vs ‘clinical’ is not a phenotypic trait. Rather, strains within P. fluorescens subclade III will colonize and persist in any niche that provides the requirements necessary for growth.http://deepblue.lib.umich.edu/bitstream/2027.42/116129/1/12864_2015_Article_2261.pd
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Continuation vs Discontinuation of Renin-Angiotensin System Inhibitors Before Major Noncardiac Surgery
ImportanceBefore surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines.ObjectiveTo evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery.Design, setting, and participantsRandomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France.InterventionPatients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115).Main outcomes and measuresThe primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery.ResultsOf the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes.Conclusions and relevanceAmong patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy.Trial registrationClinicalTrials.gov Identifier: NCT03374449
Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.
Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress
Performance of novel VUV-sensitive Silicon Photo-Multipliers for nEXO
Liquid xenon time projection chambers are promising detectors to search for
neutrinoless double beta decay (0), due to their response
uniformity, monolithic sensitive volume, scalability to large target masses,
and suitability for extremely low background operations. The nEXO collaboration
has designed a tonne-scale time projection chamber that aims to search for
0 of \ce{^{136}Xe} with projected half-life sensitivity of
~yr. To reach this sensitivity, the design goal for nEXO is
1\% energy resolution at the decay -value (~keV).
Reaching this resolution requires the efficient collection of both the
ionization and scintillation produced in the detector. The nEXO design employs
Silicon Photo-Multipliers (SiPMs) to detect the vacuum ultra-violet, 175 nm
scintillation light of liquid xenon. This paper reports on the characterization
of the newest vacuum ultra-violet sensitive Fondazione Bruno Kessler VUVHD3
SiPMs specifically designed for nEXO, as well as new measurements on new test
samples of previously characterised Hamamatsu VUV4 Multi Pixel Photon Counters
(MPPCs). Various SiPM and MPPC parameters, such as dark noise, gain, direct
crosstalk, correlated avalanches and photon detection efficiency were measured
as a function of the applied over voltage and wavelength at liquid xenon
temperature (163~K). The results from this study are used to provide updated
estimates of the achievable energy resolution at the decay -value for the
nEXO design
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