In-person versus virtual administration of the American College of Rheumatology gold standard cognitive battery in systemic lupus erythematosus: Are they interchangeable?

OBJECTIVE: During the COVID-19 pandemic, many research studies were adapted, including our longitudinal study examining cognitive impairment (CI) in systemic lupus erythematosus (SLE). Cognitive testing was switched from in-person to virtual. This analysis aimed to determine if the administration method (in-person vs. virtual) of the ACR-neuropsychological battery (ACR-NB) affected participant cognitive performance and classification. METHODS: Data from our multi-visit, SLE CI study included demographic, clinical, and psychiatric characteristics, and the modified ACR-NB. Three analyses were undertaken for cognitive performance: (1) all visits, (2) non-CI group visits only and (3) intra-individual comparisons. A retrospective preferences questionnaire was given to participants who completed the ACR-NB both in-person and virtually. RESULTS: We analysed 328 SLE participants who had 801 visits (696 in-person and 105 virtual). Demographic, clinical, and psychiatric characteristics were comparable except for ethnicity, anxiety and disease-related damage. Across all three comparisons, six tests were consistently statistically significantly different. CI classification changed in 11/71 (15%) participants. 45% of participants preferred the virtual administration method and 33% preferred in-person. CONCLUSIONS: Of the 19 tests in the ACR-NB, we identified one or more problems with eight (42%) tests when moving from in-person to virtual administration. As the use of virtual cognitive testing will likely increase, these issues need to be addressed - potentially by validating a virtual version of the ACR-NB. Until then, caution must be taken when directly comparing virtual to in-person test results. If future studies use a mixed administration approach, this should be accounted for during analysis.

Spatiotemporal behaviors of the ridership of a public transportation system during an epidemic outbreak: case of MERS in Seoul.

During May and June 2015, an outbreak of the Middle East respiratory syndrome (MERS) occurred in Korea, which raised the fear of contagion throughout society and suppressed the use of public transportation systems. Exploring daily ridership data of the Seoul bus transportation system, along with the number of infected patients and search volume in web portals, we observe that ridership decreased abruptly while attention was heavily focused online. Then this temporal reduction recovered exponentially with a characteristic time of 3 weeks when newly confirmed cases began to decrease. We also find with the data of ranked keywords of web portals that areas with severely reduced ridership tended to cluster and spatiotemporal variations of such clusters were highly associated with general hospitals where MERS patients were treated. On the other hand, the spatial reduction in ridership relaxed algebraically with the distance from a general hospital while the outbreak was severe. We further probe the influence of the epidemic outbreak in the framework of linear response theory, which relates the responses to the epidemic outbreak ("perturbation") with correlations in the absence of the perturbation. Indeed, the spatial correlation function of the ridership changes is observed to follow a power law, sharing the same exponent as the spatial relaxation of the response function. This new theoretical approach offers a useful tool for understanding responses of public transportation system to epidemic or accidental disasters.

Autoantibodies in SLE: prediction and the p value matrix.

Autoantibodies (AA) and antinuclear antibodies (ANA) serve as key diagnostic and classification criteria for systemic lupus erythematosus (SLE). More than 200 different AA have been reported in SLE, although only a handful (<20) are considered "mainstream" because they are widely and routinely used in diagnostic, research and clinical medicine. Although the vast majority of AA have been relegated to the diminished status of "orphan" AA, some serve as predictors of SLE because they first appear in very early or subclinical SLE. Some AA are pathogenic, whereas others are thought to protect against or ameliorate disease progression and, hence, taken together can be used as predictive biomarkers of prognosis. Although studies have shown that specific AA are detected in the preclinical phase of SLE and are biomarkers of increased risk of developing the disease, AA are currently not widely used to predict very early SLE in individuals who have low pretest probability of disease. With the advent of multianalyte arrays with analytic algorithms, emerging evidence indicates that when certain combinations of biomarkers, such as the interferon signature and stem cell factor accompany AA and ANA, the predictive power for SLE is markedly increased.

The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

Preventing the development of SLE: identifying risk factors and proposing pathways for clinical care.

Although challenging, developing evidence-based approaches to an early and accurate diagnosis of systemic lupus erythematosus is a key approach to preventing disease and lupus-associated morbidity and mortality. Advances in our understanding of preclinical and incomplete lupus erythematosus have enabled the identification of risk factors that may predict disease and the development of potential strategies aimed at primary prevention. Emerging data support the notion that there is a temporal disease progression from initial asymptomatic autoimmunity (preclinical lupus) through early clinical features of the disease (incomplete lupus erythematosus) to finally becoming fully classifiable systemic lupus erythematosus (complete lupus erythematosus). Here, we review the demographic, clinical, biomarker as well as genetic and environmental features that are reported to increase the risk of disease progression. Based on these risk factors, we propose a clinical care pathway for patients with early disease. We envisage that such a pathway, through early identification of disease, may improve patient outcomes, while reducing health care costs.

Generalized hydromechanical model for stomatal responses to hydraulic perturbations.

Stomata respond in a common pattern to various hydraulic perturbations on any part of the 'soil-plant-air' system: initial transient 'wrong-way' responses and final stationary 'right-way' responses. In order to describe this pattern on the basis of statistical physics, we propose a simple model where turgor pressure of a cell is taken to be a power function of its volume, and obtain results in qualitative agreement with experimental data for responses to a variety of hydraulic perturbations: Firstly, stationary stomatal conductance as a function of the vapor pressure deficit divides into three regimes characterized by sensitivities of the stomatal conductance and the transpiration rate with respect to vapor pressure deficit; secondly, for every hydraulic perturbation, the initial transient 'wrong-way' responses always appear; thirdly, on condition that water is supplied insufficiently, stomatal oscillations are often observed; finally, stomatal responses following leaf excision exhibit, after the initial transient wrong-way responses, slow relaxation to stomatal closing. In particular, comparison of areoles having different numbers of stomata demonstrates that areoles with small numbers of stomata tend to provoke lack of water in the soil as well as in the plant. In addition, our model also describes well dependence of the stomatal conductance on temperature. It may be extended further to describe stomatal responses to other environmental factors such as carbon dioxide, light, and temperature.

A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes.

BACKGROUND: This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. PATIENTS AND METHODS: Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. RESULTS: Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9-78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). CONCLUSIONS: Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. CLINICALTRIALSGOV NUMBER: NCT01164176.

Identification and characterization of the pyrokinin/pheromone biosynthesis activating neuropeptide family of G protein-coupled receptors from Ostrinia nubilalis.

Insects have two closely related G protein-coupled receptors belonging to the pyrokinin/pheromone biosynthesis activating neuropeptide (pyrokinin/PBAN) family, one with the ligand PBAN or pyrokinin-2 and another with diapause hormone or pyrokinin-1 as a ligand. A related receptor is activated by products of the capa gene, periviscerokinins. Here we characterized the PBAN receptor and the diapause hormone receptor from the European corn borer, Ostrinia nubilalis. We also identified a partial sequence for the periviscerokinin receptor. Quantitative PCR of mRNA for all three receptors indicated differential expression in various life stages and tissues. All three splice variants of the PBAN receptor were identified with all variants found in pheromone gland tissue. Immunohistochemistry of V5 tags of expressed receptors indicated that all three variants and the diapause hormone receptor were expressed at similar levels in Spodoptera frugiperda 9 (Sf9) cells. However, the A- and B-variants were not active in our functional assay, which confirms studies from other moths. Functional expression of the C-variant indicated that it is has a 44 nM half effective concentration for activation by PBAN. The diapause hormone receptor was activated by diapause hormone with a 150 nM half effective concentration.

Fragility, Stokes-Einstein violation, and correlated local excitations in a coarse-grained model of an ionic liquid.

Dynamics of a coarse-grained model for the room-temperature ionic liquid, 1-ethyl-3-methylimidazolium hexafluorophosphate, couched in the united-atom site representation are studied via molecular dynamics simulations. The dynamically heterogeneous behavior of the model resembles that of fragile supercooled liquids. At or close to room temperature, the model ionic liquid exhibits slow dynamics, characterized by nonexponential structural relaxation and subdiffusive behavior. The structural relaxation time, closely related to the viscosity, shows a super-Arrhenius behavior. Local excitations, defined as the displacement of an ion exceeding a threshold distance, are found to be mainly responsible for structural relaxation in the alternating structure of cations and anions. As the temperature is lowered, excitations become progressively more correlated. This results in the decoupling of exchange and persistence times, reflecting a violation of the Stokes-Einstein relation.

Identification of a new member of the PBAN family of neuropeptides from the fire ant, Solenopsis invicta.

Neuropeptide hormones produced by neurosecretory cells in the central or peripheral nervous systems regulate various physiological and behavioral events during insect development and reproduction. PBAN/Pyrokinin is a major neuropeptide family, characterized by a 5-amino-acid C-terminal sequence, FXPRLamide. This family of peptides has been implicated in regulating various physiological functions including, pheromone biosynthesis, muscle contraction, diapause induction or termination, melanization, and puparium formation in different insect species. In the present study, we report a new member of the PBAN family from the red imported fire ant, Solenopsis invicta, Soi-PBAN, composed of 26-AA (GSGEDLSYGDAYEVDEDDHPLFVPRL). Three additional peptides were deduced from Soi-PBAN cDNA: 15-AA (TSQDIASGMWFGPRL), 8-AA (QPQFTPRL) and 9-AA (LPWIPSPRL), that correspond to diapause hormone (DH), beta-neuropeptide (NP), and gamma-NP, which are found in many lepidopteran moths. Five peptides, DH, alpha, beta, gamma NPs, and PBAN are encoded from PBAN genes of lepidopteran moths, but in the fire ant the alpha-NP is missing. Each of the four synthetic peptides from the fire ant Soi-PBAN cDNA showed significant pheromonotropic activity in a moth model, indicating that these peptides are cross-reactive. Soi-beta-NP induced the highest amount of pheromone production of the four peptides evaluated. The Soi-DH homologue had the lowest pheromonotropic activity, but was still significantly greater than control values. When the deduced amino acid sequences (entire ORF domains) from Soi-PBAN cDNA were compared with other known sequences, the fire ant was most similar to the honey bee, but phylogenetically distant from moth and beetle species. Soi-PBAN (26-AA) unlike the other three peptides shows a low degree of sequence identity with honeybee PBAN (33-AA). Based on the amino acid sequences encoded from insect PBAN genes identified to date, neuropeptide diversity is correlated with the taxonomic or phylogenetic classification of Insecta. From the present study we report the first neuropeptide identified and characterized from the central nervous system of Formicidae.

1/t pressure and fermion behaviour of water in two dimensions.

A variety of metal vacuum systems display the celebrated 1/t pressure, namely power-law dependence on time t, with the exponent close to unity, the origin of which has been a long-standing controversy. Here we propose a chemisorption model for water adsorbates, based on the argument for fermion behaviour of water vapour adsorbed on a stainless-steel surface, and obtain analytically the power-law behaviour of pressure, with an exponent of unity. Further, the model predicts that the pressure should depend on the temperature T according to T(3/2), which is indeed confirmed by our experiment. Our results should help elucidate the unique characteristics of the adsorbed water.

Experimental microencapsulation of porcine and rat pancreatic islet cells with air-driven droplet generator and alginate.

Transplantation of microencapsulated islets is proposed as an ideal therapy for the treatment of type 1 diabetes mellitus without immunosuppression. This strategy is based on the principle that foreign cells are protected from the host immune system by an artificial membrane. The aim of this study was to establish an ideal condition of microencapsulation using an air-driven droplet generator and alginate in vitro. The optimal conditions for islet encapsulation were an alginate inflow rate of 10 mL/h, CO2 flow rate of 2.0 L/min in a concentration of 2% alginate. For 2.5% alginate, the alginate inflow rate of 20 mL/h, CO2 flow rate 3.0 L/min was ideal; alginate inflow rate of 40 mL/h, CO2 flow rate of 4.0 L/min showed good microcapsules at 3% alginate. Viability of encapsulated islets was greater than 90%. In terms of insulin secretion, encapsulated islets secreted insulin in response to glucose in static culture medium. However, there was no normal response to low or high glucose challenge with a stimulation index less than 2.0. Microencapsulation of pig islets was successfully performed with air-driven droplet generator and alginate in vitro. Further studies about biocompatibility and glucose control in vivo may provide a useful tool for treatment of patients with diabetes mellitus.

Improved islet yields after purification following the novel endogenous trypsin inhibitor and histidine-tryptophan-ketoglutarate treatment in pigs.

BACKGROUND: Adult porcine islet xenotransplantation into humans is greatly diminished by the difficulty to isolate islets because of their fragility. The goal of this study was to improve the efficacy of islet yields using endogenous trypsin inhibitor and histidine-tryptophan-ketoglutarate (HTK) perfusate. METHOD: We compared two porcine islet isolation protocols: Eurocollins solution for in situ pancreas perfusion without use of an endogenous trypsin inhibitor versus HTK solution including endogenous trypsin inhibitor for pancreas perfusion. RESULTS: Endogenous trypsin inhibitor and HTK strategies significantly improved total islet yield, recovery, and islet index after purification (P < .05), whereas unpurified islet yield did not increase. An average of 228,000 +/- 95,000 islet equivalents (IEQ) (n = 20) purified islets were obtained in the first group compared with 115,000 +/- 56,000 IEQ (n = 18) in the second group. The average islet index was significantly increased in the first group compared with the second group before and after purification: before: 0.28 versus 0.49 versus after: 0.25 versus 0.4 (P < .05). At this time, islet purity, viability, and stimulation index did not show a significant difference between groups. CONCLUSION: Our study showed that endogenous trypsin inhibitor and HTK strategies significantly improved purified islet isolation efficacy because of reduction of islet fragility.

Effects of solute electronic polarizability on solvation in a room-temperature ionic liquid.

The effects of solute polarizability on solvation and solute transport in the room-temperature ionic liquid 1-ethyl-3-methylimidazolium hexafluorophosphate (EMI+PF(6)-) are investigated via molecular dynamics simulations. A valence-bond description is employed to account for the instantaneous adjustment of the solute electronic charge distribution to the fluctuating solvent environment. It is found that the ultrafast inertial component of solvation dynamics becomes slower as the solute polarizability grows. Moreover, its contribution to overall solvent relaxation becomes reduced with increasing polarizability, especially in the case of nonequilibrium solvation dynamics. Overall, the inclusion of the solute electronic polarizability in the simulations improves the agreement with time-dependent Stokes shift measurements.

Triamcinolone acetonide protects the rat retina from STZ-induced acute inflammation and early vascular leakage.

Streptozotocin (STZ) has been commonly used to induce in vivo and in vitro hyperglycemic diabetes and its toxicity leads to inflammation and vascular injury. Triamcinolone acetonide (TA), as an anti-angiogenic/anti-inflammatory drug, is clinically used to improve the visual acuity in neovascular and edematous ocular diseases. The aim of this study was to investigate the effect of TA on early inflammation and vascular leakage in the retina of STZ-induced hyperglycemic rats. Hyperglycemia was induced in 8-week-old male Sprague-Dawley (SD) rats by a single intraperitoneal injection of STZ (65 mg/kg); only rats with blood glucose levels >13.9 mmol/l 1 day after STZ injection were included in STZ-hyperglycemic group. Sex- and age-matched SD rats injected with buffer were used as the control group. One day before STZ and buffer injection, 2 microl TA (4 mg/ml in saline) and 2 microl saline were intravitreal-injected into the right and the left eyes of rats, respectively. Retinal vascular leakage was measured using the Evans-blue method. Changes in pro-inflammatory target genes, such as tumor necrotic factor (TNF)-alpha, intracellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were assessed by immunoblottings, immunostaining, and ELISA analyses. Vascular hyperleakage and up-regulation of most pro-inflammatory genes peaked within a few days after STZ injection and had recovered. However, these changes were blocked by TA pretreatment. Our data suggest that TA controls STZ-induced early vascular leakage and temporary pro-inflammatory signals in the rat retina.

Magnetization of circular DNA.

We investigate the orbital magnetization of DNA molecules in the relaxed circular structure. It is shown that DNA of homogeneous sequence exhibits paramagnetic responses to external magnetic fields and, surprisingly, the magnetism of circular DNA is equivalent to that of linear DNA. This turns out to result from the fact that the electron population is localized largely on one of the strands. More intriguingly, the magnetic susceptibility is observed to depend on the ring topology defined by the linking number. We also consider sequence heterogeneity and find that the magnetization displays characteristic oscillations, the pattern of which depends crucially on the sequence and the base content.

Dynamics of analyst forecasts and emergence of complexity: Role of information disparity.

We report complex phenomena arising among financial analysts, who gather information and generate investment advice, and elucidate them with the help of a theoretical model. Understanding how analysts form their forecasts is important in better understanding the financial market. Carrying out big-data analysis of the analyst forecast data from I/B/E/S for nearly thirty years, we find skew distributions as evidence for emergence of complexity, and show how information asymmetry or disparity affects financial analysts' forming their forecasts. Here regulations, information dissemination throughout a fiscal year, and interactions among financial analysts are regarded as the proxy for a lower level of information disparity. It is found that financial analysts with better access to information display contrasting behaviors: a few analysts become bolder and issue forecasts independent of other forecasts while the majority of analysts issue more accurate forecasts and flock to each other. Main body of our sample of optimistic forecasts fits a log-normal distribution, with the tail displaying a power law. Based on the Yule process, we propose a model for the dynamics of issuing forecasts, incorporating interactions between analysts. Explaining nicely empirical data on analyst forecasts, this provides an appealing instance of understanding social phenomena in the perspective of complex systems.

Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib.

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+ B-cell malignancies.

Collective oscillations, bicluster motion, and dynamical order in a system of globally coupled rotors with repulsive interactions.

We perform extensive numerical simulations on a system of globally coupled rotors with repulsive interactions. By controlling systematically initial conditions, we determine the criterion for the emergence of bicluster motion. It is found that stable bicluster motion emerges at low temperatures, where the initial kinetic energy accounts for less than about 60% of the total energy. Also observed are collective oscillations of the potential energy and the magnetization, which are persistent. With appropriately chosen initial conditions, the system exhibits characteristic motion where biclusters keep forming and disappearing continually. It is argued that such bicluster motion is closely related to the dynamical order suggested recently.

Health status and resonance in a model for living organisms under periodic stress and healing.

We apply the dynamic model for failures to a living organism under periodic stress and study how the health status of the organism evolves. It is found that without healing, the average fraction of intact cells decays either stepwise to zero or to a constant value far from zero, depending on the peak value of the periodic stress. As the parameter measuring the healing probability is raised from zero, the fraction exhibits oscillating behavior, reminiscent of periodic synchronization. The power spectrum at the stress frequency at first increases with the healing parameter, then decreases, which may be called healing resonance. We also study the time evolution of the system in the case that the healing parameter varies periodically with time and observe a transition from the unhealthy state to the healthy one as the healing frequency increases. This suggests how to adjust the frequency of medical treatment to the optimum.