Role of the mononuclear cell infiltrate in Graves' orbitopathy (GO): results of a large cohort study.

OBJECTIVE: The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves' orbitopathy (GO) is not completely defined. Here we investigated the relationship between the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients. METHODS: We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological evaluation was performed in all patients, as well as immunohistochemistry for CD3, CD4, CD8, CD56 (T-cell markers), CD25 (T and B-cell marker), CD20, CD19 (B-cell markers), and CD138 (plasmacell marker) in specimens collected at decompressive surgery. RESULTS: Having established cutoff values for each marker, cell infiltrates were found in 60 patients (78.9%; CD3: 39.4%, CD4 55.2%, CD8 50%, CD56: 0%, CD25: 28.9%, CD20: 51.3%, CD19: 25%, CD138: 26.3%). Eleven (14.4%) stained exclusively for CD138 (plasmacells). Patients with CD4-positive mononuclear cells had a significantly greater GO clinical activity score (CAS) (mean difference 1.07, 95% CI - 0.33 to - 1.82, P = 0.004 by univariate, P = 0.05 by multivariate analysis). CAS as well as the remaining GO features were not affected significantly by the mononuclear cell subpopulations in multivariate analyses. CONCLUSIONS: Mononuclear cell infiltrates are present in the majority of GO patients, with a small percentage represented exclusively by plasmacells. CD4 cells exert a major role on GO activity. These findings may represent a further advancement in the comprehension of GO pathogenesis.

Correlation between serum anti-TSH receptor autoantibodies (TRAbs) and the clinical feature of Graves' orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Several studies support the involvement of TSH receptor autoantibodies (TRAbs) in the pathogenesis of GO, and a correlation between GO features and TRAbs has been reported, but not confirmed by all studies. Thus, we conducted a cross-sectional investigation to determine whether there is a correlation between TRAbs and the clinical features of GO in an initial phase of the eye disease. METHODS: Ninety consecutive patients with untreated GO (67 women and 23 men, age 48.9 ± 12.6 years) were included. Patients who had received treatments other than anti-thyroid drugs for hyperthyroidism or lubricants for GO were excluded. All patients underwent an endocrinological and ophthalmological evaluation, the latter including exophthalmometry, measurement of eyelid width, clinical activity score (CAS), visual acuity, assessment of diplopia, and NOSPECS score. TRAb levels were measured by a third-generation competitive immunoassay. RESULTS: There was a statistically significant, direct correlation between serum TRAb levels and CAS by linear regression analysis (R = 0.278, P = 0.007). The correlation was confirmed by a multiple regression analysis (R = 0.285; P = 0.006) including age and FT3 levels, which also correlated with CAS. There were no relationships between TRAbs and exophthalmometry, eyelid aperture, degree of diplopia, visual acuity, and NOSPECS score. CONCLUSIONS: The levels of TRAb in subjects with a recent-onset, untreated GO are directly correlated with the clinical activity of the disease, confirming a possible role of these antibodies in the pathogenesis of GO.

Putative protective role of autoantibodies against the insulin-like growth factor-1 receptor in Graves' Disease: results of a pilot study.

BACKGROUND: The insulin-like growth factor-1 receptor (IGF-1R) is a key element in the pathogenesis of Graves' Orbitopathy (GO), but the role of IGF-1R autoantibodies (IGF-1RAbs) has not been established. METHODS: We designed a cross-sectional investigation to measure IGF-1RAbs in patients with Graves' disease (GD), with or without GO, who underwent radioiodine therapy followed by glucocorticoids (GC). Twenty-nine patients were included, 15 of which with GO. Patients were evaluated at baseline and three and 6 months after radioiodine. The primary objective was the prevalence of positive tests for IGF-1RAbs. The secondary objectives were: (1) IGF-1RAbs concentrations and their variations; (2) relationship between IGF-1RAbs and the features of GO; (3) relationship between IGF-1RAbs and anti-thyroid autoantibodies. RESULTS: IGF-1RAbs above the cut-off value were found only in one patient with GD without GO. IGF-1RAb levels were greater in patients with GD without GO, at baseline (P < 0.0001), and after three (P < 0.0001) and six (P = 0.0001) months. No correlations were observed between IGF-1RAbs and the features of GO, nor between IGF-1RAbs and anti-thyroglobulin or anti-thyroperoxidase autoantibodies. There was an inverse correlation between anti-TSH receptor autoantibodies (TRAbs) and IGF-1RAb levels in GD patients with GO at 6 months (P = 0.03). CONCLUSIONS: IGF-1RAbs appear to be greater in patients with GD without GO compared with those with GO, suggesting a putative protective role of IGF-1RAbs on the development of GO, in line with the beneficial effects of Teprotumumab on GO. The inverse correlation between IGF-1RAbs and TRAbs 6 months after radioiodine may reflect antigen spreading and/or GC treatment.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

Potential paths for the introduction of risk analysis to improve the veterinary epidemiology curriculum in Ukraine.

The main purpose of veterinary education institutions is to prepare qualified, well-trained and knowledgeable professionals ready to serve local and global communities. Veterinary programmes vary within and among countries, creating a disparity in competencies. In less-developed economies, adhering to the World Organisation for Animal Health (OIE) â€ËœDay 1 competencies' and following its â€ËœGuidelines for a Model Core Veterinary Curriculum' may decrease this discrepancy. The authors offer a comparison of Ukraine's veterinary epidemiology curriculum with the OIE suggested â€ËœCore Veterinary Curriculum', particularly for infectious disease pathology in which epidemiology is taught, and propose different paths to structure advanced educational programmes in epidemiology. This course is relevant for the development of international animal trade and expansion of markets for animal products in Ukraine.

Le principal objectif des établissements d'enseignement vétérinaire consiste à préparer des professionnels qualifiés, bien formés et compétents prêts à se mettre au service de leur communauté locale et, plus largement, de la communauté mondiale. Les programmes d'enseignement de la médecine vétérinaire varient d'un pays à l'autre et parfois même à l'échelle nationale, aboutissant ainsi à des compétences disparates. Dans les pays en développement, l'adhésion aux recommandations de l'Organisation mondiale de la santé animale (OIE) sur les compétences minimales attendues des jeunes diplômés en médecine vétérinaire (compétences dites « au premier jour ¼) et aux lignes directrices de l'OIE relatives au Cursus de formation initiale vétérinaire permet de réduire ces disparités. Les auteurs procèdent à une comparaison entre le cursus d'épidémiologie vétérinaire en Ukraine et le cursus de formation initiale vétérinaire recommandé par l'OIE, en particulier en ce qui concerne les cours de pathologie des maladies infectieuses qui intègrent une composante épidémiologique ; ils proposent ensuite différentes voies permettant de structurer des programmes d'enseignement de haut niveau en épidémiologie. Ces formations sont nécessaires pour soutenir les échanges internationaux d'animaux et améliorer l'accès aux marchés des produits d'origine animale ukrainiens. L'épidémiologie est une discipline essentielle pour le Secteur de l'évaluation des risques, récemment créés au sein des Services nationaux ukrainiens chargés de la sécurité sanitaire des aliments et la protection des consommateurs. La formation professionnelle est d'une importance cruciale et les vétérinaires diplômés issus des institutions ukrainiennes seront dotés des compétences de base essentielles pour commencer à travailler à l'appui des échanges internationaux d'animaux et de produits d'origine animale et rejoindre la fonction publique. Les objectifs à long terme visent à améliorer les programmes d'enseignement vétérinaire en Ukraine, en réformant l'enseignement de l'épidémiologie, et à concevoir et diffuser un modèle d'évaluation du contenu des cours d'épidémiologie dans les écoles vétérinaires dans l'ensemble du pays.

Los establecimientos de enseñanza veterinaria tienen por principal cometido preparar a profesionales cualificados, bien formados e informados y prestos para servir a la población local y mundial. Dado que los programas de enseñanza veterinaria varían entre países y dentro de ellos, también difieren las competencias adquiridas. En economías poco desarrolladas, el hecho de guiarse por las «competencias mínimas¼ del recién titulado, según las define la Organización Mundial de Sanidad Animal (OIE), y de seguir las pautas del «Modelo de plan de estudios básico de formación veterinaria¼ de la OIE puede ayudar a reducir estas disparidades. Los autores comparan el plan de estudios ucraniano en materia de epidemiología veterinaria con el «Plan de estudios básico de formación veterinaria¼ recomendado por la OIE, sobre todo en lo tocante a las enfermedades infecciosas, pues en esta materia se inscribe la enseñanza de la epidemiología, y proponen diferentes fórmulas para estructurar programas de formación avanzada al respecto. Esta formación reviste interés para el desarrollo del comercio internacional de animales y la expansión de los mercados de productos animales en Ucrania. La epidemiología es esencial para el Sector de la evaluación de riesgos recién creados en el Servicio Estatal Ucraniano de Higiene de los Alimentos y Protección del Consumidor. La formación de profesionales reviste máxima importancia. Los veterinarios titulados por establecimientos ucranianos contarán con los conocimientos básicos necesarios para empezar a trabajar en el comercio de animales y productos de origen animal o para administraciones públicas. El objetivo a largo plazo se cifra en mejorar el plan de estudios veterinarios de Ucrania introduciendo cambios en las clases de epidemiología y en elaborar una plantilla común para evaluar los contenidos de epidemiología impartidos en las facultades de veterinaria de cualquier parte del país.

Efficient synthesis of organic thioacetates in water.

Thioacetates as precursors of thiols are interesting starting points for synthesizing other organosulfur compounds. Herein, we propose a simple, efficient and fast method to obtain organic thioacetates using water as a solvent. Taking into account the great attention that has been paid toward environmentally friendly synthetic procedures in the past decades, we prove the role and the strength of the thioacetate anion as a nucleophile for nucleophilic displacement reactions in an aqueous medium. The reactions were carried out under pH control, to prevent the decomposition of the mesylate starting materials, using potassium carbonate as a safe and mild base. A simple work up allows products to be obtained with excellent yield and acceptable purity.

Antioxidant effects of ß-carotene, but not of retinol and vitamin E, in orbital fibroblasts from patients with Graves' orbitopathy (GO).

BACKGROUND: Oxidative stress is involved in the pathogenesis of Graves' orbitopathy (GO) and several antioxidant agents, namely, selenium, quercetin, enalapril, vitamin C, N-acetyl-L-cysteine, and melatonin, have been shown to reduce oxidative stress and its consequences in primary culture of orbital fibroblasts. In addition, selenium is effective for the treatment of mild GO. Here, we investigated the action of three additional antioxidants in orbital fibroblasts, namely, retinol, ß-carotene, and vitamin E. METHODS: Primary cultures of orbital fibroblasts were established from GO patients and control subjects. To induce oxidative stress, cells were treated with H2O2, after which glutathione disulfide (GSSG) (a parameter of oxidative stress), cell proliferation, hyaluronic acid, TNFα, IFNγ, and IL1ß were measured. RESULTS: H2O2-dependent oxidative stress (augmented GSSG) was associated with increased cell proliferation and cytokine release. All the three antioxidant substances reduced GSSG in both GO and control fibroblasts. ß-carotene reduced proliferation in GO, but not in control fibroblasts. IL1ß was reduced by all three substances. Retinol reduced IFNγ in GO and control fibroblasts. CONCLUSIONS: Our study supports an antioxidant role of retinol, ß-carotene, and vitamin E in orbital fibroblasts from patients with GO and provides a basis for a possible clinical use these substances.

Action of three bioavailable antioxidants in orbital fibroblasts from patients with Graves' orbitopathy (GO): a new frontier for GO treatment?

OBJECTIVE: Oxidative stress is involved in the pathogenesis of Graves' orbitopathy (GO) and an antioxidant approach has been advocated for GO treatment. Here, we investigated the action of three antioxidants in orbital fibroblasts, namely, vitamin C, N-acetyl-L-cysteine, and melatonin. METHODS: Primary cultures of orbital fibroblasts from six GO patients and six control subjects were established. Cells were treated with H2O2 to induce oxidative stress. Cell vitality assays were performed to determine the non-cytotoxic dose of each antioxidant. The following assays were performed: glutathione disulfide (GSSG), as a measure of oxidative stress, cell proliferation, hyaluronic acid (HA), TNFα, IFNγ, and IL1ß. RESULTS: H2O2 induced oxidative stress (augmented GSSG), increased cell proliferation as well as cytokine release, but did not affect HA release. All of the three antioxidant substances reduced H2O2-dependent oxidative stress. Vitamin C reduced proliferation in GO, but not in control fibroblasts. N-acetyl-L-cysteine reduced proliferation and IFNγ in GO, and HA and IL1ß in both GO and control fibroblasts. Melatonin reduced IL1ß and HA in GO and control fibroblasts, and IFNγ only in GO fibroblasts. CONCLUSIONS: Our study provides evidence in support of an antioxidant role of vitamin C, N-acetyl-L-cysteine and melatonin in orbital fibroblasts. Some of the effects of these compounds are exclusive to GO fibroblasts, whereas some other are observed also in control fibroblasts. Our observations provide a basis for a possible clinical use of these substances in patients with GO.

Relationship between serum cholesterol and Graves' orbitopathy (GO): a confirmatory study.

BACKGROUND: It has been suggested that high cholesterol represents a risk factor for Graves' orbitopathy (GO). In a recent cross-sectional study, a correlation between cholesterol and the presence of GO was found in patients with a Graves' disease (GD) of recent onset. To confirm this observation, we conducted a retrospective investigation in consecutive patients with GD. The primary outcome was the relationship between the presence of GO and low-density lipoprotein (LDL)-cholesterol. METHODS: The design entailed the inclusion of consecutive patients with a GD of recent onset, with or without GO, who came to our observation to receive radioiodine over a period of 6 months, and a stratification aimed at having two homogeneous group of patients in terms of thyroid function. A total of 86 patients fulfilled the inclusion and evaded the exclusion criteria. All patients underwent an ophthalmological assessment and serum lipids were measured. RESULTS: Serum levels of LDL-cholesterol were significantly higher in patients with GO (135.3 ± 41.3 mg/dL) compared with those without GO (106.6 ± 23.9 mg/dL, P = 0.0007). In a similar manner, serum levels of total cholesterol were higher in patients with GO (211.6 ± 44.0 mg/dL) than in those without GO (176.0 ± 27.2 mg/dL, P = 0.0001). There was no relationship between GO severity and activity and cholesterol. There was no relationship between GO and high-density lipoprotein-cholesterol or triglycerides. CONCLUSIONS: Our study confirms a relationship between the presence of GO and cholesterol in patients with GD of recent onset. Whether lowering of cholesterol ameliorates, GO remains to be established.

Use of low-dose radioiodine ablation for Graves' orbitopathy: results of a pilot, perspective study in a small series of patients.

OBJECTIVE: Elimination of thyroid antigens by total thyroid ablation (TTA), namely, thyroidectomy followed by radioiodine, may be beneficial for Graves' Orbitopathy (GO). TTA is usually performed with a 131I dose of 30 mCi. In Italy, this dose must be followed by a 24-h protected hospitalization, with increase in the waiting lists. In contrast, a 15 mCi dose can be given without hospitalization and with lower costs. Here, we investigated whether a lower dose of radioiodine can be used to ablate thyroid remnants in patients with GO, after thyroidectomy. METHODS: The study was performed in two small groups of consecutive thyroidectomized patients (six patients per group) with Graves' hyperthyroidism and GO. Patients underwent ablation with either 15 or 30 mCi of 131I following treatment with recombinant human TSH (rhTSH). The primary outcome was rhTSH-stimulated serum thyroglobulin (Tg) at 6 months. The secondary outcome was baseline Tg at 6 months. RESULTS: Baseline Tg and rhTSH-stimulated Tg after at 6 months did not differ between two groups, suggesting a similar extent of ablation. rhTSH-stimulated Tg was reduced significantly compared with rhTSH-stimulated Tg at ablation in both groups. GO outcome following treatment with intravenous glucocorticoids did not differ between the two groups. CONCLUSIONS: Our findings may provide a preliminary basis for the use of a 15 mCi dose of radioiodine upon rhTSH stimulation in thyroidectomized patients with Graves' hyperthyroidism and GO.

Effect of participation in a park-based afterschool program on cardiovascular disease risk among severely obese youth.

OBJECTIVES: The prevalence of severe obesity in youth is rising, despite reports of obesity rates stabilizing overall. While reports on treatment outcomes for youth with severe obesity (bariatric surgery, behavioral and pharmacological treatments) exist, very few community-based programs have reported changes in health outcomes in this population. We assessed changes in cardiovascular health risk profiles among racial/ethnic minority youth with severe obesity who participated in Fit2Play™, a park-based afterschool health promotion program. STUDY DESIGN: A longitudinal cohort study. METHODS: Children aged 6-14 years (N = 1546, 51% Hispanic, 44% non-Hispanic black) who participated in the Fit2Play™ in one of 34 urban park sites for one school year over five separate school years (2010-2015) had height, weight, four-site skinfold thicknesses, systolic blood pressure (SBP)/diastolic blood pressure (DBP), fitness tests, and a health/wellness knowledge test collected at the beginning and end of the school year. Two-level repeated measures mixed models examined changes in cardiovascular health outcomes (body mass index [BMI], skinfold thickness, systolic/diastolic blood pressure percentile [SBPP/DBPP], cardiorespiratory fitness [PACER]) in youth with severe obesity over 1- and 2-year follow-up. RESULTS: Compared with baseline, BMI decreased 13% (incidence rate ratio [IRR] 95% confidence interval [CI]: 0.83-0.90), sumof skinfold thicknesses decreased 5% (IRR 95% CI: 0.91-0.99), SBPP decreased 5% (IRR 95% CI: 0.90-0.99), DBPP decreased 19% (IRR 95% CI: 0.77-0.86), and PACER scores increased 12% (IRR 95% CI: 1.0-1.27) after two years of participation in the Fit2Play™ program. CONCLUSIONS: Findings here support community/park-based youth programs as effective and accessible treatment options for reducing cardiovascular disease risk among youth with severe obesity.

Randomized clinical trial of psychological support and sleep adjuvant measures for postoperative sleep disturbance in patients undergoing oesophagectomy.

BACKGROUND: Major surgery such as oesophagectomy requires a postoperative stay in intensive care. Painful stimuli lead to sleep disturbance and impairment in quality of life. The aim of this study was to evaluate the effect of psychological counselling and sleep adjuvant measures on postoperative quality of sleep and quality of life. METHODS: This RCT was performed between January 2013 and October 2015. Patients undergoing oesophagectomy for cancer were randomized into one of four groups receiving: psychological counselling plus sleep adjuvant measures during the ICU stay; psychological counselling alone; sleep adjuvant measures alone during the ICU stay; or standard care. The primary endpoint was impairment in quality of life measured using the European Organisation for Research and Treatment of Cancer C30-QL2 questionnaire between admission for surgery and discharge from hospital. The secondary endpoint was impairment in quality of sleep assessed by means of the Pittsburgh Sleep Quality Index between admission for surgery and hospital discharge. RESULTS: The local ethics committee approved the early termination of the study because of relevant changes in the ICU setting. Some 87 patients were randomized and 74 patients were evaluated in the analysis. Psychological counselling reduced the impairment in quality of life (odds ratio 0·23, 95 per cent c.i. 0·09 to 0·61) and in quality of sleep (odds ratio 0·27, 0·10 to 0·73). CONCLUSION: Perioperative psychological support reduces impairment in quality of life and quality of sleep after oesophagectomy. Registration number: NCT01738620 (http://www.clinicaltrials.gov).

Graves' orbitopathy, idiopathic orbital inflammatory pseudotumor and Epstein-Barr virus infection: a serological and molecular study.

OBJECTIVE: One of the hypotheses on the pathogenesis of autoimmune diseases, including Graves' disease (GD) and Graves' orbitopathy (GO), involves bacterial or viral infections. Recently, Epstein-Barr virus (EBV) has been proposed to play a role in the pathogenesis of idiopathic orbital inflammatory pseudotumor (IOIP) in Asians. The aim of the present study was to investigate the possible association of GO with EBV infection/exposure, as compared with IOIP, using serum and tissue samples, as well as primary cultures of orbital fibroblasts. METHODS: Thirty-one patients were studied, including four with IOIP, ten with GO, nine with GD without GO and eight control patients without IOIP, GD and GO. All patients with IOIP and GO underwent orbital decompression. Control patients underwent palpebral surgery. Fibroadipose orbital tissue samples were collected. Serum anti-EBV antibodies were measured in all patients. EBV-DNA was measured in blood samples, orbital tissue samples and primary cultures of orbital fibroblasts. RESULTS: Serum assays showed that the vast majority of patients have had a previous exposure to EBV, but no one had an acute infection. EBV-DNA was detected in ~40% of blood samples from GO, GD and control patients, but in none of the IOIP samples. EBV-DNA was not detected in any of the orbital tissue samples tested or in primary cultures of orbital fibroblasts. CONCLUSIONS: EBV infection does not seem to be associated with GD, GO and IOIP in Caucasians. Whether EBV is involved in IOIP in Asians or other populations remains to be confirmed.

Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

PURPOSE: Intravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves' orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention) and 24 (follow-up) weeks, particularly in patients initially unresponsive. METHODS: Our database (Bartalena et al. J Clin Endocrinol Metab 97:4454-4463, 10), comprising 159 patients given three different cumulative doses of methylprednisolone (2.25, 4.98, 7.47 g) was analyzed, pooling data for analyses. Responses at 6 weeks were compared with those at 12 and 24 weeks using three outcomes: overall ophthalmic involvement [composite index (CI)]; quality of life (QoL); Clinical Activity Score (CAS). Responses were classified as "Improved", "Unchanged", "Deteriorated", compared to baseline. RESULTS: Deteriorated patients at 6 weeks for CI (n = 8) remained in the same category at 12 weeks and 7/8 at 24 weeks. Improved patients at 6 weeks for CI (n = 51) remained in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively. Unchanged patients at 6 weeks (n = 100) eventually improved in 28% of cases (CI), 58% (CAS), 32% (QoL). There was no glucocorticoid dose-dependent difference in the influence of early response on later outcomes. CONCLUSIONS: Patients who deteriorate at 6 weeks after ivGCs are unlikely to benefit from continuing ivGCs. Patients unresponsive at 6 weeks still have a significant possibility of improvement later. Accordingly, they may continue ivGC treatment, or, alternatively, possibly stop ivGCs and be switched to a second-line treatment.

Influenza surveillance in animals: what is our capacity to detect emerging influenza viruses with zoonotic potential?

A survey of national animal influenza surveillance programmes was conducted to assess the current capacity to detect influenza viruses with zoonotic potential in animals (i.e. those influenza viruses that can be naturally transmitted between animals and humans) at regional and global levels. Information on 587 animal influenza surveillance system components was collected for 99 countries from Chief Veterinary Officers (CVOs) (n = 94) and published literature. Less than 1% (n = 4) of these components were specifically aimed at detecting influenza viruses with pandemic potential in animals (i.e. those influenza viruses that are capable of causing epidemic spread in human populations over large geographical regions or worldwide), which would have zoonotic potential as a prerequisite. Those countries that sought to detect influenza viruses with pandemic potential searched for such viruses exclusively in domestic pigs. This work shows the global need for increasing surveillance that targets potentially zoonotic influenza viruses in relevant animal species.

Long-term outcome of Graves' orbitopathy following high-dose intravenous glucocorticoids and orbital radiotherapy.

OBJECTIVE: Intravenous (iv) glucocorticoids (GC) (ivGC) and orbital radiotherapy (ORT) are commonly used in active Graves' orbitopathy (GO), with favorable outcomes in up to 80% of patients. However, little is known on the factors that may affect GO outcome in the long term, an issue that we investigated here. METHODS: We studied retrospectively 96 untreated patients with GO, identified out of 787 consecutive patients who came to our GO Clinic for a follow-up visit between September 2010 and June 2013. After the first observation, patients were treated with ivGC and ORT and were then re-examined after a median period of 55.5 months. The primary end-point was the possible relation between GO outcome and several individual variables. RESULTS: Exophthalmometry, eyelid aperture, CAS, diplopia and visual acuity (the latter only in patients with an initial reduction) improved significantly after treatment. Overall, 67.7% of patients had improved and were considered as responders, whereas the remaining (29.1% stable and 4.5% worsened) were considered as non-responders. Age, smoking, thyroid volume, thyroid treatment, serum anti-TSH receptor autoantibodies and individual GO features at first observation did not affect the outcome of GO, which, in contrast, was affected by gender and by the time elapsed between first and last observation. Thus, the prevalence of responders was higher in females (76.4 vs 48% in males, P = 0.02) and the time elapsed between first and last observation was greater in responders (58 vs 39 months in non-responders, P = 0.02). Whereas the prevalence of responders and non-responders was similar up to 36 months, there was an increase in responders beginning between 37 and 48 months and reaching a peak of ~80% between 61 and 72 months, to plateau thereafter. CONCLUSIONS: Given the limitations of retrospective investigations, our study confirms that the combination of GC and ORT is effective in GO and shows that females have greater chances to respond to treatment. The notorious tendency of GO to improve spontaneously with time most likely contributes the long-term outcome of the eye syndrome.

A theoretical study of the L3 pre-edge XAS in Cu(II) complexes.

L2,3 spectra of Cu(II) complexes have been simulated by means of time dependent DFT. Besides the agreement between theory and experiment, the adopted approach provided further insights into the use of the Cu(II) L3-edge intensity and position to investigate the Cu-ligand symmetry-restricted covalency and the ligand-field strength.

Influenza at the animal-human interface: a review of the literature for virological evidence of human infection with swine or avian influenza viruses other than A(H5N1).

Factors that trigger human infection with animal influenza virus progressing into a pandemic are poorly understood. Within a project developing an evidence-based risk assessment framework for influenza viruses in animals, we conducted a review of the literature for evidence of human infection with animal influenza viruses by diagnostic methods used. The review covering Medline, Embase, SciSearch and CabAbstracts yielded 6,955 articles, of which we retained 89; for influenza A(H5N1) and A(H7N9), the official case counts of t he World Health Organization were used. An additional 30 studies were included by scanning the reference lists. Here, we present the findings for confirmed infections with virological evidence. We found reports of 1,419 naturally infected human cases, of which 648 were associated with avian influenza virus (AIV) A(H5N1), 375 with other AIV subtypes, and 396 with swine influenza virus (SIV). Human cases naturally infected with AIV spanned haemagglutinin subtypes H5, H6, H7, H9 and H10. SIV cases were associated with endemic SIV of H1 and H3 subtype descending from North American and Eurasian SIV lineages and various reassortants thereof. Direct exposure to birds or swine was the most likely source of infection for the cases with available information on exposure.

Longitudinal Impacts of Precision Greenness on Alzheimer's Disease.

BACKGROUND: The potential for greenness as a novel protective factor for Alzheimer's disease (AD) requires further exploration. OBJECTIVES: This study assesses prospectively and longitudinally the association between precision greenness - greenness measured at the micro-environmental level, defined as the Census block - and AD incidence. DESIGN: Older adults living in consistently high greenness Census blocks across 2011 and 2016 were compared to those living in consistently low greenness blocks on AD incidence during 2012-2016. SETTING: Miami-Dade County, Florida, USA. PARTICIPANTS: 230,738 U.S. Medicare beneficiaries. MEASUREMENTS: U.S. Centers for Medicare and Medicaid Services Chronic Condition Algorithm for AD based on ICD-9 codes, Normalized Difference Vegetation Index, age, sex, race/ethnicity, neighborhood income, and walkability. RESULTS: Older adults living in the consistently high greenness tertile, compared to those in the consistently low greenness tertile, had 16% lower odds of AD incidence (OR=0.84, 95% CI: 0.76-0.94, p=0.0014), adjusting for age, sex, race/ethnicity, and neighborhood income. Age, neighborhood income and walkability moderated greenness' relationship to odds of AD incidence, such that younger ages (65-74), lower-income, and non-car dependent neighborhoods may benefit most from high greenness. CONCLUSIONS: High greenness, compared to low greenness, is associated with lower 5-year AD incidence. Residents who are younger and/or who reside in lower-income, walkable neighborhoods may benefit the most from high greenness. These findings suggest that consistently high greenness at the Census block-level, may be associated with reduced odds of AD incidence at a population level.

Dual-phase digital lock-in implementation based on Nyquist rate and sampling subtraction.

Lock-in amplifiers (LIA) are widely used in laboratory environments to detect low-amplitude signals buried in noise as well as real and imaginary parts of a complex quantity. They are based on the technique of synchronous detection, where the signal of interest is modulated into a desired frequency, sent to the medium or device to be analyzed, and captured by a detector. The detector scheme relies on the concept of phase-sensitive detection, generally resulting in two components: in-phase and quadrature. This article shows a very simple and low computational-cost way to implement a dual-phase LIA, using readily available microcontrollers, running a simple and fast algorithm. Three examples of signal detection are presented (sound wave signal, impedance meter, and weak signal recovery) to point out the flexibility and capabilities of the proposed methodology.