Essential thrombocythemia: challenges in clinical practice and future prospects.

Essential thrombocythemia (ET) was first described in 1934, and subsequently, progress has been made in better understanding the molecular pathogenesis and which patients may have greatest risk of progression or vascular events. However, it has been more than a decade since a new therapy has been approved for ET. We are beginning to understand more comprehensively both the heterogeneity of this disease, which is largely driven by driver mutation status, as well as the effect of disease-related symptoms, such as fatigue, on patients. In this review we provide a practical overview of diagnosis and management of ET with focus on challenging patient scenarios and some consideration of what comprehensive care might entail. Finally, we also discuss newer therapies and how these might be assessed.

Power coupling losses for misaligned and mode-mismatched higher-order Hermite-Gauss modes.

This paper analytically and numerically investigates misalignment and mode-mismatch-induced power coupling coefficients and losses as a function of Hermite-Gauss (HG) mode order. We show that higher-order HG modes are more susceptible to beam perturbations when, for example, coupling into optical cavities: the misalignment and mode-mismatch-induced power coupling losses scale linearly and quadratically with respect to the mode indices, respectively. As a result, the mode-mismatch tolerance for the ${{\rm HG}_{3,3}}$ mode is reduced to a factor of 0.28 relative to the currently used ${{\rm HG}_{0,0}}$ mode. This is a potential hurdle to using higher-order modes to reduce thermal noise in future gravitational-wave detectors.

Sudden cardiac death associated with premature atheroma in the young: an autopsy study emphasising single-vessel lesions.

UNLABELLED: Aims This is the first autopsy study in the United Kingdom to analyse the demographic and pathological characteristics of atheroma associated with sudden cardiac death in young people. METHODS: An observational retrospective study of referred cases of sudden cardiac death in the young (⩽35 years) associated with premature atheroma was carried out. RESULTS: In total, 46 cases were referred, with a median age of 30 years (27, 32); 72% of the referred cases were male, with a mean body mass index of 30 kg/m2. Circumstances of death were as follows: at rest (n=21), exertion (n=7), in bed (n=7), related to drugs/alcohol (n=4), and unknown (n=7). A previous cardiac history was provided in 10 cases. A history of class A/B drug use was found in eight cases. There was macroscopic evidence of infarction in 10 cases (acute, n=3 and chronic, n=7). Microscopically, 10 cases demonstrated contraction band necrosis, 11 acute infarction, and 11 chronic infarction. Single-vessel disease predominated (n=28). The left anterior descending coronary artery was involved in 39/46 cases. Thrombosis was seen in 16 cases, mainly due to erosion; one case showed dual pathology with arrhythmogenic right ventricular cardiomyopathy and another showed left ventricular hypertrophy. CONCLUSIONS: This study highlights premature atheroma mainly in a single vessel in young people with or without evidence of ischaemic damage in the ventricle. Dual pathology may occur. The role of arrhythmias and channelopathies are important considerations. Premature atheroma should prompt investigation for dyslipidaemias in family members.

Type A and AB thymomas: histological features associated with increased stage.

AIMS: The current WHO classification of thymic epithelial neoplasms describes type A and type AB thymomas as behaving 'like benign neoplasms'. However, recent published data suggest that rare cases may show more aggressive behaviour. The aim of this study was to assess the frequency of atypical cases, and to determine whether atypia is associated with more advanced disease. METHODS AND RESULTS: One hundred and twenty-one thymomas (type A, n = 68; type AB, n = 53) were retrospectively reviewed for 'atypical' features (nuclear pleomorphism, mitotic activity, and necrosis). Logistic regression was used to ascertain the association with increasing Masaoka-Koga stage. Where available, follow-up data were also reviewed. There were 72 stage I, 42 stage II, five stage III and two stage IV tumours. Only the presence of necrosis showed a significant association with increased stage in univariate and multivariate analysis. Nuclear atypia and increased mitotic activity were not associated with increasing stage of disease. CONCLUSIONS: Our data support the concept of there being more aggressive atypical variants of both type A and type AB thymoma, and suggest that the presence of necrosis could be used to predict aggressive behaviour.

The use of guideline images to improve histological estimation of hepatic steatosis.

BACKGROUND & AIMS: Guideline images of specific fat proportionate area (FPA) percentages have recently been published to aid the histological assessment of liver steatosis as subjective estimates of FPA are usually overestimated. To assess, (i) the effect of guideline images on accuracy and concordance of estimated FPA (eFPA), (ii) experience of steatosis grading systems on eFPA, (iii) the effect of magnification on assessment of FPA (iv) and produce a range of guideline images at x4 objective magnification (OM). METHODS: Two circulations of sample images (C1 and C2) were circulated to UK liver external quality assessment histopathology scheme members who were asked to independently evaluate steatosis. Each circulation consisted of 15 images taken at both x20 and x4OM representing the full range of steatosis. C1 was distributed first, then C2 with guideline images of FPA 6 weeks later. RESULTS: Participants overestimated FPA in C1. In C2, there was significant improvement in accuracy (P < 0.001) of eFPA for sample images with mFPA >5%. Concordance of x4OM eFPA was substantial in both circulations (C1 K = 0.878, C2 K = 0.724). CONCLUSION: The tendency to overestimate eFPA has been corroborated and can be largely corrected with the use of guideline images (without needing digital image analysis). There is a need to redefine steatosis grades that are clinically significant and validated using an accurate quantification of steatosis.

Hepatic steatosis estimated microscopically versus digital image analysis.

BACKGROUND & AIMS: Evaluate in liver biopsies: (i) interobserver agreement of estimates of fat proportionate area (eFPA) and steatosis grading, (ii) the relationship between steatosis grades and measured fat proportionate area (mFPA, digital image analysis), (iii) the accuracy of eFPA, (iv) to present images to aid standardization and accuracy of eFPA. METHODS: Twenty-one liver biopsies were selected from the Royal Free Hospital (RFH) histopathology archive to represent the full range of histopathological steatosis severity. As many non-overlapping fields of parenchyma as possible were photographed at ×20 objective magnification from the biopsies (n = 651). A total of 15 sample images were selected to represent the range of steatosis seen. Twelve hepatopathologists from 11 sites worldwide independently evaluated the sample images for steatosis grade [normal (none)/mild/moderate/severe], and eFPA (% area of liver parenchyma occupied by fat). RESULTS: The hepatopathologists had good linear correlation between eFPA and mFPA for sample images (r = 0.924, P < .001) and excellent concordance (kappa = 0.91, P < 0.001). Interobserver concordance of steatosis grade showed 'substantial agreement' (kappa = 0.64). There was significant difference between eFPA and mFPA in the sample images for mild, moderate and severe steatosis (P = 0.024, P < 0.001, P < 0.001 respectively): the observers consistently over-estimated the eFPA. CONCLUSION: Hepatopathologists showed 'excellent' interobserver agreement in eFPA and 'substantial' agreement in assigning steatosis grade (precision was high). However, compared with mFPA, eFPA was inaccurate. eFPA systematically exceeds mFPA; generally the overestimation increases with severity of steatosis. Considering that non-invasive technologies for estimating liver fat utilize histopathology as reference, such assessments would benefit from quantitative validation of visually estimated microscopic liver fat percentages.