Emergence of a Norm from Resistance: Using Simulation to Explore the Macro Implications of Social Identity Theory

We usually hope that social norms discourage injustice. However, we are all witnesses to harmful norms enforced by governments, such as xenophobia, which need to be contested and changed. Previous studies have concluded that it is possible to change a harmful norm through contestation by powerless actors if suitable structural conditions exist. However, these structural conditions have not been sufficiently studied and, as such, are the focus of this paper. Our paper begins with a review of well-established micro-level theories of social identity theory (SIT), recast as a set of 42 discrete theoretical statements. These statements are then re-expressed in the form of a systems-level theory of macro-changes in societal norms using the system dynamics approach. The over-time dynamic behavior simulated using this structure is compared to events in two well-known case studies of changes in societal norms: women’s suffrage between 1830 and 1920, and the emergence of more tolerant lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) norms in the US between 1950 and 2018. Further simulations of the model explore the roles of anger and social outrage, foreshadowing the ability of simulation-based experiments, such as the one presented here, to explore in a robust way a wide range of (undemocratic) regimes under counter-factual conditions

Thymectomy in the treatment of ocular myasthenia gravis

AbstractBackground: Thymectomy is an effective and accepted treatment for myasthenia gravis, but thymectomy for ocular myasthenia gravis (Osserman stage I) is controversial. Objective: To assess the efficacy and propriety of thymectomy for the treatment of ocular myasthenia gravis. Methods: We conducted a review and follow-up of all patients who had thymectomy for the treatment of ocular myasthenia gravis between 1970 and 1998 at the University of California, Davis, Medical Center, and the University of Rome, “La Sapienza,” Rome, Italy. Patient response to thymectomy was categorized as follows: cured, patients who became symptom-free and required no further medication; improved, patients who required less medication and whose symptoms were less severe; unchanged, patients whose symptoms and medications were the same; worse, patients who had more severe symptoms, needed more medication, or died. Results: Sixty-one patients (mean age 37 years; range 14–73 years) were followed up for a mean duration of 9 years (range 0.5–29 years). Ocular myasthenia gravis with mixed and cortical thymomas, stages I to IV, occurred in 12 patients, and ocular myasthenia without thymomas occurred in 49 patients. Transsternal thymectomy (n = 55) and transcervical thymectomy (n = 6) resulted in cure in 31 (51%) patients, improvement in 12 (20%) patients, no change in 16 (26%) patients, and worsening of symptoms (including 1 postoperative death) in 2 patients. Patient outcomes were statistically independent of the duration of preoperative symptoms (mean 9.5 months), patient age, or the presence or absence of thymoma. In patients with ocular myasthenia, 70% were cured or improved after thymectomy; in the subgroup of patients with ocular myasthenia and thymoma, 67% were cured or improved. Conclusion: Thymectomy is an effective and safe treatment for patients with ocular myasthenia gravis

3,4-Diaminopyridine Base Effectively Treats the Weakness of Lambert-Eaton Myasthenia

Introduction: 3,4-diaminopyridine has been used to treat Lambert Eaton myasthenia (LEM) for thirty years despite the lack of conclusive evidence of efficacy. Methods: We conducted a randomized double-blind placebo-controlled withdrawal study in LEM patients who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in Triple Timed Up-and-Go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM–related weakness (W-SAS). Results: 32 participants were randomized to continuous 3,4-DAP or placebo. None of the 14 receiving continuous 3,4-DAP had >30% deterioration in 3TUG time vs 72% of the 18 who tapered to placebo (p<0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (p<0.0001). Need for rescue and adverse events were more common in the placebo group. Discussion: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM

Validation of the triple timed up‐and‐go test in Lambert‐Eaton myasthenia

Introduction There are no validated, practical, and quantitative measures of disease severity in Lambert‐Eaton myasthenia (LEM). Methods Data from the Effectiveness of 3,4‐Diaminopyridine in Lambert‐Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up‐and‐go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. Results The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4‐diaminopyridine free base. Worsening patient‐reported Weakness Self‐Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. Discussion The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM

Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART

BACKGROUND: The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART. METHODS AND FINDINGS: Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance. CONCLUSIONS: We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period

International consensus guidance for management of myasthenia gravis

Altres ajuts: Supported by a grant from the Myasthenia Gravis Foundation of America (MGFA).To develop formal consensus-based guidance for the management of myasthenia gravis (MG). In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide

RGS12 Interacts with the SNARE-binding Region of the Ca v 2.2 Calcium Channel

Activation of GABAB receptors in chick dorsal root ganglion (DRG) neurons inhibits the Cav2.2 calcium channel in both a voltage-dependent and voltage-independent manner. The voltage-independent inhibition requires activation of a tyrosine kinase that phosphorylates the alpha1 subunit of the channel and thereby recruits RGS12, a member of the "regulator of G protein signaling" (RGS) proteins. Here we report that RGS12 binds to the SNARE-binding or "synprint" region (amino acids 726-985) in loop II-III of the calcium channel alpha1 subunit. A recombinant protein encompassing the N-terminal PTB domain of RGS12 binds to the synprint region in protein overlay and surface plasmon resonance binding assays; this interaction is dependent on tyrosine phosphorylation and yet is within a sequence that differs from the canonical NPXY motif targeted by other PTB domains. In electrophysiological experiments, microinjection of DRG neurons with synprint-derived peptides containing the tyrosine residue Tyr-804 altered the rate of desensitization of neurotransmitter-mediated inhibition of the Cav2.2 calcium channel, whereas peptides centered about a second tyrosine residue, Tyr-815, were without effect. RGS12 from a DRG neuron lysate was precipitated using synprint peptides containing phosphorylated Tyr-804. The high degree of conservation of Tyr-804 in the SNARE-binding region of Cav2.1 and Cav2.2 calcium channels suggests that this region, in addition to the binding of SNARE proteins, is also important for determining the time course of the modulation of calcium current via tyrosine phosphorylation

Development of a novel scheme for long-term body temperature monitoring: a review of benefits and applications

Body temperature is a health or disease marker that has been in clinical use for centuries. The threshold currently applied to define fever, with small variations, is 38 °C. However, current approaches do not provide a full picture of the thermoregulation process and its correlation with disease. This paper describes a new non-invasive body temperature device that improves the understanding of the pathophysiology of diseases by integrating a variety of temperature data from different body locations. This device enables to gain a deeper insight into fever, endogenous rhythms, subject activity and ambient temperature to provide anticipatory and more efficient treatments. Its clinical use would be a big step in the overcoming of the anachronistic febrile/afebrile dichotomy and walking towards a system medicine approach to certain diseases. This device has already been used in some clinical applications successfully. Other possible applications based on the device features and clinical requirements are also described in this paper.Cuesta Frau, D.; Varela Entrecanales, M.; Valor Pérez, R.; Vargas, B. (2015). Development of a novel scheme for long-term body temperature monitoring: a review of benefits and applications. Journal of Medical Systems. 39(4):1-7. doi:10.1007/s10916-015-0209-3S17394Gai, M., Merlo, I., Dellepiane, S., Cantaluppi, V., Leonardi, G., Fop, F., Guarena, C., Grassi, G., and Biancore, L., Glycemic pattern in diabetic patients on hemodialysis: Continuous Glucose Monitoring (CGM) analysis. Blood Purif. 38(1):68–73 , 2014.Kondziella, D., Friberg, C.K., Wellwood, I., Reiffurth, C., Fabricius, M., and Dreier, J.P.: Continuous EEG monitoring in aneurysmal subarachnoid hemorrhage: A systematic review. Neurocrit. Care (2014)Ciccone, A., Celani, M.G., Chiaramonte, R., Rossi, C., and Righetti, E., Continuous versus intermittent physiological monitoring for acute stroke. Cochrane Database Syst. Rev. 31, 2013.Kushimoto, S., Yamanouchi, S., Endo, T., Sato, T., Nomura, R., Fujita, M., Kudo, D., Omura, T., Miyagawa, N., and Sato, T., Body temperature abnormalities in non-neurological critically ill patients: A review of the literature. J. Intensive Care 2, 2014.Mc Callum, L., and Higgings, D., Measuring body temperature. Nursing Times 108:20–22, 2012.Varela, M., Ruiz-Esteban, R., Martinez-Nicolas, A., Cuervo-Arango, A., Barros, C., and Delgado, E.G., Catching the spike and tracking the flow: Holter-temperature monitoring in patients admitted in a general internal medicine ward. Int. J. Clin. Pract. 65(12):1283–1288, 2011.Lopes, F., Peres, D., Bross, A., Melot, C., and Vincent, J.L., Serial evaluation of the SOFA score to predict outcome in critically ill patients. J. Am. Med. Assoc. 286:1754–1758, 2001.Vincent, J.L., and Moreno, R., Clinical review: Scoring systems in the critically ill. Crit. Care, 14, 2010.Sund-Levander, M., and Grodzinsky, E., Time for a change to assess and evaluate body temperature in clinical practice. Int. J. Nurs. Pract. 15:241–249, 2009.Cuesta-Frau, D., Varela, M., Aboy, M., and Miro, P., Description of a portable wireless device for body temperature acquisition and analysis. Sensors 9(10):7648–7663, 2009.Varela, M., Cuesta-Frau, D., Madrid, J.A., Churruca, J., Miro-Matinez, P., Ruiz, R., and Marinez, C., Holter monitoring of central peripheral temperature: Possible uses and feasibility study in outpatient settings. J. Clin. Monit. Comput. 4(23):209–216, 2009.Jordan, J., Miro, P., Cuesta-Frau, D., Varela, M., and Vargas B.: Aplicacion de analisis multivariante para la deteccion de estados prefebriles en pacientes ingresados (in Spanish), XXXIV Congreso Nacional de Estadistica e Investigacion Operativa, Castellon (Spain) (2013)Richman, J., and Moorman, J.R., Physiological time-series analysis using approximate entropy and sample entropy. Am. J. Physiol. Heart Circ. Physiol. 278(6):H2039–2049, 2000.Young, P., Saxena, M., Eastwood, G.M., Bellomo, R., and Beasley, R., Fever and fever management among intensive care patients with known or suspected infection: A multicentre prospective cohort study. Crit. Care Resusc. 13:97–102 , 2011.Drewry, A.M., Fuller, B.M., Bailey, T.C., and Hotchkiss, R.S., Body temperature patterns as a predictor of hospital-acquired sepsis in afebrile adult intensive care unit patients: A case-control study. Crit. Care,17, 2013.Musher, D., Fainstein, V., Young, E., and Pruett, T., Fever patterns. Their lack of significance. Arch. Intern. Med. 139(11):1225–8, 1979.Varela, M., Calvo, M., Chana, M., Gomez-Mestre, I., Asensio, R., and Galdos, P., Clinical implications of temperature curve complexity in critically ill patients. Crit. Care Med. 33(12):2764–2771, 2005.Varela, M., Churruca, J., Gonzalez, A., Martin, A., Ode, J., and Galdos, P., Temperature curve complexity predicts survival in critically ill patients. Am. J. Respir. Crit. Care Med. 174(3):290–298, 2006.Cuesta-Frau, D., Varela, M., Miro, P., Galdos, P., Abasolo, D., Hornero, R., and Aboy, M., Predicting survival in critical patients by use of body temperature regularity measurement based on Approximate Entropy. Med. Biol. Eng. Computing 45:671–678, 2007.Mackiowak, P. Temperature regulation and the pathogenesis of fever, Principles and Practice of Infectious Diseases, pp. 765–778. New York: Churchill Livingston Elsevier, 2010.Cherbuin N., and Brinkman C., Cognition is cool: Can hemispheric activation be assessed by tympanic membrane thermometry? Brain Cogn. 54:228–231, 2004

Treatment of Myasthenia Gravis Based on Its Immunopathogenesis

The prognosis of myasthenia gravis (MG) has improved dramatically due to advances in critical-care medicine and symptomatic treatments. Its immunopathogenesis is fundamentally a T-cell-dependent autoimmune process resulting from loss of tolerance toward self-antigens in the thymus. Thymectomy is based on this immunological background. For MG patients who are inadequately controlled with sufficient symptomatic treatment or fail to achieve remission after thymectomy, remission is usually achieved through the addition of other immunotherapies. These immunotherapies can be classified into two groups: rapid induction and long-term maintenance. Rapid induction therapy includes intravenous immunoglobulin (IVIg) and plasma exchange (PE). These produce improvement within a few days after initiation, and so are useful for acute exacerbation including myasthenic crisis or in the perioperative period. High-dose prednisone has been more universally preferred for remission induction, but it acts more slowly than IVIg and PE, commonly only after a delay of several weeks. Slow tapering of steroids after a high-dose pulse offers a method of maintaining the state of remission. However, because of significant side effects, other immunosuppressants (ISs) are frequently added as "steroid-sparing agents". The currently available ISs exert their immunosuppressive effects by three mechanisms: 1) blocking the synthesis of DNA and RNA, 2) inhibiting T-cell activation and 3) depleting the B-cell population. In addition, newer drugs including antisense molecule, tumor necrosis factor alpha receptor blocker and complement inhibitors are currently under investigation to confirm their effectiveness. Until now, the treatment of MG has been based primarily on experience rather than gold-standard evidence from randomized controlled trials. It is hoped that well-organized studies and newer experimental trials will lead to improved treatments