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A retrospective longitudinal cohort study of the clinical burden in myasthenia gravis.
No full textBACKGROUND
Patients with generalized myasthenia gravis (MG) often experience debilitating exacerbations, with the possibility of life-threatening respiratory crises requiring hospitalization. Long-term longitudinal studies are needed to understand the burden of MG, including in patients whose disease is refractory to conventional treatment.
METHODS
A retrospective, longitudinal, cohort study was conducted of patients in England aged ≥ 18 years with treatment-refractory or non-refractory MG, using data recorded during 1997-2016 in the Clinical Practice Research Datalink and the Hospital Episode Statistics databases. A control cohort of patients without MG, matched to the patients in the treatment-refractory MG cohort, was also identified. Outcome measures included myasthenic crises, MG exacerbations, MG-related hospitalizations, comorbidities, and all-cause mortality. Descriptive statistics were calculated for the overall MG population. For continuous variables, between-cohort comparisons were made using t tests for normally distributed data and Mann-Whitney U tests for non-normally distributed data. For categorical data, the comparisons were made by chi-squared tests. Differences in clinical outcomes between cohorts were modeled using negative binomial regression.
RESULTS
A total of 1149 patients with MG were included. Overall, 18.4% of patients experienced myasthenic crises, 24.6% experienced exacerbations, and 38.6% underwent MG-related hospitalizations. Most of these events occurred within 2-3 years of diagnosis. Patients with MG refractory to conventional treatment (n = 66) experienced more exacerbations and MG-related hospitalizations than patients with non-refractory disease (n = 1083). Patients with refractory MG experienced a higher frequency of renal disease and hypertension compared with patients with non-refractory MG, and with matched patients without MG. They were also more likely to have diabetes and congestive heart failure than the matched controls. Rates of all-cause mortality during the follow-up period did not differ between patients with refractory MG and non-refractory MG.
CONCLUSIONS
These results show that conventional treatments for MG are not adequately managing patients' symptoms and that patients with refractory MG are more likely to experience certain comorbidities than those with non-refractory MG or matched controls without MG. Future research should focus on the impact of newer targeted therapies on long-term clinical outcomes and comorbid conditions
Airway remodelling rather than cellular infiltration characterises both type2 cytokine biomarker-high and -low severe asthma.
No full textBACKGROUND
The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type-2 (T2) cytokine biology which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood.
OBJECTIVES
To explore airway pathology in T2 biomarker-high and -low severe asthma.
METHODS
T2 biomarker-high severe asthma (T2-high, n=17) was compared to biomarker-intermediate (T2-intermediate, n=21) and biomarker-low (T2-low, n=20) severe asthma, and healthy controls (n=28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD and LTE measurements.
RESULTS
Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodeling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared to health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5, and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD and LTE , were increased in T2-high and T2-intermediate asthma compared to healthy controls.
CONCLUSIONS
Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodeling persists, and may be important for residual disease expression beyond eosinophilic exacerbations
Coating (Coating to Optimize Aneurysm Treatment in the New Flow Diverter Generation) study. The first randomized controlled trial evaluating a coated flow diverter (p64 MW HPC): study design.
No full textBACKGROUND
Due to its high efficacy, flow diversion is increasingly used in the management of unruptured and recanalized aneurysms. Because of the need for perioperative dual antiplatelet treatment (DAPT), flow diversion is not indicated for the treatment of ruptured aneurysms. To overcome this major limitation, surface modification-'coating'-of flow diverters has been developed to reduce platelet aggregation on the implanted device, reduce thromboembolic complications, and facilitate the use of coated flow diverter treatment in patients with single antiplatelet treatment (SAPT). COATING (Coating to Optimize Aneurysm Treatment in the New Flow Diverter Generation) is a prospective, randomized, multicenter trial that aims to determine whether the use of the coated flow diverter p64 MW HPC under SAPT is non-inferior (or even superior) to the use of the bare flow diverter p64 MW under DAPT in relation to thromboembolic and hemorrhagic complications.
METHODS
Patients with unruptured or recanalized aneurysms for which endovascular treatment with a flow diverter is indicated will be enrolled and randomly assigned on a 1:1 ratio to one of two treatment groups: p64 MW HPC with SAPT or p64 MW with DAPT.
RESULTS
The primary endpoint is the number of diffusion-weighted imaging lesions visualized via MRI assessed within 48 hours (±24 hours) of the index procedure. Secondary primary endpoints are comparing safety and efficacy in both arms.
CONCLUSIONS
This randomized controlled trial is the first to directly compare safety and efficacy of coated flow diverters under SAPT with bare flow diverters under DAPT.
TRIAL REGISTRATION NUMBER
http://clinicaltrials.gov/ - NCT04870047
Re: "Outcomes of osseointegrated implants in patients with benign and malignant pathologies of the head and neck: a 10-year single-centre study".
No full textMulticenter Evaluation of the Idylla GeneFusion in Non-Small-Cell Lung Cancer.
No full textTargeted therapy in lung cancer requires the assessment of multiple oncogenic driver alterations, including fusion genes. This retrospective study evaluated the Idylla GeneFusion prototype, an automated and ease-of-use (<2 minutes) test, with a short turnaround time (3 hours) to detect fusions involving ALK, ROS1, RET, and NTRK1/2/3 genes and MET exon 14 skipping. This multicenter study (18 centers) included 313 tissue samples from lung cancer patients with 97 ALK, 44 ROS1, 20 RET, and 5 NTRKs fusions, 32 MET exon 14 skipping, and 115 wild-type samples, previously identified with reference methods (RNA-based next generation sequencing/fluorescence in situ hybridization/quantitative PCR). Valid results were obtained for 306 cases (98%), overall concordance between Idylla and the reference methods was 89% (273/306); overall sensitivity and specificity were 85% (165/193) and 96% (108/113), respectively. Discordances were observed in 28 samples, where Idylla did not detect the alteration identified by the reference methods; and 5 samples where Idylla identified an alteration not detected by the reference methods. All of the ALK-, ROS1-, and RET-specific fusions and MET exon 14 skipping identified by Idylla GeneFusion were confirmed by reference method. To conclude, Idylla GeneFusion is a clinically valuable test that does not require a specific infrastructure, allowing a rapid result. The absence of alteration or the detection of expression imbalance only requires additional testing by orthogonal methods
Complete Versus Partial Excision of an Infected Mesh Following Abdominal Wall Hernia Repair: A Systematic Review and Meta-analysis.
No full textBACKGROUND
To evaluate comparative outcomes of complete and partial excision of infected mesh following abdominal wall hernia repair.
METHODS
A systematic search of electronic databases, including MEDLINE, EMBASE, CINAHL, and CENTRAL, and bibliographic reference lists with application of a combination of free text and controlled vocabulary search adapted to thesaurus headings, search operators and limits was conducted. Surgical site infection chronic sinus formation, recurrent hernia, and need for reoperation were the evaluated outcome measures.
RESULTS
Six comparative observational studies were identified, reporting a total of 317 patients of whom 193 underwent complete mesh excision and the remaining 123 patients underwent partial mesh excision for an infected mesh following abdominal wall hernia repair. The complete mesh excision was associated with significantly lower rates of SSIs (OR: .36; 95% CI, .16-.81, = .01), chronic sinus formation (OR: .11; 95% CI, .02-.71, = .02), and reoperation (OR: .10; 95% CI, .03-.33, = .0001) compared to the partial mesh excision. There was no significant difference in hernia recurrence rate (OR: 3.96.16, 95% CI .62-25.44, = .15) between two groups. The between-study heterogeneity was moderate in all the analyses.
CONCLUSIONS
Complete mesh excision may be associated with lower SSI, chronic sinus formation and need for reoperation when compared to the partial mesh excision in an infected mesh event. However, the available evidence has failed to report the outcomes with respect to the main confounding factors which, together with other important outcomes such as fistula formation, should be considered by future high quality research
Analysis and results from a UK national dose audit of paediatric CT examinations.
No full textOBJECTIVE
To present the results following a UK national patient dose audit of paediatric CT examinations, to propose updated UK national diagnostic reference levels (DRLs) and to analyse current practice to see if any recommendations can be made to assist with optimisation.
METHODS
A UK national dose audit was undertaken in 2019 focussing on paediatric CT examinations of the head, chest, abdomen/pelvis and cervical spine using the methods proposed by the International Commission on Radiological Protection. The audit pro-forma contained mandatory fields, of which the post-examination dosimetry (volume CT dose index and dose-length product) and the patient weight (for body examinations) were the most important.
RESULTS
Analysis of the data submitted indicates that it is appropriate to propose national DRLs for CT head examinations in the 0-<1, 1-<5, 5-<10 and 10-<15 year age ranges. This extends the number of age categories of national DRLs from those at present and revises the existing values downwards. For CT chest examinations, it is appropriate to propose national DRLs for the first time in the UK for the 5-<15, 15-<30, 30-<50 and 50-<80 kg weight ranges. There were insufficient data received to propose national DRLs for abdomen/pelvis or cervical spine examinations. Recommendations towards optimisation focus on the use of tube current (mA) modulation, iterative reconstruction and the selection of examination tube voltage (kV).
CONCLUSION
Updated UK national DRLs are proposed for paediatric CT examinations of the head and chest.
ADVANCES IN KNOWLEDGE
A national patient dose audit of paediatric CT examinations has led to the proposal of updated national DRLs
Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial.
No full textPURPOSE
Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS).
METHODS
This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers.
RESULTS
No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO/FiO < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365.
CONCLUSIONS
Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population
Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.
No full textBACKGROUND
Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined.
OBJECTIVE
To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS.
DESIGN
Cross-sectional study.
SETTING
14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016).
PARTICIPANTS
1305 prospectively recruited persons with benign adrenal tumors.
MEASUREMENTS
Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: 138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry.
RESULTS
Of the 1305 participants, 49.7% had NFAT ( = 649; 64.1% women), 34.6% had MACS-1 ( = 451; 67.2% women), 10.7% had MACS-2 ( = 140; 73.6% women), and 5.0% had CS ( = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased.
LIMITATIONS
Cross-sectional design; possible selection bias.
CONCLUSION
A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes.
PRIMARY FUNDING SOURCE
Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research
Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects.
No full textTetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology