5366 research outputs found
Sort by
EACVI communication paper: first international young dedicated multimodal cardiovascular imaging simulation education event organized by the ESC.
No full textA Phase 1b Trial to Assess the Pharmacokinetics of Ezutromid in Pediatric Duchenne Muscular Dystrophy Patients on a Balanced Diet.
No full textEzutromid (SMT C1100) is a small-molecule utrophin modulator that was developed to treat Duchenne muscular dystrophy (DMD). Previous clinical trials of this agent revealed lower exposure in DMD patients compared with healthy volunteers, which may reflect differences in diet. This study evaluated the pharmacokinetics of ezutromid in patients with DMD who followed a balanced diet. This was a multicenter, double-blind, placebo-controlled, ascending single and multiple oral dose study. Twelve pediatric patients were randomly allocated to 1 of 3 treatment sequences within which were 3 treatment periods of 2 weeks each. Each patient received, in a dose-escalating fashion, 1250 mg and 2500 mg twice daily (BID) of ezutromid administered orally as a microfluidized suspension (F3) with placebo in the other treatment period. Throughout the study, patients followed a balanced diet including recommended proportions of major food groups and administration of drug accompanied with 100 mL of full-fat milk. This approach improved the absorption of ezutromid, resulting in higher systemic exposure, with considerable variability in exposure between patients at each dose level. Single and multiple oral doses of 1250 mg and 2500 mg BID were considered safe and well tolerated. No severe or serious adverse events and no study discontinuations due to adverse events were reported. This study provides assurance that, with the formulation tested (F3) and instructions regarding food (balanced diet and whole-fat milk), 2500 mg BID of ezutromid achieves plasma concentrations that, based on preclinical studies, should be able to modulate utrophin expression in future clinical trials
Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC subtype diffuse large B cell lymphoma.
No full textThe Epstein-Barr virus (EBV) is found almost exclusively in the activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focussed on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCL and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this we found that LMP1-expressing primary ABC-DLBCL were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. This article is protected by copyright. All rights reserved
Healthcare Providers Underestimate Patients' Glucocorticoid Use in Crohn's Disease.
No full textBACKGROUND
One of the therapy goals for Crohn's disease (CD) is glucocorticoid-free remission. Studies have shown care setting-specific variations in inflammatory bowel disease (IBD) management.
AIMS
The principal objective of this study was to assess concordance between patient-reported and physician-reported outcomes in two different care settings (IBD centers and community practices).
METHODS
Data of overall and long-term (≥ 3 months) glucocorticoid, immunosuppressant, and biologics use in participants ≥ 18 years old with a confirmed diagnosis of CD were collected. HCPs were grouped by IBD centers and community practices. Quality of life (using EuroQol 5D [EQ-5D]) and work/activity days lost were assessed. Agreement between patients' and HCPs' responses to survey questions was tested using kappa statistics.
RESULTS
Data from 812 patients were examined. Significantly more patients versus HCPs reported oral glucocorticoid use (25.9% vs. 20.8%, κ = 0.735, P < 0.0001). Long-term use of oral glucocorticoids was similar for patients versus HCPs (67.7% vs. 63.8%, κ = 0.598, P = 0.53). Immunosuppressant use was 52.4% vs. 51.1% (κ = 0.784) and biologics use was 49.5% vs. 47.0% (κ = 0.909) for patients vs. HCPs. Patients and HCPs reported greater rates of symptom improvement with vs without biologic therapy (patients: 33.3% vs 16.8%; HCPs: 29.3% vs 13.5%, both P < 0.001). Patients with versus without routine follow-up were less likely to be treated with long-term glucocorticoid monotherapy (10.3% vs. 20.7%, P < 0.01) and had fewer lost work/activity days (5 vs. 8 days, P < 0.05).
CONCLUSIONS
Patients reported more oral glucocorticoid use than physicians thought. Routine follow-up and higher rates of biologic use are associated with improvement in disease symptoms and general health among patients with CD
Prescribing in 2019: what are the safety concerns?
No full textINTRODUCTION
Unintended harm from prescribing errors remains a prevalent concern in healthcare leading to significant morbidity and mortality around the world. Prescribers face new challenges to their practice in modern times such as increasingly complex health-care systems, an aging population with increasing multimorbidity, and rapid growth in the number of novel medicines. Areas covered: Prescribing concerns in modern practice are outlined based on seminal literature in this area and the author's continual academic oversight of this topic. Major UK and international reports have been used to highlight the important emerging issues in prescribing, and focused literature searches performed to highlight key papers supporting this review. Expert opinion: Whilst there are many ways to consider mitigating the risk of harm from prescribing, it is suggested that a tripartite approach is required. Patients and carers are essential partners in the process and shared decision-making has replaced paternalistic practice in achieving joint prescribing decisions. Comprehensive and coordinated care is critical to avoid fragmented care and poor transfer of prescribing information. Lastly, a whole systems approach is crucial to ensure that all prescribers are supported (and not overwhelmed) when making safe, effective and timely prescribing decisions
Health-related quality of life and costs in Sjögren's syndrome.
No full textHealth-related quality of life (HRQoL) has an increasing role in medical decision-making. This review of the literature aims to provide an overview on HRQoL, costs, and work disability in SS, a disease characterized by focal lymphocytic infiltration of exocrine glands with no therapeutics of proven immunomodulatory potential. HRQoL is markedly reduced in SS in multiple studies across many countries when compared with HRQoL in healthy controls. The reduction in HRQoL is similar to that observed in other chronic diseases such as RA, SLE, FM and, interestingly, non-SS sicca syndrome. Impaired HRQoL in SS has been found to be associated with fatigue, pain/articular involvement, ocular and oral involvement, pruritus, sexual dysfunction, impaired sleep, pulmonary manifestations, psychological dysfunction and impaired physical function. Until now, no therapeutic has been shown to improve HRQoL in an adequately powered double-blind, placebo-controlled randomized controlled trial. Although primary SS does not, in general, impair life expectancy and is often inappropriately considered a benign 'nuisanvce' disease for those patients without systemic manifestations, the associated costs and work disability are striking. This, together with the significant reduction in HRQoL, strongly argues for the development of new therapeutic approaches to manage this neglected disease
Associations between Hemodialysis Facility Practices to Manage Fluid Volume and Intradialytic Hypotension and Patient Outcomes.
No full textBACKGROUND AND OBJECTIVES
Fluid overload and intradialytic hypotension are associated with cardiovascular events and mortality in patients on hemodialysis. We investigated associations between hemodialysis facility practices related to fluid volume and intradialytic hypotension and patient outcomes.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Data were analyzed from 10,250 patients in 273 facilities across 12 countries, from phase 4 of the Dialysis Outcomes and Practice Patterns Study (DOPPS; 2009-2012). Cox regression models (shared frailty) were used to estimate associations between facility practices reported by medical directors in response to the DOPPS Medical Directors Survey and all-cause and cardiovascular mortality and hospitalization, and cardiovascular events, adjusting for country, age, sex, dialysis vintage, predialysis systolic BP, cardiovascular comorbidities, diabetes, body mass index, smoking, residual kidney function, dialysis adequacy, and vascular access type.
RESULTS
Of ten facility practices tested (chosen ), having a protocol that specifies how often to assess dry weight in most patients was associated with lower all-cause (hazard ratio [HR], 0.78; 99% confidence interval [99% CI], 0.64 to 0.94) and cardiovascular mortality (HR, 0.72; 99% CI, 0.55 to 0.95). Routine orthostatic BP measurement to assess dry weight was associated with lower all-cause hospitalization (HR, 0.86; 99% CI, 0.77 to 0.97) and cardiovascular events (HR, 0.85; 99% CI, 0.73 to 0.98). Routine use of lower dialysate temperature to limit or prevent intradialytic hypotension was associated with lower cardiovascular mortality (HR, 0.76; 99% CI, 0.58 to 0.98). Routine use of an online volume indicator to assess dry weight was associated with higher all-cause hospitalization (HR, 1.19; 99% CI, 1.02 to 1.38). Routine use of sodium modeling/profiling to limit or prevent intradialytic hypotension was associated with higher all-cause mortality (HR, 1.36; 99% CI, 1.14 to 1.63), cardiovascular mortality (HR, 1.34; 99% CI, 1.04 to 1.73), and cardiovascular events (HR, 1.21; 99% CI, 1.03 to 1.43).
CONCLUSIONS
Hemodialysis facility practices relating to the management of fluid volume and intradialytic hypotension are associated with patient outcomes
PLA-Based Mineral-Doped Scaffolds Seeded with Human Periapical Cyst-Derived MSCs: A Promising Tool for Regenerative Healing in Dentistry.
No full textHuman periapical cyst mesenchymal stem cells (hPCy-MSCs) are a newly discovered cell population innovatively collected from inflammatory periapical cysts. The use of this biological waste guarantees a source of stem cells without any impact on the surrounding healthy tissues, presenting a valuable potential in tissue engineering and regenerative medicine applications. In the present study, hPCy-MSCs were collected, isolated, and seeded on three experimental mineral-doped porous scaffolds produced by the thermally-induced phase-separation (TIPS) technique. Mineral-doped scaffolds, composed of polylactic acid (PLA), dicalcium phosphate dihydrate (DCPD), and/or hydraulic calcium silicate (CaSi), were produced by TIPS (PLA-10CaSi, PLA-5CaSi-5DCPD, PLA-10CaSi-10DCPD). Micro-CT analysis evaluated scaffolds micromorphology. Collected hPCy-MSCs, characterized by cytofluorimetry, were seeded on the scaffolds and tested for cell proliferation, cells viability, and gene expression for osteogenic and odontogenic differentiation (DMP-1, OSC, RUNX-2, HPRT). Micro-CT revealed an interconnected highly porous structure for all the scaffolds, similar total porosity with 99% open pores. Pore wall thickness increased with the percentage of CaSi and DCPD. Cells seeded on mineral-doped scaffolds showed a superior proliferation compared to pure PLA scaffolds (control), particularly on PLA-10CaSi-10DCPD at day 12. A higher number of non-viable (red stained) cells was observable on PLA scaffolds at days 14 and 21. DMP-1 expression increased in hPCy-MSCs cultured on all mineral-doped scaffolds, in particular on PLA-5CaSi-5DCPD and PLA-10CaSi-10DCPD. In conclusion, the innovative combination of experimental scaffolds colonized with autologous stem cells from periapical cyst represent a promising strategy for regenerative healing of periapical and alveolar bone
Training and assessment in flexible sigmoidoscopy: using a novel direct observation of procedural skills (DOPS) assessment tool.
No full textBACKGROUND AND AIMS
Data supporting milestone development during flexible sigmoidoscopy (FS) training are lacking. We aimed to present validity evidence for our formative direct observation of procedural skills (DOPS) assessment in FS, and use DOPS to establish competency benchmarks and define learning curves for a national training cohort.
METHODS
This prospective UK-wide (211 centres) study included all FS formative DOPS assessments submitted to the national e-portfolio. Reliability was estimated from generalisability theory analysis. Item and global DOPS scores were correlated with lifetime procedure count to study learning curves, with competency benchmarks defined using contrasting groups analysis. Multivariable binary logistic regression was performed to identify independent predictors of DOPS competence.
RESULTS
This analysis included 3,616 DOPS submitted for 468 trainees. From generalisability analysis, sources of overall competency score variance included: trainee ability (27%), assessor stringency (15%), assessor subjectivity attributable to the trainee (18%) and case-to-case variation (40%), which enabled the modelling of reliability estimates. The competency benchmark (mean DOPS score: 3.84) was achieved after 150-174 procedures. Across the cohort, competency development occurred in the order of: pre-procedural (50-74), non-technical (75-149), technical (125-174) and post-procedural (175-199) skills. Lifetime procedural count (p<0.001), case difficulty (p<0.001), and lifetime formative DOPS count (p=0.001) were independently associated with DOPS competence, but not trainee or assessor specialty.
CONCLUSION
Sigmoidoscopy DOPS can provide valid and reliable assessments of competency during training and can be used to chart competency development. Contrary to earlier studies, based on destination-orientated endpoints, overall competency in sigmoidoscopy was attained after 150 lifetime procedures
Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.
No full textFrontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02