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Myocardial Storage, Inflammation, and Cardiac Phenotype in Fabry Disease After One Year of Enzyme Replacement Therapy.
No full textBACKGROUND
Cardiac response to enzyme replacement therapy (ERT) in Fabry disease is typically assessed by measuring left ventricular mass index using echocardiography or cardiovascular magnetic resonance, but neither quantifies myocardial biology. Low native T1 in Fabry disease represents sphingolipid accumulation; late gadolinium enhancement with high T2 and troponin elevation reflects inflammation. We evaluated the effect of ERT on myocardial storage, inflammation, and hypertrophy.
METHODS
Twenty patients starting ERT (60% left ventricular hypertrophy-positive) were compared with 18 patients with early disease and 18 with advanced disease over 1 year at 3 centers. Cardiovascular magnetic resonance (left ventricular mass index, T1, T2, global longitudinal strain, and late gadolinium enhancement) and biomarkers (high-sensitive troponin-T and NT-proBNP [N-terminal Pro-B-type natriuretic peptide]) at baseline (pre-ERT) and 12 months were performed. Early disease controls were stable, treatment-naïve patients (mainly left ventricular hypertrophy-negative); advanced disease controls were stable, established ERT patients (mainly left ventricular hypertrophy-positive).
RESULTS
Over 1 year, early disease controls increased maximum wall thickness and left ventricular mass index (9.8±2.7 versus 10.2±2.6 mm; =0.010; 65±15 versus 67±16 g/m; =0.005) and native T1 fell (981±58 versus 959±61 ms; =0.002). Advanced disease controls increased T2 in the late gadolinium enhancement area (57±6 versus 60±7 ms; =0.023) with worsening global longitudinal strain (-13.2±3.4 versus -12.1±4.8; =0.039). Newly treated patients had a small reduction in maximum wall thickness (14.8±5.9 versus 14.4±5.7 mm; =0.028), stable left ventricular mass index (93±42 versus 92±40 g/m; =0.186) and a reduction in T1 lowering (917±49 versus 931±54 ms; =0.017).
CONCLUSIONS
Fabry myocardial phenotype development is different at different disease stages. After 1 year of ERT initiation, left ventricular hypertrophy-positive patients have a detectable, small reduction in left ventricular mass and storage
Characterising burden of treatment in cystic fibrosis to identify priority areas for clinical trials.
No full textIn a recent James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF) the top priority clinical research question was: "What are effective ways of simplifying the treatment burden of people with CF?" We aimed to summarise the lived experience of treatment burden and suggest research themes aimed at reducing it. An online questionnaire was co-produced and responses subjected to quantitative and thematic analysis. 941 survey responses were received (641 from lay community). People with CF reported a median of 10 (interquartile range: 6-15) current treatments. Seven main themes relating to simplifying treatment burden were identified. Treatment burden is high, extending beyond time taken to perform routine daily treatments, with impact varying according to person-specific factors. Approaches to communication, support, evaluation of current treatments, service set-up, and treatment logistics (obtaining/administration) contribute to burden, offering scope for evaluation in clinical trials or service improvement
Efficacy and safety of topical and systemic medications: a systematic literature review informing the EULAR recommendations for the management of Sjögren's syndrome.
No full textObjective
To evaluate current evidence on the efficacy and safety of topical and systemic medications in patients with primary Sjögren syndrome (SjS) to inform European League Against Rheumatism treatment recommendations.
Methods
The MEDLINE, EMBASE and Cochrane databases were searched for case-control/prospective cohort studies, randomised controlled trials (RCTs) and systematic reviews.
Results
Current evidence in primary SjS patients fulfilling the 2002 criteria is based on the data from 9 RCTs, 18 prospective cohort studies and 5 case-control studies. Two Cochrane systematic literature reviews (SLRs) have reported that topical treatments for dry mouth and dry eye are safe and effective. Ocular cyclosporine A was safe and effective in two RCTs including 1039 patients with dry eye syndrome. Two Cochrane SLRs on serum tear drops and plugs showed inconsistency in possible benefits, both for symptoms and objective measures. Five RCTs reported significant improvements in oral dryness and salivary flow rates for pilocarpine and cevimeline. An RCT showed no significant placebo-differences for hydroxychloroquine 400 mg/day for the primary outcome (visual analogue scale (VAS) composite of dryness, fatigue and pain). We identified seven RCTs carried out in primary SjS patients. RCTs using infliximab, anakinra and baminercept found no placebo-differences for the primary outcomes. The two largest RCTs randomised 255 patients to receive rituximab or placebo and reported no significant results in the primary outcome (VAS composite), while prospective studies suggested efficacy in systemic disease.
Conclusion
The current evidence supporting the use of the main topical therapeutic options of primary SjS is solid, while limited data from RCTs are available to guide systemic therapies
Cabins, castles, and constant hearts: rhythm control therapy in patients with atrial fibrillation.
No full textRecent innovations have the potential to improve rhythm control therapy in patients with atrial fibrillation (AF). Controlled trials provide new evidence on the effectiveness and safety of rhythm control therapy, particularly in patients with AF and heart failure. This review summarizes evidence supporting the use of rhythm control therapy in patients with AF for different outcomes, discusses implications for indications, and highlights remaining clinical gaps in evidence. Rhythm control therapy improves symptoms and quality of life in patients with symptomatic AF and can be safely delivered in elderly patients with comorbidities (mean age 70 years, 3-7% complications at 1 year). Atrial fibrillation ablation maintains sinus rhythm more effectively than antiarrhythmic drug therapy, but recurrent AF remains common, highlighting the need for better patient selection (precision medicine). Antiarrhythmic drugs remain effective after AF ablation, underpinning the synergistic mechanisms of action of AF ablation and antiarrhythmic drugs. Atrial fibrillation ablation appears to improve left ventricular function in a subset of patients with AF and heart failure. Data on the prognostic effect of rhythm control therapy are heterogeneous without a clear signal for either benefit or harm. Rhythm control therapy has acceptable safety and improves quality of life in patients with symptomatic AF, including in elderly populations with stroke risk factors. There is a clinical need to better stratify patients for rhythm control therapy. Further studies are needed to determine whether rhythm control therapy, and particularly AF ablation, improves left ventricular function and reduces AF-related complications
Residual Adrenal Function in Autoimmune Addison's Disease - Effect of Dual Therapy with Rituximab and Depot Tetracosactide.
No full textCONTEXT
In autoimmune Addison's disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy and poorer quality of life.
OBJECTIVE
To restore adrenocortical steroidogenic function in recent onset AAD.
DESIGN
Open-label, multi-centre trial of immunotherapy and trophic stimulation in new-onset AAD. Serial measurement of serum and urine corticosteroids at baseline and throughout 72-week follow-up period.
SETTING
Endocrine Departments and Clinical Research Facilities at 5 UK tertiary centres.
PATIENTS
Thirteen subjects (9 female, 4 male; aged 19-64 years) with AAD confirmed by high ACTH, low circulating cortisol (basal <100nmol/L or post-tetracosactide <300nmol/L) and positive serum 21-hydroxylase antibodies.
INTERVENTION
All subjects received dual therapy with B-lymphocyte depleting immunotherapy (rituximab 1g given twice) and repeated depot tetracosactide (1mg alternate days for 12 weeks).
MAIN OUTCOME MEASURE
Restoration of normal glucocorticoid secretion (stimulated cortisol >550nmol/L) at Week 48.
RESULTS
Ten of 13 (77%) had detectable stimulated serum cortisol (26-265nmol/L) at trial entry. Following intervention, 7/13 (54%) had an increase in stimulated cortisol measurement, with a peak response of 325nmol/L at Week 18 in one subject. Increased steroid metabolites, assayed by urine GC-MS at Week 12 and Week 48, was detected in 8/13 (62%), reflecting an increase in endogenous steroidogenesis. Four of 13 had Residual Adrenal Function at 72 weeks.
CONCLUSION
Combined treatment with rituximab and depot tetracosactide did not restore normal adrenal function. Nevertheless, adrenocortical plasticity is demonstrated in some patients and this has the potential to be exploited to improve adrenal function
Genomic Mutation Identification in Mice Using Illumina Sequencing and Linux-Based Computational Methods.
No full textGenetically modified mice are an essential tool for modeling disease-causing mechanisms and discovering gene function. SNP genotyping was traditionally used to associate candidate regions with traits in the mouse, but failed to reveal novel variants without further targeted sequencing. Using a robust set of computational protocols, we present a platform to enable scientists to detect variants arising from whole-genome and exome sequencing experiments. This article guides researchers on aligning reads to the mouse genome, quality-assurance strategies, mutation discovery, comparing mutations to previously discovered mouse SNPs, and the annotation of novel variants, in order to predict mutation consequences on the protein level. Challenges unique to the mouse are discussed, and two protocols use self-contained containers to maintain version control and allow users to adapt our approach to new techniques by upgrading container versions. Our protocols are suited for servers or office workstations and are usable by non-bioinformatics specialists. © 2019 by John Wiley & Sons, Inc
Healthcare resource utilization by patients with treatment-refractory myasthenia gravis in England.
No full textTo examine healthcare resource utilization associated with refractory myasthenia gravis (MG) in England. This was a retrospective cohort study of linked data from the Clinical Practice Research Datalink and the Hospital Episode Statistics database collected between 1997 and 2016. Included patients were ≥18 years of age at the index MG diagnosis. Patients with refractory MG were identified using an algorithm based on treatments received. Healthcare resource utilization since the index date was compared between refractory and non-refractory cohorts. The study included 1149 patients with MG, of whom 66 (5.7%) were refractory. Sex and age at diagnosis did not significantly differ between the refractory and non-refractory cohorts. Rates of healthcare resource utilization per person-year were significantly higher ( < .05) for patients with refractory compared to non-refractory MG for GP visits, visits to other healthcare professionals, outpatient visits and inpatient hospitalization. Patients in the refractory cohort spent more total days hospitalized since the index visit than patients in the non-refractory cohort (median, 33 vs. 16 days [ < .0001]). The algorithm for identifying refractory patients did not include clinical criteria. Also, treatments administered in hospitals or by specialists were not available in the databases. Patients in England with refractory MG more often visit healthcare providers, are hospitalized and visit an emergency room than patients with non-refractory MG
Breadth and Depth: Three-Dimensional Endoscopic Field of View: Two-Dimensional Versus Three-Dimensional Endoscopic Field of View.
No full textBACKGROUND
Three-dimensional (3D) endoscopy is an emerging tool in ear-nose-throat (ENT) and skull base surgery with the benefit of providing real-time depth perception. Several investigators have reported that the field of view (FOV) is reduced in 3D endoscopes compared with regular 2-dimensional (2D) endoscopes. Thus, we objectively compared the FOV of 2D and 3D endoscopes.
METHODS
Using a standard 2D and 2 different 3D ENT endoscopes, images were captured of 1-mm graph paper from a set distance of 6 cm. The FOV was calculated from these images and compared among the endoscopes.
RESULTS
The VisionSense 3D endoscope had a slightly smaller FOV (9.1 cm vs. 10.1 cm; -9.9%), and the Karl Storz 3D endoscope showed a slightly larger FOV (10.4 cm vs. 10.1 cm; +3.0%). However, the results were complicated by the different-shaped images produced by the 3D endoscopes.
CONCLUSION
The differences in the FOV between the 2D and 3D endoscopes used in ENT surgery were not clinically significant. Thus, the FOV should not be considered a limitation of 3D technology
A retrospective review of 12 patients with trichotillomania treated in a psychodermatology service.
No full textTrichotillomania is a condition characterized by the pulling of hair from anywhere on the body and is classified as an obsessive-compulsive and related disorder. Patients with hair disorders are commonly referred to psychodermatology services, and can represent a management challenge. Few publications exist that report outcomes for patients with trichotillomania in real clinical practice. We report 12 such patients seen within our own psychodermatology service, who were managed using a variety of treatment strategies. The rate of defaulting of appointments was high, but improvements were seen in patients engaging with services