Summary
Management of GO must be based on the assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score (CAS), while severity is classified, ...according to EUGOGO as mild, moderate‐to‐severe and sight‐threatening. Prompt restoration of stable euthyroidism is recommended in the presence of GO. In moderate‐severe disease, steroids have been widely employed because of their anti‐inflammatory activity, although 20–30% of patients are not responsive or present with disease reactivation at the end of therapy. Some novel immunosuppressors have been employed in clinical studies and showed interesting results. Potential targets for therapy in GO are the TSH and the IGF‐1 receptor on the fibroblasts, inflammatory cytokines, B and T cells and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti‐sIL‐6R antibody, inactivates GO. Consistent data on the efficacy of rituximab have been reported over the past decade and more recently in randomized controlled trials. The availability of new therapies will expand the therapeutic options for GO patients and allow clinicians to really personalize the treatment to better suit the patients’ unmet needs.
Background:
Optimal doses of iv glucocorticoids for Graves' orbitopathy (GO) are undefined.
Methods:
We carried out a multicenter, randomized, double-blind trial to determine efficacy and safety of ...three doses of iv methylprednisolone in 159 patients with moderate to severe and active GO. Patients were randomized to receive a cumulative dose of 2.25, 4.98, or 7.47 g in 12 weekly infusions. Efficacy was evaluated objectively at 12 wk by blinded ophthalmologists and subjectively by blinded patients (using a GO specific quality of life questionnaire). Adverse events were recorded at each visit.
Results:
Overall ophthalmic improvement was more common using 7.47 g (52%) than 4.98 g (35%; P = 0.03) or 2.25 g (28%; P = 0.01). Compared with lower doses, the high-dose regimen led to the most improvement in objective measurement of ocular motility and in the Clinical Activity Score. The Clinical Activity Score decreased in all groups and to the least extent with 2.25 g. Quality of life improved most in the 7.47-g group, although not reaching statistical significance. No significant differences occurred in exophthalmos, palpebral aperture, soft tissue changes, and subjective diplopia score. Dysthyroid optic neuropathy developed in several patients in all groups. Because of this, differences among the three groups were no longer apparent at the exploratory 24-wk visit. Major adverse events were slightly more frequent using the highest dose but occurred also using the lowest dose. Among patients whose GO improved at 12 wk, 33% in the 7.47-group, 21% in the 4.98-group, and 40% in the 2.25-group had relapsing orbitopathy after glucocorticoid withdrawal at the exploratory 24-wk visit.
Conclusions:
The 7.47-g dose provides short-term advantages over lower doses. However, this benefit is transient and associated with slightly greater toxicity. The use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This may suggest that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to most severe cases of GO.
Despite recent advances in Monte Carlo path tracing at interactive rates, denoised image sequences generated with few samples per‐pixel often yield temporally unstable results and loss of ...high‐frequency details. We present a novel adaptive rendering method that increases temporal stability and image fidelity of low sample count path tracing by distributing samples via spatio‐temporal joint optimization of sampling and denoising. Adding temporal optimization to the sample predictor enables it to learn spatio‐temporal sampling strategies such as placing more samples in disoccluded regions, tracking specular highlights, etc; adding temporal feedback to the denoiser boosts the effective input sample count and increases temporal stability. The temporal approach also allows us to remove the initial uniform sampling step typically present in adaptive sampling algorithms. The sample predictor and denoiser are deep neural networks that we co‐train end‐to‐end over multiple consecutive frames. Our approach is scalable, allowing trade‐off between quality and performance, and runs at near real‐time rates while achieving significantly better image quality and temporal stability than previous methods.
Conjunctival tumors involving non-limbal locations, such as the fornix and canthus, are typically excised using a "non-touch" technique, often with a wide surgical margin. Reconstruction of these ...large defects can be difficult due to the contour of the ocular surface and are often complicated by shortening of the fornix, symblepharon formation, and restriction of eye movements. In our experience, the use of amniotic membrane grafts combined with the sealant properties of fibrin glue such as Tisseel® has improved our surgical outcomes during the reconstruction phase. We would like to highlight and describe our surgical technique using fibrin glue and squint hooks to aid amniotic membrane graft reconstruction for surgically challenging locations in the fornix and canthus following excision of conjunctival lesions, with excellent surgical outcomes.
The medical treatment of Graves' orbitopathy (GO) is usually reserved to moderate to severe disease. Steroids have been widely employed and possess anti-inflammatory activity, but about 20-30% of ...patients are not responsive and about 20% present with disease recurrence. Immunosuppressive therapy alternative to corticosteroids may target the different antigens involved in pathogenic mechanisms of GO. Some have already been employed in clinical studies and showed interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the TSH receptor and the IGF-1 receptor on the fibroblasts, inflammatory cytokines, B and T cells. Most promising results are obtained by interacting with the PIK3/mTORC1 signaling cascades for adipogenesis and the anti-IGF-1R with the monoclonal antibody teprotumumab. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials. Clinical practice will greatly benefit from the use of disease modifying agents in GO, as compared to steroids, currently standard treatment for GO. Among these, rituximab may be useful, especially in patients resistant to steroid or with contraindications to steroids. However, larger randomized controlled trials are needed for definitive data on the potential disease-modifying role of rituximab in GO. Direct targeting of the orbital fibroblast via immunosuppression or nonimmunosuppressive drugs is emerging as a promising alternative.
Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the ...incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000.
GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.
Abstract
Tradeoffs between the energetic benefits and costs of traits can shape species and trait distributions along environmental gradients. Here we test predictions based on such tradeoffs using ...survival, growth, and 50 photosynthetic, hydraulic, and allocational traits of ten
Eucalyptus
species grown in four common gardens along an 8-fold gradient in precipitation/pan evaporation (
P/E
p
) in Victoria, Australia. Phylogenetically structured tests show that most trait-environment relationships accord qualitatively with theory. Most traits appear adaptive across species within gardens (indicating fixed genetic differences) and within species across gardens (indicating plasticity). However, species from moister climates have lower stomatal conductance than others grown under the same conditions. Responses in stomatal conductance and five related traits appear to reflect greater mesophyll photosynthetic sensitivity of mesic species to lower leaf water potential. Our data support adaptive cross-over, with realized height growth of most species exceeding that of others in climates they dominate. Our findings show that pervasive physiological, hydraulic, and allocational adaptations shape the distributions of dominant
Eucalyptus
species along a subcontinental climatic moisture gradient, driven by rapid divergence in species
P/E
p
and associated adaptations.
Metabolic syndrome (MetS) and prostate cancer (PCa) are highly prevalent conditions worldwide. Current evidence suggests the emerging hypothesis that MetS could play a role in the development and ...progression of several neoplasms. The aims of this study are to evaluate the impact of MetS and MetS factors on PCa incidence, on the risk of high-grade PCa and to analyze the role of MetS and single MetS components on the development of aggressive PCa features.
A systematic literature search and analysis on PubMed, EMBASE, Cochrane and Academic One File databases until September 2015 was performed by 2 independent reviewers to evaluate the associations between MetS and PCa incidence, and between MetS and high-grade PCa incidence (bioptical Gleason Score⩾8, Prognostic Group 4-5 according to the novel prostate cancer grading system). Also the association between MetS and individual MetS components with pathological Gleason Score⩾8, extra-capsular extension, seminal vesicle invasion, positive surgical margins and biochemical recurrence (defined as two consecutive PSA values ⩾0.2 ng ml
after radical prostatectomy) was evaluated.
24 studies were selected including a total of 132 589 participants of whom 17.35% had MetS. There was a slight association between MetS and PCa incidence (odds ratio (OR)=1.17 (1.00-1.36), P=0.04) and between high-grade PCa and MetS (OR= 1.89 (1.50-2.38), P<0.0001) but the studies were statistically heterogeneous. No association was found between MetS components and PCa risk except for hypertension. MetS was significantly associated with pathologic Gleason Score⩾8 (OR= 1.77 (1.34-2.34); P<0.01), extra-capsular extension (OR=1.13 (1.09-1.18); P<0.01), seminal vesicle invasion (OR=1.09 (1.07-1.12); P<0.01), positive surgical margins (OR=1.67 (1.47-1.91); P<0.01) and biochemical recurrence (OR=1.67 (1.04-2.69); P<0.01).
The presence of MetS is associated with worse oncologic outcomes in men with PCa, in particular with more aggressive tumor features, and biochemical recurrence.
We report a case of a patient who presented with symptoms of acute onset scleritis in the left eye but was found to have an underlying necrotic choroidal melanoma. Asymptomatic choroidal melanoma can ...undergo spontaneous necrosis and manifest as severe scleritis and should be considered as an important differential.
► The cyclic softening is intrinsic to tempered martensitic lath/subgrain structure. ► It is due to the decrease of dislocation density and to the subgrain coarsening. ► Optimizing the creep ...resistance do not limit the cyclic softening effect. ► Better initial creep properties lead to correct remaining creep strength after cycling.
The present article compares the cyclic behaviour of various 9–12%Cr steels, both commercial grades and optimized materials (in terms of creep strength). These materials were subjected to high temperature fatigue and creep-fatigue loadings. TEM examinations of the microstructure after cyclic loadings were also carried out. It appears that all the tempered ferritic–martensitic steels suffer from a cyclic softening effect linked to the coarsening of the subgrains and laths and to the decrease of the dislocation density. These changes of the microstructure lead to a drastic loss in creep strength for all the materials under study. However, due to a better precipitation state, several materials optimized for their creep strength still present a good creep resistance after cyclic softening. These results are discussed and compared to the literature in terms of the physical mechanisms responsible for cyclic and creep deformation at the microstructural scale.
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