Use and cost of disease-modifying therapies by Sonya Slifka Study participants: has anything really changed since 2000 and 2009?

Background:Disease-modifying therapies benefit individuals with relapsing forms of multiple sclerosis, but their utility remains unclear for those without relapses. Objective:To determine disease-modifying therapy use and costs in 2009, compare use in 2009 and 2000, and examine compliance with evidence-based guidelines. Methods:We determined the extent and characteristics of disease-modifying therapy use by participants in the Sonya Slifka Longitudinal Multiple Sclerosis Study (Slifka) in 2000 (n=2156) and 2009 (n=2361) and estimated out-of-pocket and total (payer) costs for 2009. Two multivariable logistic regressions predicted disease-modifying therapy use. Results:Disease-modifying therapy use increased from 55.3% in 2000 to 61.5% in 2009. In 2009, disease-modifying therapy use was reported by 76.5% of participants with relapsing-remitting multiple sclerosis, 73.2% with progressive-relapsing multiple sclerosis, 62.5% with secondary progressive multiple sclerosis, and 41.8% with primary progressive multiple sclerosis. Use was significantly associated with relapsing-remitting multiple sclerosis, shorter duration of illness, one to two relapses per year, non-ambulatory symptoms, using a cane, younger age, higher family income, and having health insurance. Average annual costs in 2009 were US$939-3101 for patients and US$16,302-18,928 for payers. Conclusion:Use rates were highest for individuals with relapsing-remitting multiple sclerosis, but substantial for those with progressive courses although clinical trials have not demonstrated significant benefits for them

Glucose and GLP-1 Stimulate cAMP Production via Distinct Adenylyl Cyclases in INS-1E Insulinoma Cells

In β cells, both glucose and hormones, such as GLP-1, stimulate production of the second messenger cAMP, but glucose and GLP-1 elicit distinct cellular responses. We now show in INS-1E insulinoma cells that glucose and GLP-1 produce cAMP with distinct kinetics via different adenylyl cyclases. GLP-1 induces a rapid cAMP signal mediated by G protein–responsive transmembrane adenylyl cyclases (tmAC). In contrast, glucose elicits a delayed cAMP rise mediated by bicarbonate, calcium, and ATP-sensitive soluble adenylyl cyclase (sAC). This glucose-induced, sAC-dependent cAMP rise is dependent upon calcium influx and is responsible for the glucose-induced activation of the mitogen-activated protein kinase (ERK1/2) pathway. These results demonstrate that sAC-generated and tmAC-generated cAMP define distinct signaling cascades

Early non-psychotic deviant behaviour as an endophenotypic marker in bipolar disorder, schizo-affective disorder and schizophrenia

Objective: To determine and compare the incidence of early non-psychotic deviant behaviour (i.e. under the age of ten) in Afrikaner patients with bipolar disorder, schizo-affective disorder and schizophrenia. Methods: Patients with bipolar disorder, schizo-affective disorder and schizophrenia were interviewed using a structured questionnaire probing for early deviant childhood behaviour starting before the age of 10 years. Information from close family members was also obtained where possible. Seven areas of possible deviance were probed into: social dysfunction, unprovoked aggression, extreme anxiety, chronic sadness, extreme odd behaviours, attention impairment and learning difficulties. Demographic data included: age, marital status, gender, and years of formal education. The following clinical features were also recorded: age of onset of illness and suicide attempts. Results: A total of 74 patients diagnosed with bipolar disorder, 43 patients diagnosed with schizo-affective disorder and 80 patients diagnosed with schizophrenia were interviewed. Early deviant behaviour was statistically more prevalent in schizophrenia (65%) and schizo-affective disorder (60,5%), than in the bipolar group (21,6%). Deviant childhood behaviour was grouped into 3 clusters: social functioning impairment cluster (social isolation, aggression, extreme odd behavior), mood/anxiety cluster (extreme fears, chronic sadness) and a cognitive impairment cluster (attention impairment, learning disability). Bipolar patients showed significantly less social functioning and cognitive impairment compared to patients with schizo-affective disorder and schizophrenia. Conclusion: Our findings suggest that early deviant behaviour may be a possible endophenotypic marker in schizophrenia and schizoaffective disorder. Keywords: early non-psychotic deviant behaviour, endophenotype, bipolar disorder, schizo-affective disorder, schizophrenia South African Psychiatry Review Vol. 8(4) 2005: 153-15

Use of QuantiFERON®-TB Gold in-tube culture supernatants for measurement of antibody responses.

QuantiFERON®-TB Gold in-tube (QFT-GIT) supernatants may be important samples for use in assessment of anti-tuberculosis (TB) antibodies when only limited volumes of blood can be collected and when a combination of antibody and cytokine measurements are required. These analytes, when used together, may also have the potential to differentiate active pulmonary TB (APTB) from latent TB infection (LTBI). However, few studies have explored the use of QFT-GIT supernatants for investigations of antibody responses. This study determined the correlation and agreement between anti-CFP-10 and anti-ESAT-6 antibody concentrations in QFT-GIT nil supernatant and serum pairs from 68 TB household contacts. We also explored the ability of Mycobacterium tuberculosis (M.tb) specific antibodies, or ratios of antibody to interferon gamma (IFN-γ) in QFT-GIT supernatants, to differentiate 97 APTB cases from 58 individuals with LTBI. Sputum smear microscopy was used to define APTB, whereas the QFT-GIT and tuberculin skin test were used to define LTBI. There were strong and statistically significant correlations between anti-CFP-10 and anti-ESAT-6 antibodies in unstimulated QFT-GIT supernatants and sera (r = 0.89; p<0.0001 for both), and no significant differences in antibody concentration between them. Anti-CFP-10 & anti-ESAT-6 antibodies differentiated APTB from LTBI with sensitivities of 88.7% & 71.1% and specificities of 41.4% & 51.7% respectively. Anti-CFP-10 antibody/M.tb specific IFN-γ and anti-ESAT-6 antibody/M.tb specific IFN-γ ratios had sensitivities of 48.5% & 54.6% and specificities of 89.7% and 75.9% respectively. We conclude that QFT-GIT nil supernatants may be used in the place of sera when measuring antibody responses, reducing blood volumes needed for such investigations. Antibodies in QFT-GIT nil supernatants on their own discriminate APTB from LTBI with high sensitivity but have poor specificity, whereas the reverse is true when antibodies are used in combination with M.tb specific cytokines. Further antibody and antibody/cytokine combinations need to be explored to achieve better diagnostic accuracy

Agreement and Discrepancy on Emotional and Behavioral Problems Between Caregivers and HIV-Infected Children and Adolescents From Uganda.

Background: HIV-infected children and adolescents (CA-HIV) face significant mental health challenges related to a broad range of biological and psychosocial factors. Data are scarce on the agreement and discrepancy between caregivers and CA-HIV regarding emotional and behavioral problems (EBPs) in CA-HIV. Objectives: We determined agreement between self- versus caregiver- reported EBPs and describe factors associated with informant discrepancy among caregiver-youth dyads who participated in the "Mental health among HIV-infected CHildren and Adolescents in KAmpala and Masaka, Uganda" (CHAKA) study. Methods: In a cross-sectional sample, caregiver-reported EBPs were assessed with the Child and Adolescent Symptom Inventory-5 (CASI-5), and self-reported problems were evaluated with the Youth Inventory-4 (YI-4) in 469 adolescents aged 12-17 years and the Child Inventory-4 (CI-4) in 493 children aged 8-11 years. Adolescents were questioned about experiences of HIV stigma. Caregiver psychological distress was assessed with the Self-Reporting Questionnaire (SRQ-20). Linear regression models were applied to identify variables associated with discrepancy scores. Results: Self-reported emotional problems (EPs) were present in 28.8% of adolescents and 36.9% of children, and 14.5% of adolescents self-reported behavioral problems (BPs). There was only a modest correlation (r ≤ 0.29) between caregiver- and CA-HIV-reported EBPs, with caregivers reporting more EPs whereas adolescents reported more BPs. Informant discrepancy between adolescents and caregivers for BPs was associated with adolescent age and caregiver's employment and HIV status. Among adolescents, EP discrepancy scores were associated with adolescent's WHO HIV clinical stage, caregiver level of education, and caregivers caring for other children. Among children, EP discrepancy scores were associated with child and caregiver age, caregiver level of education, and caregiver self-rated health status. HIV stigma and caregiver psychological distress were also associated with discrepancy, such that adolescents who experienced HIV stigma rated their EPs as more severe than their caregivers did and caregivers with increased psychological distress rated EBPs as more severe than CA-HIV self-rated. Conclusions: EBPs are frequently endorsed by CA-HIV, and agreement between informants is modest. Informant discrepancy is related to unique psychosocial and HIV-related factors. Multi-informant reports enhance the evaluation of CA-HIV and informant discrepancies can provide additional insights into the mental health of CA-HIV

Internalizing Mental Disorders and Accelerated Cellular Aging Among Perinatally HIV-Infected Youth in Uganda.

Introduction: Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated. Objective: We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY). Methods: IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe). t-tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex. Results: We observed longer rTL among cases of IMDs compared with controls (p < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (p < 0.001). The same statistical difference was observed when cases and controls were individually analyzed (p < 0.001). We found no significant difference in rTL between cases and controls at 12 months (p = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. Conclusion: rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings

The “Soluble” Adenylyl Cyclase in Sperm Mediates Multiple Signaling Events Required for Fertilization

SummaryMammalian fertilization is dependent upon a series of bicarbonate-induced, cAMP-dependent processes sperm undergo as they “capacitate,” i.e., acquire the ability to fertilize eggs. Male mice lacking the bicarbonate- and calcium-responsive soluble adenylyl cyclase (sAC), the predominant source of cAMP in male germ cells, are infertile, as the sperm are immotile. Membrane-permeable cAMP analogs are reported to rescue the motility defect, but we now show that these “rescued” null sperm were not hyperactive, displayed flagellar angulation, and remained unable to fertilize eggs in vitro. These deficits uncover a requirement for sAC during spermatogenesis and/or epididymal maturation and reveal limitations inherent in studying sAC function using knockout mice. To circumvent this restriction, we identified a specific sAC inhibitor that allowed temporal control over sAC activity. This inhibitor revealed that capacitation is defined by separable events: induction of protein tyrosine phosphorylation and motility are sAC dependent while acrosomal exocytosis is not dependent on sAC

An integrated environmental and human systems modeling framework for Puget Sound restoration planning

Local, state, federal, tribal and private stakeholders have committed significant resources to restoring Puget Sound’s terrestrial-marine ecosystem. Though jurisdictional issues have promoted a fragmented approach to restoration planning, there is growing recognition that a more coordinated systems-based restoration approach is needed to achieve recovery goals. This presentation describes our collaborative effort to develop and apply an integrated environmental and human systems modeling framework for the Puget Sound Basin, inclusive of all marine and land areas (1,020 and 12,680 sq. mi.). Our goal is to establish a whole-basin systems modeling framework that dynamically simulates biophysical interactions and transfers (water, nutrients, contaminants, biota) across terrestrial-marine boundaries. The core environmental models include a terrestrial ecohydrological model (VELMA), an ocean circulation and biogeochemistry model (Salish Sea Model), and an ocean food web model (Atlantis). This environmental subsystem will be linked with an agent-based modeling subsystem (e.g., Envision) that allows human decision-makers to be represented in whole-basin simulations. The integrated environmental and human systems framework aims to facilitate discourse among different stakeholders and decision makers (agents) and enable them play out the ecological, social and economic consequences of alternative ecosystem restoration choices. All of these models are currently being applied in Puget Sound, but they have not yet been integrated. The linked models will better capture the propagation of human impacts throughout the terrestrial-marine ecosystem, and thereby provide a more effective decision support tool for addressing restoration of high priority environmental endpoints, such as the Vital Signs identified by the Puget Sound Partnership (http://www.psp.wa.gov/vitalsigns/). Our overview will include examples of existing stand-alone model applications, and conceptual plans for linking models across terrestrial-marine boundaries. The Puget Sound multi-model framework described here can potentially be expanded to address the entire Salish Sea transboundary ecosystem (https://www.eopugetsound.org/maps/salish-sea-basin-and-water-boundaries)

The Computational Complexity of Generating Random Fractals

In this paper we examine a number of models that generate random fractals. The models are studied using the tools of computational complexity theory from the perspective of parallel computation. Diffusion limited aggregation and several widely used algorithms for equilibrating the Ising model are shown to be highly sequential; it is unlikely they can be simulated efficiently in parallel. This is in contrast to Mandelbrot percolation that can be simulated in constant parallel time. Our research helps shed light on the intrinsic complexity of these models relative to each other and to different growth processes that have been recently studied using complexity theory. In addition, the results may serve as a guide to simulation physics.Comment: 28 pages, LATEX, 8 Postscript figures available from [email protected]