Measurements of nematic susceptibility with phase sensitive nuclear magnetic resonance in pulsed strain fields.

We present nuclear magnetic resonance data in BaFe2As2 in the presence of pulsed strain fields that are interleaved in time with the radio frequency excitation pulses. In this approach, the preceding nuclear magnetization acquires a phase shift that is proportional to the strain and pulse time. The sensitivity of this approach is limited by the homogeneous decoherence time, T2, rather than the inhomogeneous linewidth. We measure the nematic susceptibility as a function of temperature and demonstrate a three orders of magnitude improvement in sensitivity. This approach will enable studies of the strain response in a broad range of materials that previously were inaccessible due to inhomogeneous broadening.

Inverse Laplace transformation analysis of stretched exponential relaxation.

We investigate the effectiveness of the Inverse Laplace Transform (ILT) analysis method to extract the distribution of relaxation rates from nuclear magnetic resonance data with stretched exponential relaxation. Stretched-relaxation is a hallmark of a distribution of relaxation rates, and an analytical expression exists for this distribution for the case of a spin-1/2 nucleus. We compare this theoretical distribution with those extracted via the ILT method for several values of the stretching exponent and at different levels of experimental noise. The ILT accurately captures the distributions for ß≲0.7, and for signal to noise ratios greater than ∼40; however the ILT distributions tend to introduce artificial oscillatory components. We further use the ILT approach to analyze stretched relaxation for spin I>1/2 and find that the distributions are accurately captured by the theoretical expression for I=1/2. Our results provide a solid foundation to interpret distributions of relaxation rates for general spin I in terms of stretched exponential fits.

Antithyroid drugs in Graves' hyperthyroidism: differences between "block and replace" and "titration" regimes in frequency of euthyroidism and Graves' orbitopathy during treatment.

PURPOSE: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves' hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether 'Block and Replace' (B + R) and 'Titration' (T) regimes are equivalent in terms of frequency of euthyroidism and Graves' Orbitopathy (GO) during ATD therapy. METHODS: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution's policy. RESULTS: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27-0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%. CONCLUSION: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

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.

Uniaxial strain control of spin-polarization in multicomponent nematic order of BaFe2As2.

The iron-based high temperature superconductors exhibit a rich phase diagram reflecting a complex interplay between spin, lattice, and orbital degrees of freedom. The nematic state observed in these compounds epitomizes this complexity, by entangling a real-space anisotropy in the spin fluctuation spectrum with ferro-orbital order and an orthorhombic lattice distortion. A subtle and less-explored facet of the interplay between these degrees of freedom arises from the sizable spin-orbit coupling present in these systems, which translates anisotropies in real space into anisotropies in spin space. We present nuclear magnetic resonance studies, which reveal that the magnetic fluctuation spectrum in the paramagnetic phase of BaFe2As2 acquires an anisotropic response in spin-space upon application of a tetragonal symmetry-breaking strain field. Our results unveil an internal spin structure of the nematic order parameter, indicating that electronic nematic materials may offer a route to magneto-mechanical control.

Nuclear magnetic resonance probe head design for precision strain control.

We present the design and construction of an NMR probe to investigate single crystals under strain at cryogenic temperatures. The probe head incorporates a piezoelectric-based apparatus from Razorbill Instruments that enables both compressive and tensile strain tuning up to strain values on the order of 0.3% with a precision of 0.001%. 75As NMR in BaFe2As2 reveals large changes to the electric field gradient and indicates that the strain is homogeneous to within 16% over the volume of the NMR coil.

Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement.

BACKGROUND: 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. CONCLUSION: 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.

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.

NMR Evidence for Inhomogeneous Nematic Fluctuations in BaFe_{2}(As_{1-x}P_{x})_{2}.

We present evidence for nuclear spin-lattice relaxation driven by glassy nematic fluctuations in isovalent P-doped BaFe_{2}As_{2} single crystals. Both the ^{75}As and ^{31}P sites exhibit a stretched-exponential relaxation similar to the electron-doped systems. By comparing the hyperfine fields and the relaxation rates at these sites we find that the As relaxation cannot be explained solely in terms of magnetic spin fluctuations. We demonstrate that nematic fluctuations couple to the As nuclear quadrupolar moment and can explain the excess relaxation. These results suggest that glassy nematic dynamics are a common phenomenon in the iron-based superconductors.

Coexistence of cluster spin glass and superconductivity in Ba(Fe(1-x)Co(x))2As2 for 0.060≤x≤0.071.

We present 75As nuclear magnetic resonance data from measurements of a series of Ba(Fe(1-x)Co(x))2As2 crystals with 0.00≤x≤0.075 that reveals the coexistence of frozen antiferromagnetic domains and superconductivity for 0.060≤x≤0.071. Although bulk probes reveal no long range antiferromagnetic order beyond x=0.06, we find that the local spin dynamics reveal no qualitative change across this transition. The characteristic domain sizes vary by more than an order of magnitude, reaching a maximum variation at x=0.06. This inhomogeneous glassy dynamics may be an intrinsic response to the competition between superconductivity and antiferromagnetism in this system.

Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy.

BACKGROUND: Optimal doses of i.v. 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 i.v. 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.

Rituximab treatment in patients with active Graves' orbitopathy: effects on proinflammatory and humoral immune reactions.

In active Graves' orbitopathy (GO), proinflammatory cytokines predominate. Circulating thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) have been correlated with GO clinical activity and severity. In preliminary studies rituximab (RTX), an anti-CD 20 monoclonal antibody, has induced clinical improvement of active GO without a change in serum anti-thyroid antibodies. We have studied whether RTX in GO acts by affecting proinflammatory cytokines and thyroid and orbital-directed antibodies. Ten patients with GO were treated with RTX, administered twice intravenously (i.v.) (1000 mg) at days 1 and 15, and 20 with methylprednisolone, administered weekly i.v. (500 mg), for 16 weeks. Patients were studied before treatment, at B cell depletion and at 4, 8, 16, 20, 30 and 50 weeks. Peripheral lymphocytes, serum interleukin (sIL)-6, sIL-6r, chemokine (C-X-C motif) ligand 10 (CXCL10), TRAb and stimulating antibodies (TSAb) and autoantibodies against orbital calsequestrin, collagen XIII and flavoprotein subunit of succinate dehydrogenase (FP-SDH) were measured at baseline and after treatment. Serum IL-6 and sIL-6R concentrations did not change after RTX [P = not significant (n.s.)]. Serum CXCL10 increased after RTX at B cell depletion and at 30 weeks (P < 0·003). Serum TSAb did not change in relation to TRAb, nor did antibodies against orbital antigens (P = n.s.). In conclusion, this study shows that RTX in GO does not affect humoral reactions. The observed increase of serum CXCL10 concentrations at B cell depletion may result from cell lysis. We suggest that RTX may exert its effect in GO by inhibiting B cell antigen presentation.

NMR investigation of superconductivity and Antiferromagnetism in CaFe2As2 under pressure.

We report 75As NMR measurements in CaFe2As2, made under applied pressures up to 0.83 GPa produced by a standard clamp pressure cell. Our data reveal phase segregation of paramagnetic and antiferromagnetic (AFM) phases over a range of pressures, with the AFM phase more than 90% dominant at low temperatures. In situ rf susceptibility measurements indicate the presence of superconductivity. 75As spin-lattice relaxation experiments indicate that the 75As nuclei sample the superconductivity while in the magnetically ordered environment.

Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis.

CONTEXT: The reactivation of Graves' orbitopathy (GO) after radioiodine (RAI) for Graves' disease (GD) is a known effect, and its clinical relevance is controversial. Prevention of RAI-induced GO activation is possible in at-risk patients with oral glucocorticoids (OGC). OBJECTIVES: The aim of the study was to analyze the effects of RAI on GO with or without prophylactic steroids based on known risk factors and to compare the effectiveness of prophylaxis with iv glucocorticoids (IVGC) and OGC. DESIGN: We conducted a retrospective study in which patients were assessed before and 1-12 months after RAI. PATIENTS AND SETTING: A total of 113 patients were included in the study; 83 underwent RAI without prophylactic steroids for the absence of risk of activation, and 30 were treated with either OGC (n = 21) or IVGC (n = 9). MAIN OUTCOME MEASURES: We analyzed the prevalence of GO activation with or without steroid prophylaxis and the difference in the prevalence of GO activation after OGC or IVGC. RESULTS: GO activation was observed in 7.2% of patients without and 33.3% of patients with steroid prophylaxis (P < 0.0001), for an overall prevalence of 14.6%. GO activation occurred in 47.6% of patients treated with OGC but in none of the nine patients treated with IVGC (P = 0.0001). Disease activation was more prevalent in males (P < 0.02) and in older patients (P = 0.04) with a shorter duration of GD (P < 0.01) and time from GO onset (P < 0.01). CONCLUSIONS: GO may occur after RAI in approximately 15% of patients also in the absence of signs of active GO. Prophylactic OGC did not prevent GO activation in a large proportion of patients, compared to IVGC.

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures.

AIM: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves' orbitopathy (GO) receiving surgery for disfiguring proptosis. METHOD: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. RESULTS: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. CONCLUSIONS: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

Field-induced coupled superconductivity and spin density wave order in the heavy fermion compound CeCoIn5.

The high-field superconducting state in CeCoIn(5) has been studied by transverse field muon spin rotation measurements with an applied field parallel to the crystallographic c axis close to the upper critical field mu(0)H(c2) = 4.97 T. At magnetic fields mu(0)H > or = 4.8 T the muon Knight shift is enhanced and the superconducting transition changes from second order towards first order as predicted for Pauli-limited superconductors. The field and temperature dependence of the transverse muon spin relaxation rate sigma reveal paramagnetic spin fluctuations in the field regime from 2 T < or = mu(0)H < 4.8 T. In the normal state close to H(c2) correlated spin fluctuations as described by the self-consistent renormalization theory are observed. The results support the formation of a mode-coupled superconducting and antiferromagnetically ordered phase in CeCoIn(5) for H directed parallel to the c axis.

75As NMR studies of superconducting LaFeAsO0.9F0.1.

We have performed 75As nuclear magnetic resonance measurements on aligned powders of the new LaFeAsO0.9F0.1 superconductor. In the normal state, we find a strong temperature dependence of the spin shift and Korringa behavior of the spin lattice relaxation rate. In the superconducting state, we find evidence for line nodes in the superconducting gap and spin-singlet pairing. Our measurements reveal a strong anisotropy of the spin lattice relaxation rate, which suggests that superconducting vortices contribute to the relaxation rate when the field is parallel to the c axis but not for the perpendicular direction.

New immunomodulators in the treatment of Graves' ophthalmopathy.

Steroids have been used in the therapy of the moderate to severe forms of Graves' ophthalmopathy (GO) and other autoimmune diseases as they act only as general immunosuppressants. Previous work has shown that blocking the CD-20 receptor on B lymphocytes has significantly affected the clinical course of GO, by rapidly reducing inflammation and the degree of proptosis. We have studied nine patients with Graves' disease, of whom seven had active GO and two, with newly diagnosed hyperthyroidism, only mild lid signs. We also studied a group of 20 consecutive patients, treated with intravenous glucocorticoids (IVGC) according to a standard protocol. Patients treated with RTX (1000mg i.v. twice at two-week interval) and those treated with IVGC (500mg i.v. for 16 weeks) were studied monthly up to 12 months after the first drug infusion. By ophthalmological examination, GO was assessed by the clinical activity score (CAS) and by the NOSPECS score. Thyroid function and lymphocyte count were measured by standardized methods. RTX was well-tolerated and only minor side-effects were reported in 30% of patients during the first infusion. All patients attained peripheral B-cell depletion with the first RTX infusion. All but one patients showed both CD20+ cells and CD19+ cells depletion, while one had persistent 3-5% CD19+ cells in the periphery, mostly CD19+5+. Thyroid function was not affected by RTX therapy. Titers of antithyroglobulin (TgAb), antithyroperoxidase and anti-TSH receptor antibodies (TRAb) did not change significantly (P=NS) and did not correlate to CD20+ depletion (P=NS). CAS values decreased significantly (P<0.0001). Proptosis decreased significantly after RTX in both patients with active GO (ANOVA; P<0.0001) and in those with Graves' hyperthyroidism and lid signs (ANOVA; P<0.003). The degree of inflammation (NOSPECS class 2) decreased significantly in response to RTX (ANOVA; P<0.001). In patients treated with IVGC, mean CAS value decreased significantly less than in those treated with RTX (P<0.05). Adverse effects were more frequent after IVGC (45% of patients). Seventy-five percent of patients responded to IVGC and 10% showed relapse of active GO six to eight weeks after withdrawal. The results of this study on RTX in GO suggest that the drug is effective in modifying the disease course and that the improvement of the clinical activity of GO after RTX was more significant than after IVGC. We did not observe relapse of active GO, even after B-cell return in peripheral blood. This might be related to the persistence of a significant degree of B-cell depletion after RTX observed in the peripheral blood as late as two years of follow-up. RTX therapy was also effective in improving proptosis and soft tissue inflammation. The mechanism by which RTX affects GO is unknown. It may act as a true immunosuppressor by switching off reactions inducing the active phase of TAO, perhaps by influencing the cytokine production in the orbit or by inducing depletion of antigen presenting B-cells.

Interacting antiferromagnetic droplets in quantum critical CeCoIn5.

The heavy fermion superconductor CeCoIn5 can be tuned between superconducting and antiferromagnetic ground states by hole doping with Cd. Nuclear magnetic resonance data indicate that these two orders coexist microscopically with an ordered moment approximately 0.7 microB. As the ground state evolves, there is no change in the low-frequency spin dynamics in the disordered state. These results suggest that the magnetism emerges locally in the vicinity of the Cd dopants.

Microscopic evidence for field-induced magnetism in CeCoIn5.

We present NMR data in the normal and superconducting states of CeCoIn5 for fields close to H(c2)(0)=11.8 T in the ab plane. Recent experiments identified a first-order transition from the normal to superconducting state for H>10.5 T, and a new thermodynamic phase below 290 mK within the superconducting state. We find that the Knight shifts of the In(1), In(2), and the Co are discontinuous across the first-order transition and the magnetic linewidths increase dramatically. The broadening differs for the three sites, unlike the expectation for an Abrikosov vortex lattice, and suggests the presence of static spin moments in the vortex cores. In the low-temperature and high-field phase, the broad NMR lineshapes suggest ordered local moments, rather than a long-wavelength quasiparticle spin density modulation expected for an FFLO phase.