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Sample records for 12-step naive treatment

  1. Alcoholics Anonymous and 12-step alcoholism treatment programs.

    PubMed

    Humphreys, Keith

    2003-01-01

    Alcoholics Anonymous (AA) self-help groups are the most commonly accessed component of the de facto system of care for alcohol problems in the United States. Further, AA's concepts and approach have strongly influenced a significant number of professional treatment programs. Nevertheless, only a modest number of longitudinal, comparative outcome studies on AA and on professional 12-step treatment programs have been conducted, which has limited both the certainty and scope of conclusions that can be drawn about these interventions. Research indicates that participation in Alcoholics Anonymous and in 12-step treatment are associated with significant reductions in substance abuse and psychiatric problems. Further, such interventions, it has been found, reduce health care costs over time in naturalistic, quasi-experimental, and experimental studies. Evaluation studies have also begun to illuminate the processes through which self-help groups and 12-step treatment programs exert their effects. To build on this knowledge base, future research should (1) be methodologically flexible and well-matched to its phenomenon of interest, (2) include evaluation of the unique features of self-help organizations, (3) increase representation of African-Americans and women in research samples, and (4) increase statistical power through larger sample sizes and more reliable measurement. Key content areas for future enquiry include further longitudinal evaluation of the outcomes of participation in AA and 12-step treatment (particularly in outpatient samples); better specification of the aspects of AA that influence outcome; and individual-, community-, and health organization-level controlled studies of the health care cost consequences of 12-step interventions.

  2. Climate for Innovation, 12-Step Orientation, & Tobacco Cessation Treatment

    PubMed Central

    Laschober, Tanja C.; Eby, Lillian T.

    2013-01-01

    This study examined the relationship between (1) three indicators of climate for innovation (clinician skills, absence of program obstacles, policy-related incentives) and adoption extensiveness of both behavioral treatments for tobacco cessation (TC) and system-level support for TC in substance use disorder treatment programs, (2) a program’s 12-step treatment orientation and adoption extensiveness, and (3) whether 12-step treatment orientation moderates the relationship between climate for innovation and adoption extensiveness. Data were obtained from a random sample of 1,006 program administrators. Hierarchical regression results showed that both absence of program obstacles and policy-related incentives are positively related to adoption extensiveness. Twelve-step treatment orientation is neither related to adoption extensiveness nor a moderator of the relationship between climate for innovation and adoption extensiveness. Although the adoption of both behavioral treatments for TC and system-level support for TC is not extensive, we conclude that a 12-step treatment orientation neither hampers nor promotes adoption extensiveness. PMID:24355811

  3. Climate for innovation, 12-step orientation, and tobacco cessation treatment.

    PubMed

    Muilenburg, Jessica L; Laschober, Tanja C; Eby, Lillian T

    2014-04-01

    This study examined the relationship between (1) three indicators of climate for innovation (clinician skills, absence of program obstacles, policy-related incentives) and adoption extensiveness of both behavioral treatments for tobacco cessation (TC) and system-level support for TC in substance use disorder treatment programs, (2) a program's 12-step treatment orientation and adoption extensiveness, and (3) whether 12-step treatment orientation moderates the relationship between climate for innovation and adoption extensiveness. Data were obtained from a random sample of 1006 program administrators. Hierarchical regression results showed that both absence of program obstacles and policy-related incentives are positively related to adoption extensiveness. Twelve-step treatment orientation is neither related to adoption extensiveness nor a moderator of the relationship between climate for innovation and adoption extensiveness. Although the adoption of both behavioral treatments for TC and system-level support for TC is not extensive, we conclude that a 12-step treatment orientation neither hampers nor promotes adoption extensiveness. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Influence of religiosity on 12-step participation and treatment response among substance-dependent adolescents.

    PubMed

    Kelly, John F; Pagano, Maria E; Stout, Robert L; Johnson, Shannon M

    2011-11-01

    Religious practices among adults are associated with more 12-step participation which, in turn, is linked to better treatment outcomes. Despite recommendations for adolescents to participate in mutual-help groups, little is known about how religious practices influence youth 12-step engagement and outcomes. This study examined the relationships among lifetime religiosity, during-treatment 12-step participation, and outcomes among adolescents, and tested whether any observed beneficial relation between higher religiosity and outcome could be explained by increased 12-step participation. Adolescents (n = 195; 52% female, ages 14-18) court-referred to a 2-month residential treatment were assessed at intake and discharge. Lifetime religiosity was assessed with the Religious Background and Behaviors Questionnaire; 12-step assessments measured meeting attendance, step work (General Alcoholics Anonymous Tools of Recovery), and Alcoholics Anonymous (AA)/Narcotics Anonymous (NA)-related helping. Substance-related outcomes and psychosocial outcomes were assessed with toxicology screens, the Adolescent-Obsessive Compulsive Drinking Scale, the Children's Global Assessment Scale, and the Narcissistic Personality Inventory. Greater lifetime formal religious practices at intake were associated with increased step work and AA/NA-related helping during treatment, which in turn were linked to improved substance outcomes, global functioning, and reduced narcissistic entitlement. Increased step work mediated the effect of religious practices on increased abstinence, whereas AA/NA-related helping mediated the effect of religiosity on reduced craving and entitlement. Findings extend the evidence for the protective effects of lifetime religious behaviors to an improved treatment response among adolescents and provide preliminary support for the 12-step proposition that helping others in recovery may lead to better outcomes. Youth with low or no lifetime religious practices may assimilate

  5. A Multivariate Process Model of Adolescent 12-Step Attendance and Substance Use Outcome Following Inpatient Treatment

    PubMed Central

    Kelly, John F.; Myers, Mark G.; Brown, Sandra A.

    2007-01-01

    A common recommendation for youth treated for substance abuse is to attend 12-step groups. However, little is known regarding the effects of this adult-derived prescription on substance use outcomes for teens. This study examined (a) the relation between 12-step attendance and substance use outcome in the 6 months postdischarge from inpatient care and (b) a process model of how 12-step attendance during the first 3 months postdischarge affects proximal outcomes of motivation, coping, and self-efficacy, measured at 3 months, and how these, in tum, affect ultimate substance use outcome in the following 3 months. Adolescent inpatients (N = 99) were assessed during treatment and 3 and 6 months postdischarge. Results revealed modest beneficial effects of 12-step attendance, which were mediated by motivation but not by coping or self-efficacy. Findings suggest that closer attention be paid to motivational factors in the treatment of adolescent substance abuse. PMID:11130156

  6. Influence of Religiosity on 12-Step Participation and Treatment Response Among Substance-Dependent Adolescents*

    PubMed Central

    Kelly, John F.; Pagano, Maria E.; Stout, Robert L.; Johnson, Shannon M.

    2011-01-01

    Objective: Religious practices among adults are associated with more 12-step participation which, in turn, is linked to better treatment outcomes. Despite recommendations for adolescents to participate in mutual-help groups, little is known about how religious practices influence youth 12-step engagement and outcomes. This study examined the relationships among lifetime religiosity, during-treatment 12-step participation, and outcomes among adolescents, and tested whether any observed beneficial relation between higher religiosity and outcome could be explained by increased 12-step participation. Method: Adolescents (n = 195; 52% female, ages 14–18) court-referred to a 2-month residential treatment were assessed at intake and discharge. Lifetime religiosity was assessed with the Religious Background and Behaviors Questionnaire; 12-step assessments measured meeting attendance, step work (General Alcoholics Anonymous Tools of Recovery), and Alcoholics Anonymous (AA)/Narcotics Anonymous (NA)-related helping. Substance-related outcomes and psychosocial outcomes were assessed with toxicology screens, the Adolescent–Obsessive Compulsive Drinking Scale, the Children's Global Assessment Scale, and the Narcissistic Personality Inventory. Results: Greater lifetime formal religious practices at intake were associated with increased step work and AA/NA-related helping during treatment, which in turn were linked to improved substance outcomes, global functioning, and reduced narcissistic entitlement. Increased step work mediated the effect of religious practices on increased abstinence, whereas AA/NA-related helping mediated the effect of religiosity on reduced craving and entitlement. Conclusions: Findings extend the evidence for the protective effects of lifetime religious behaviors to an improved treatment response among adolescents and provide preliminary support for the 12-step proposition that helping others in recovery may lead to better outcomes. Youth with low or

  7. The motivation for drug abuse treatment: testing cognitive and 12-step theories.

    PubMed

    Bell, D C; Montoya, I D; Richard, A J; Dayton, C A

    1998-11-01

    The purpose of this paper is to evaluate two models of behavior change: cognitive theory and 12-step theory. Research subjects were drawn from three separate, but parallel, samples of adults. The first sample consisted of out-of-treatment chronic drug users, the second consisted of drug users who had applied for treatment at a publicly funded multiple-provider drug treatment facility, and the third consisted of drug users who had applied for treatment at an intensive outpatient program for crack cocaine users. Cognitive theory was supported. Study participants applying for drug abuse treatment reported a higher level of perceived problem severity and a higher level of cognitive functioning than out-of-treatment drug users. Two hypotheses drawn from 12-step theory were not supported. Treatment applicants had more positive emotional functioning than out-of-treatment drug users, and one treatment-seeking sample had higher self-esteem.

  8. Buprenorphine treatment and 12-step meeting attendance: Conflicts, compatibilities, and patient outcomes

    PubMed Central

    Monico, Laura B.; Gryczynski, Jan; Mitchell, Shannon Gwin; Schwartz, Robert P.; O’Grady, Kevin E.; Jaffe, Jerome H.

    2015-01-01

    This analysis examines patient experiences and outcomes with 12-step recovery group attendance during buprenorphine maintenance treatment (BMT), two approaches with traditionally divergent philosophies regarding opioid medications for treatment of opioid use disorder. Using quantitative (n=300) and qualitative (n=20) data collected during a randomized trial of counseling services in buprenorphine treatment, this mixed-methods analysis of African Americans in BMT finds the number of NA meetings attended in the prior 6 months was associated with a higher rate of retention in BMT (p<.001) and heroin/cocaine abstinence at 6 month follow-up (p=.005). However, patients whose counselors required them to attend 12-step meetings did not have better outcomes than patients not required to attend such meetings. Qualitative narratives highlighted patients’ strategies for managing dissonant viewpoints on BMT and disclosing BMT status in community 12-step meetings. Twelve-step meeting attendance is associated with better outcomes for BMT patients over the first 6 months of treatment. However, there is no benefit to requiring meeting attendance as a condition of treatment, and clinicians should be aware of potential philosophical conflicts between 12-step and BMT approaches. PMID:25986647

  9. Characteristics of clinicians likely to refer clients to 12-Step programs versus a diversity of post-treatment options.

    PubMed

    Fenster, Judy

    2006-07-27

    Most clients in substance abuse treatment are referred for continuing care. However, post-treatment services vary widely in their approaches to helping individuals achieve better substance use outcomes. This study examined the attitudes of outpatient treatment staff who refer clients exclusively to 12-Step groups (12-Step subgroup) and staff who refer clients both to 12-Step groups and to other continuing care options (Diversity subgroup) toward seven mutual-aid and professional psychosocial post-treatment options: Twelve-Step Programs (12-Step), Cognitive-Behavioral Therapy (CBT), Moderation Management (MM), Smart Recovery((R)) (SMART), Psychodynamic-oriented Therapy (PSY), Secular Organizations for Sobriety (SOS), and Women for Sobriety (WFS). A large percentage of clinicians lacked knowledge about the effectiveness of all alternatives to 12-Step programs with the exception of CBT. Clinicians in the 12-Step subgroup were more likely than those in the Diversity subgroup to be unfamiliar with alternatives to 12-Step programs and to believe less strongly in the effectiveness of CBT and PSY. A logistic regression found beliefs about CBT effectiveness and clinician preference for the 12-Step model to be related to the likelihood of referring exclusively to 12-Step groups. Findings suggest that clinicians could benefit from information and training on assessing and referring clients to various options for continuing care.

  10. The role of vocational behaviors preceding and during 12-step oriented treatment.

    PubMed

    Kingree, J B

    1997-01-01

    This study examined the role of vocational behaviors in the treatment of 80 crack users. The study had two general aims: (a) to predict which crack users had acquired jobs after 30 days in treatment; and (b) to examine if vocational behaviors assessed at admission and follow-up accounted for variations in recovery motivation, psychological functioning, and treatment completion. Multivariate analyses identified four predictors (race, having a polysubstance problem, 12-step sponsor, and specific job skill) of job acquisition. Multivariate analyses also indicated that past year employment was negatively related to recovery motivation but positively related to psychological functioning and treatment completion, and that job acquisition was negatively related to one measure of recovery motivation but positively related to psychological functioning. Future research should use multiple group designs to examine the effects associated with including a vocational component in treatment programs.

  11. Influence of outpatient treatment and 12-step group involvement on one-year substance abuse treatment outcomes.

    PubMed

    Ouimette, P C; Moos, R H; Finney, J W

    1998-09-01

    This study examined whether substance abuse patients self-selecting into one of three aftercare groups (outpatient treatment only, 12-step groups only, and outpatient treatment and 12-step groups) and patients who did not participate in aftercare differed on 1-year substance use and psychosocial outcomes. A total of 3,018 male patients filled out a questionnaire at intake and 1 year following discharge from treatment. Patients were classified into aftercare groups at follow-up using information from VA databases and self-reports. Patients who participated in both outpatient treatment and 12-step groups fared the best on 1-year outcomes. Patients who did not obtain aftercare had the poorest outcomes. In terms of the amount of intervention received, patients who had more outpatient mental health treatment, who more frequently attended 12-step groups or were more involved in 12-step activities had better 1-year outcomes. In addition, patients who kept regular outpatient appointments over a longer time period fared better than those who did not. Encouraging substance abuse patients to regularly attend both outpatient aftercare and self-help groups may improve long-term outcomes.

  12. Social Recovery Model: An 8-Year Investigation of Adolescent 12-step Group Involvement following Inpatient Treatment

    PubMed Central

    Kelly, John F.; Brown, Sandra A.; Abrantes, Ana; Kahler, Christopher; Myers, Mark

    2013-01-01

    Background Despite widespread use of 12-step treatment approaches and referrals to Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) by youth providers, little is known about the significance of these organizations in youth addiction recovery. Furthermore, existing evidence is based mostly on short-term follow-up and is limited methodologically. Methods Adolescent inpatients (N = 160; M age = 16, 40% female) were followed at 6-months, and at 1, 2, 4, 6, and 8 years post-treatment. Time-lagged, generalized estimating equations (GEE) modeled treatment outcome in relation to AA/NA attendance controlling for static and time-varying covariates. Robust regression (LOWESS) explored dose-response thresholds of AA/NA attendance on outcome. Results AA/NA attendance was common and intensive early post-treatment, but declined sharply and steadily over the 8-year period. Patients with greater addiction severity and those who believed they could not use substances in moderation were more likely to attend. Despite declining attendance, the effects related to AA/NA remained significant and consistent. Greater early participation was associated with better long-term outcomes. Conclusions Even though many youth discontinue AA/NA over time, attendees appear to benefit, and more severely substance-involved youth attend most. Successful early post-treatment engagement of youth in abstinence-supportive social contexts, such as AA/NA, may have long-term implications for alcohol and drug involvement into young adulthood. PMID:18557829

  13. Inmate Prerelease Assessment (IPASS) Aftercare Placement Recommendation as a Predictor of Rural Inmate's 12-Step Attendance and Treatment Entry Postrelease

    ERIC Educational Resources Information Center

    Oser, Carrie B.; Biebel, Elizabeth P.; Havens, Jennifer R.; Staton-Tindall, Michele; Knudsen, Hannah K.; Mooney, Jenny L.; Leukefeld, Carl G.

    2009-01-01

    The purpose of this study is to use the Criminal Justice Drug Abuse Treatment Studies' (CJ-DATS) Inmate Prerelease Assessment (IPASS), which recommends either intensive or nonintensive treatment after release, to predict rural offenders' 12-step attendance and treatment entry within six months of release from prison. IPASS scores indicated that…

  14. Inmate Prerelease Assessment (IPASS) Aftercare Placement Recommendation as a Predictor of Rural Inmate's 12-Step Attendance and Treatment Entry Postrelease

    ERIC Educational Resources Information Center

    Oser, Carrie B.; Biebel, Elizabeth P.; Havens, Jennifer R.; Staton-Tindall, Michele; Knudsen, Hannah K.; Mooney, Jenny L.; Leukefeld, Carl G.

    2009-01-01

    The purpose of this study is to use the Criminal Justice Drug Abuse Treatment Studies' (CJ-DATS) Inmate Prerelease Assessment (IPASS), which recommends either intensive or nonintensive treatment after release, to predict rural offenders' 12-step attendance and treatment entry within six months of release from prison. IPASS scores indicated that…

  15. ATTITUDES AND BELIEFS ABOUT 12-STEP GROUPS AMONG ADDICTION TREATMENT CLIENTS AND CLINICIANS: TOWARD IDENTIFYING OBSTACLES TO PARTICIPATION

    PubMed Central

    Laudet, Alexandre B.

    2007-01-01

    Participation in 12-step groups (12SG) during and after formal treatment has been associated with positive outcome among substance users. However, the effectiveness of 12SG may be limited by high attrition rates and by low participation, areas on which there has been little research. Clinicians play an important role in fostering 12-step participation, and the insights which they develop in their practice can greatly contribute to informing the research process. Yet, little is known about clinicians’ attitudes about 12-step groups or about their experiences in referring clients. This study surveyed clients (N = 101) and clinicians (N = 102) in outpatient treatment programs to examine 12-step related attitudes and to identify potential obstacles to participation. Data collection was conducted between May 2001 and January 2002 in New York City. Both client and clinician samples were primarily African-American and Hispanic; 32% of clients reported substance use in the previous month, with crack and marijuana cited most frequently as primary drug problem. On average, clinicians had worked in the treatment field for 8 years. Both staff and clients viewed 12SG as a helpful recovery resource. Major obstacles to participation centered on motivation and readiness for change and on perceived need for help, rather than on aspects of the 12-step program often cited as points of resistance (e.g., religious aspect and emphasis on powerlessness). Clinicians also frequently cited convenience and scheduling issues as possible obstacles to attending 12SG. Clinical implications of these findings are discussed, including the importance of fostering motivation for change, the need to assess clients’ beliefs about and experiences with 12SG on a case by case basis, and to find goodness of fit between clients’ needs and inclinations on the one hand, and the tools and support available within 12-step groups on the other. PMID:14677780

  16. A pilot randomized clinical trial testing integrated 12-Step facilitation (iTSF) treatment for adolescent substance use disorder.

    PubMed

    Kelly, John F; Kaminer, Yifrah; Kahler, Christopher W; Hoeppner, Bettina; Yeterian, Julie; Cristello, Julie V; Timko, Christine

    2017-07-25

    The integration of 12-Step philosophy and practices is common in adolescent substance use disorder (SUD) treatment programs, particularly in North America. However, although numerous experimental studies have tested 12-Step facilitation (TSF) treatments among adults, no studies have tested TSF-specific treatments for adolescents. We tested the efficacy of a novel integrated TSF. Explanatory, parallel-group, randomized clinical trial comparing 10 sessions of either motivational enhancement therapy/cognitive-behavioral therapy (MET/CBT; n = 30) or a novel integrated TSF (iTSF; n = 29), with follow-up assessments at 3, 6 and 9 months following treatment entry. Out-patient addiction clinic in the United States. Adolescents [n = 59; mean age = 16.8 (1.7) years; range = 14-21; 27% female; 78% white]. The iTSF integrated 12-Step with motivational and cognitive-behavioral strategies, and was compared with state-of-the-art MET/CBT for SUD. Primary outcome: percentage days abstinent (PDA); secondary outcomes: 12-Step attendance, substance-related consequences, longest period of abstinence, proportion abstinent/mostly abstinent, psychiatric symptoms. Primary outcome: PDA was not significantly different across treatments [b = 0.08, 95% confidence interval (CI) = -0.08 to 0.24, P = 0.33; Bayes' factor = 0.28). during treatment, iTSF patients had substantially greater 12-Step attendance, but this advantage declined thereafter (b = -0.87; 95% CI = -1.67 to 0.07, P = 0.03). iTSF did show a significant advantage at all follow-up points for substance-related consequences (b = -0.42; 95% CI = -0.80 to -0.04, P < 0.05; effect size range d = 0.26-0.71). Other secondary outcomes did not differ significantly between treatments, but effect sizes tended to favor iTSF. Throughout the entire sample, greater 12-Step meeting attendance was associated significantly with longer abstinence during (r = 0.39, P = 0.008), and early following (r = 0.30, P = 0

  17. Addiction, 12-Step Programs, and Evidentiary Standards for Ethically and Clinically Sound Treatment Recommendations: What Should Clinicians Do?

    PubMed

    Mendola, Annette; Gibson, Richard L

    2016-06-01

    Addiction is a complex phenomenon characterized by a loss of control and compulsive, habitual behavior. Since there is no single, specific cause for addiction, there is no single, standard treatment for it. A variety of approaches are used, including counseling, psychotherapy, medications, and mutual help groups (MHG). The best known and most widely available approach to addiction is 12-step (TS) programs of recovery, a variety of MHG. These have been lauded as lifesaving by some and criticized by others. We argue that TS programs are an appropriate mode of help for those seeking to quit an addiction but should not be the only approach considered.

  18. Clinician recommendation of 12-step meeting attendance and discussion regarding disclosure of buprenorphine use among patients in office-based opioid treatment.

    PubMed

    Suzuki, Joji; Dodds, Tyler

    2016-01-01

    Clinicians are encouraged to include 12-step meetings, such as Alcoholics or Narcotics Anonymous (AA/NA), as ancillary services for the treatment for opioid use disorders (OUDs), even though some of these groups may not fully accept individuals receiving buprenorphine. Little is known about whether clinicians actually discuss with patients the issue of disclosure of buprenorphine use at 12-step meetings. An anonymous survey was offered to patients enrolled in office-based opioid treatment with buprenorphine to assess whether their clinicians recommended attendance at 12-step meetings and discussed the issue of disclosing their use of buprenorphine to other members. The patients' attendance at 12-step meetings was also assessed, as well as beliefs and prior experiences related to disclosure of buprenorphine use at 12-step meetings. Thirty patients completed the survey. Twenty-one respondents (75.0%) indicated that they were encouraged to attend meetings, but only 9 (33.3%) reported having any discussion with their clinicians about the issue of disclosing their use of buprenorphine at meetings. The majority (76.7%) reported attending 12-step meetings at least occasionally, and 70% reported finding the meetings helpful. Nearly one third (30%) expressed concerns that other 12-step members would not accept them if their buprenorphine status were known, and a similar proportion (37%) frequently avoided disclosing their use of buprenorphine. Clinicians recommended 12-step meetings to most patients but did not routinely discuss issues of disclosure. Despite utilizing 12-step meetings and reporting them to be helpful, many avoided disclosing their use of buprenorphine to others. More research is needed to better understand how clinicians may assist patients to best utilize 12-step meetings.

  19. A field application of the ASAM placement criteria in a 12-step model of treatment for chemical dependency.

    PubMed

    May, W W

    1998-01-01

    Procedures followed in the development of a standardized method of rating patient behavior relevant to engaging in a 12 step model of recovery are presented in the context of deriving an empirical cross-walk for the ASAM PPC. This instrument permits addictions counselors to rate the severity of operationally defined behaviors on each of the six criteria dimensions identified in the adaptation of the PPC by the WV Division on Alcoholism and Drug Abuse for use in the 14 member community mental health centers funded by the state. Substance dependent adults (N = 78), who self-selected either residential or partial day treatment at EastRidge's Addictions Treatment Center were evaluated with this procedure over a nine month period. Intercorrelations of ratings on six criteria dimensions at intake ranged from .053 to .576 and after an average length of stay of 18 days, behavioral severity on all dimensions was significantly reduced (p < .0001) on the discharge evaluation with this tool. An empirically based, treatment matching matrix, was constructed from confidence intervals calculated obtained from intake data to form norm referenced ranges for four levels of care (which equate to PPC-2 Levels: III.5, II.5, II.2, I). The utility of this methodology in facilitating the application of the WVPC and PPC-2, and the potential of the DRS as a multiple baseline measure in treatment outcome research is discussed.

  20. Young adults, social networks, and addiction recovery: post treatment changes in social ties and their role as a mediator of 12-step participation.

    PubMed

    Kelly, John F; Stout, Robert L; Greene, M Claire; Slaymaker, Valerie

    2014-01-01

    Social factors play a key role in addiction recovery. Research with adults indicates individuals with substance use disorder (SUD) benefit from mutual-help organizations (MHOs), such as Alcoholics Anonymous, via their ability to facilitate adaptive network changes. Given the lower prevalence of sobriety-conducive, and sobriety-supportive, social contexts in the general population during the life-stage of young adulthood, however, 12-step MHOs may play an even more crucial recovery-supportive social role for young adults, but have not been investigated. Greater knowledge could enhance understanding of recovery-related change and inform young adults' continuing care recommendations. Emerging adults (N = 302; 18-24 yrs; 26% female; 95% White) enrolled in a study of residential treatment effectiveness were assessed at intake, 1, 3, 6, and 12 months on 12-step attendance, peer network variables ("high [relapse] risk" and "low [relapse] risk" friends), and treatment outcomes (Percent Days Abstinent; Percent Days Heavy Drinking). Hierarchical linear models tested for change in social risk over time and lagged mediational analyses tested whether 12-step attendance conferred recovery benefits via change in social risk. High-risk friends were common at treatment entry, but decreased during follow-up; low-risk friends increased. Contrary to predictions, while substantial recovery-supportive friend network changes were observed, this was unrelated to 12-step participation and, thus, not found to mediate its positive influence on outcome. Young adult 12-step participation confers recovery benefit; yet, while encouraging social network change, 12-step MHOs may be less able to provide social network change directly for young adults, perhaps because similar-aged peers are less common in MHOs. Findings highlight the importance of both social networks and 12-step MHOs and raise further questions as to how young adults benefit from 12-step MHOs.

  1. An Exploration of the Effect of On-Site 12-Step Meetings on Post-Treatment Outcomes among Polysubstance-Dependent Outpatient Clients

    ERIC Educational Resources Information Center

    Laudet, Alexandre; Stanick, Virginia; Sands, Brian

    2007-01-01

    Rates of return to active substance use after addiction treatment tend to be high; participation in 12-step fellowships (e.g., Alcoholics Anonymous) reduces relapse rates but many clients do not attend or attend for a short period only. This quasi-experimental study uses repeated measurement to explore the role of presence/absence of on-site…

  2. An Exploration of the Effect of On-Site 12-Step Meetings on Post-Treatment Outcomes among Polysubstance-Dependent Outpatient Clients

    ERIC Educational Resources Information Center

    Laudet, Alexandre; Stanick, Virginia; Sands, Brian

    2007-01-01

    Rates of return to active substance use after addiction treatment tend to be high; participation in 12-step fellowships (e.g., Alcoholics Anonymous) reduces relapse rates but many clients do not attend or attend for a short period only. This quasi-experimental study uses repeated measurement to explore the role of presence/absence of on-site…

  3. Alcoholics Anonymous attendance following 12-step treatment participation as a link between alcoholic fathers’ treatment involvement and their children’s externalizing problems

    PubMed Central

    Andreas, Jasmina Burdzovic; O'Farrell, Timothy J

    2008-01-01

    We investigated longitudinal associations between alcoholic fathers’ 12-step treatment involvement and their children’s internalizing and externalizing problems (N=125, Mage=9.8±3.1), testing the hypotheses that fathers’ greater treatment involvement would benefit later child behavior, and that this effect would be mediated by fathers’ post-treatment behaviors. The initial association was established between fathers’ treatment involvement and children’s externalizing problems only, while structural equation (SEM) results supported mediating hypotheses. Fathers’ greater treatment involvement predicted children’s lower externalizing problems 12 months later, and fathers’ post-treatment behaviors mediated this association: greater treatment involvement predicted greater post-treatment Alcoholics Anonymous (AA) attendance, which in turn predicted greater abstinence. Finally, fathers’ abstinence was associated with lower externalizing problems in children. Theoretical and practical implications of these findings are discussed. PMID:18715745

  4. Specialized 12-step programs and 12-step facilitation for the dually diagnosed.

    PubMed

    Bogenschutz, Michael P

    2005-02-01

    The role of 12-step programs and 12-step-oriented treatments for dually diagnosed individuals (DDI) remains unclear. Here are presented the results of a pilot study in which 10 seriously mentally ill patients received a modified 12-step facilitation (TSF) therapy emphasizing engagement of DDI in a specialized 12-step program for DDI. Participants significantly increased their 12-step attendance and decreased their substance use during the 12 weeks of treatment. Larger and longer-term studies are needed to assess the efficacy of modified TSF for DDI relative to other treatments, and to determine what forms of TSF are most effective in this population.

  5. Alcoholics Anonymous attendance following 12-step treatment participation as a link between alcohol-dependent fathers' treatment involvement and their children's externalizing problems.

    PubMed

    Andreas, Jasmina Burdzovic; O'Farrell, Timothy J

    2009-01-01

    We investigated longitudinal associations between alcohol-dependent fathers' 12-step treatment involvement and their children's internalizing and externalizing problems (N = 125, M(age) = 9.8 +/- 3.1), testing the hypotheses that fathers' greater treatment involvement would benefit later child behavior and that this effect would be mediated by fathers' posttreatment behaviors. The initial association was established between fathers' treatment involvement and children's externalizing problems only, whereas Structural Equation Modeling (SEM) results supported mediating hypotheses. Fathers' greater treatment involvement predicted children's lower externalizing problems 12 months later, and fathers' posttreatment behaviors mediated this association: Greater treatment involvement predicted greater posttreatment Alcoholics Anonymous attendance, which in turn predicted greater abstinence. Finally, fathers' abstinence was associated with lower externalizing problems in children. Theoretical and practical implications of these findings are discussed.

  6. Anterior Cingulate Volumetric Alterations in Treatment-Naive Adults with ADHD: A Pilot Study

    ERIC Educational Resources Information Center

    Makris, Nikos; Seidman, Larry J.; Valera, Eve M.; Biederman, Joseph; Monuteaux, Michael C.; Kennedy, David N.; Caviness, Verne S., Jr.; Bush, George; Crum, Katherine; Brown, Ariel B.; Faraone, Stephen V.

    2010-01-01

    Objective: We sought to examine preliminary results of brain alterations in anterior cingulate cortex (ACC) in treatment-naive adults with ADHD. The ACC is a central brain node for the integration of cognitive control and allocation of attention, affect and drive. Thus its anatomical alteration may give rise to impulsivity, hyperactivity and…

  7. What Promotes Wisdom in 12-Step Recovery?

    PubMed

    DiGangi, Julia A; Majer, John M; Mendoza, Leslie; Droege, Jocelyn R; Jason, Leonard A; Contreras, Richard

    2014-01-01

    Research investigations on twelve-step groups such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) have addressed a number of resources associated with 12-step recovery. However, little is known about the role of wisdom, and whether aspects of 12-step participation might increase this resource among 12-step members. An exploratory analysis revealed that participants who reported having a "spiritual awakening" and considered themselves "members" of 12-step groups reported significantly higher levels of wisdom. Twelve-step meeting attendance was not significantly related to wisdom scores. Findings suggest certain aspects of 12-step involvement are associated with wisdom and may play a role in substance abuse recovery.

  8. What Promotes Wisdom in 12-Step Recovery?

    PubMed Central

    DiGangi, Julia A.; Majer, John M.; Mendoza, Leslie; Droege, Jocelyn R.; Jason, Leonard A.; Contreras, Richard

    2014-01-01

    Research investigations on twelve-step groups such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) have addressed a number of resources associated with 12-step recovery. However, little is known about the role of wisdom, and whether aspects of 12-step participation might increase this resource among 12-step members. An exploratory analysis revealed that participants who reported having a “spiritual awakening” and considered themselves “members” of 12-step groups reported significantly higher levels of wisdom. Twelve-step meeting attendance was not significantly related to wisdom scores. Findings suggest certain aspects of 12-step involvement are associated with wisdom and may play a role in substance abuse recovery. PMID:24932162

  9. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients

    PubMed Central

    Zhang, Jianping; Hayes, Siobhán; Sadler, Brian M; Minto, Ilisse; Brandt, Julie; Piscitelli, Steve; Min, Sherene; Song, Ivy H

    2015-01-01

    Aim Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates. Methods A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10–50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine. Results The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h–1, 17.4 l, 2.24 h−1, and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis. Conclusions A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients. PMID:25819132

  10. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients.

    PubMed

    Zhang, Jianping; Hayes, Siobhán; Sadler, Brian M; Minto, Ilisse; Brandt, Julie; Piscitelli, Steve; Min, Sherene; Song, Ivy H

    2015-09-01

    Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates. A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10-50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine. The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h(-1) , 17.4 l, 2.24 h(-1) , and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis. A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients. © 2015 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  11. Antiretroviral drug resistance and HIV-1 subtypes among treatment-naive prisoners in Kelantan, Malaysia.

    PubMed

    Ariffin, Tengku Ahmad Akram Tengku Mohd; Mohamad, Suharni; Yusuf, Wan Nazirah Wan; Shueb, Rafidah Hanim

    2014-08-13

    The widespread use of highly active antiretroviral therapy (HAART) and continuous reports of HIV-1 strains developing resistance to these drugs is rather alarming, as transmission of resistant viruses to newly infected persons is possible. This study aimed to determine HIV-1 subtypes and the prevalence of primary mutations associated with antiretroviral (ARV) resistance among treatment-naive prisoners on the east coast of Malaysia. Viral RNA was extracted from plasma samples of 21 treatment-naive prisoners. Protease (PR) and reverse transcriptase (RT) regions were amplified and sequenced. Stanford HIV database algorithms were used for interpretation of resistance, and phylogenetic analysis was performed for subtype assignment. In the PR gene, no antiviral resistance-associated mutation was detected. For RT-associated mutations, K103N was the most prevalent in sequenced samples (14.3%). Genetic subtyping on the pol gene revealed that the majority of the prisoners were infected with subtype CRF33_01B (52.4%). Continuous surveillance of newly infected individuals is required to help strategize the best antiviral treatment for these patients.

  12. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia

    PubMed Central

    Nunez, Olga; Weinstein, Barbara; Scheinberg, Priscila; Wu, Colin O.; Young, Neal S.

    2012-01-01

    Antithymocyte globulin (ATG) + cyclosporine is effective in restoring hematopoiesis in severe aplastic anemia (SAA). We hypothesized that the humanized anti-CD52 mAb alemtuzumab might be active in SAA because of its lymphocytotoxic properties. We investigated alemtuzumab monotherapy from 2003-2010 in treatment-naive, relapsed, and refractory SAA in 3 separate research protocols at the National Institutes of Health. Primary outcome was hematologic response at 6 months. For refractory disease, patients were randomized between rabbit ATG + cyclosporine (n = 27) and alemtuzumab (n = 27); the response rate for alemtuzumab was 37% (95% confidence interval [CI], 18%-57%) and for rabbit ATG 33% (95% CI, 14%-52%; P = .78). The 3-year survival was 83% (95% CI, 68%-99%) for alemtuzumab and 60% (95% CI, 43%-85%) for rabbit ATG (P = .16). For relapsed disease (n = 25), alemtuzumab was administered in a single-arm study; the response rate was 56% (95% CI, 35%-77%) and the 3-year survival was 86% (95% CI, 72%-100%). In treatment-naive patients (n = 16), alemtuzumab was compared with horse and rabbit ATG in a 3-arm randomized study; the response rate was 19% (95% CI 0%-40%), and the alemtuzumab arm was discontinued early. We conclude that alemtuzumab is effective in SAA, but best results are obtained in the relapsed and refractory settings. The present trials were registered at www.clinicaltrials.gov as NCT00195624, NCT00260689, and NCT00065260. PMID:22067384

  13. Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon.

    PubMed

    Fernández-Fournier, Mireya; Tallón-Barranco, Antonio; Chamorro, Beatriz; Martínez-Sánchez, Patricia; Puertas, Inmaculada

    2015-08-19

    In the treatment of multiple sclerosis, a change of therapy is considered after treatment failure or adverse events. Although disease modifying drugs' (DMD) efficacy and side effects have been fully analysed in clinical trials, the effects of previous therapy use are less well studied. We aimed to study medication persistence with glatiramer acetate in treatment-naive patients and in patients previously treated with interferon. A retrospective study of relapsing-remitting multiple sclerosis patients treated with glatiramer acetate in an MS Unit of a Spanish University Hospital (January 2004--September 2013). Treatment time on glatiramer acetate was studied. Reasons for treatment discontinuation were considered as follows: lack of efficacy, serious adverse event, injection-related side effect, pregnancy and lost to follow-up. Use of prior DMD was registered and analysed. Homogeneity of groups was analysed using Fisher's and Mann-Whitney's tests. The Kaplan Meier method and Cox regression model were used to estimate time to and risk of treatment discontinuation. In total, 155 relapsing-remitting multiple sclerosis patients were treated with glatiramer acetate: 100 treatment-naive patients and 55 treated previously with interferon. At the end of the study, 76 patients (49.0%) continued on glatiramer acetate (with an average treatment time (ATT) of 50.4 months, s.d.32.8) and 50 patients (32.3%) had switched therapy: 27 patients (17.4%) for inefficacy (ATT 29.2 months, s.d.17.5), 20 patients (12.9%) for injection site reactions (ATT 16.5 months, s.d.20.3) and 3 patients (1.9%) after serious adverse events (ATT 15.7 months, s.d.15.1). ATT in our cohort was 39 months (s.d.30.0), median follow-up 34 months. Six months after glatiramer acetate initiation, probability of persisting on GA was 91.4%, 82.5% after 12 months and 72.5% after 2 years. The risk of glatiramer acetate treatment discontinuation was 2.8 [1.7 - 4.8] times greater for treatment-naive patients than for

  14. Clinical features of treatment-naive patients with hepatitis B virus infection

    PubMed Central

    Wu, Wei; Zhu, Yu; Yu, Chenbo; Yang, Shigui; Ruan, Bing; Chen, Yu; Li, Lanjuan

    2017-01-01

    Abstract The aim of study was to investigate the clinical features of treatment-naive patients in 2 regions with high- and intermediate-hepatitis B endemicity level in Southeast China and provide the baseline data for monitoring health or planning therapy. This study included 8207 cases of treatment-naive patients with hepatitis B virus (HBV) infection from Yuhuan (YH, high-hepatitis B endemicity region) and Shaoxing (SX, intermediate-hepatitis B endemicity region) during 2014–2015. Clinical data were collected from the patients. Blood samples were kept for detecting hepatitis B surface antigen, hepatitis B envelope antigen (HBeAg), hepatitis B envelope antibody, hepatitis B surface antibody, hepatitis B core antibody, liver function, HBV deoxyribonucleic acid, and alpha-fetoprotein. All persons underwent B ultrasound to exclude liver cirrhosis or cancer. Of all 8207 HBsAg-positive patients, 52.9% patients were in the low-replication (LR) stage and 30.3% in the HBeAg-negative chronic hepatitis B (ENH) stage; 8.8% cases were in the ENH stage with elevated alanine aminotransferase (ALT). More male than female patients were in immune clearance (IC) or ENH stages with elevated ALT (10.4% vs 4.8%, 12.1% vs 5.3%, respectively, P < .05). The percentage of patients in IC and immune tolerant (IT) stages declined with increasing age, whereas the percentages of ENH with elevated ALT stage were highest in 40 to 60 years. The percentage of patients in IT and IC stages was higher in YH than in SX (9.4% vs 3.8%, 9.9% vs 4.2%, respectively, P < .05). More patients had HBVDNA≥105 IU/mL in YH than in SX (24.6% vs 16.0%, P < .05), and more male than female patients had HBVDNA≥105 IU/mL(24.5% vs 17.9%, P < .05). Clinical features varied in treatment-naive patients with HBV infection between different genders and regions. More attention should be paid to the surveillance and therapy of patients in YH especially male patients for the prevention and prognosis of

  15. A Discrete Choice Conjoint Experiment to Evaluate Parent Preferences for Treatment of Young, Medication Naive Children with ADHD

    ERIC Educational Resources Information Center

    Waschbusch, Daniel A.; Cunningham, Charles E.; Pelham, William E., Jr.; Rimas, Heather L.; Greiner, Andrew R.; Gnagy, Elizabeth M.; Waxmonsky, James; Fabiano, Gregory A.; Robb, Jessica A.; Burrows-MacLean, Lisa; Scime, Mindy; Hoffman, Martin T.

    2011-01-01

    The current study examined treatment preferences of 183 parents of young (average age = 5.8 years, SD = 0.6), medication naive children with ADHD. Preferences were evaluated using a discrete choice experiment in which parents made choices between different combinations of treatment characteristics, outcomes, and costs. Latent class analysis…

  16. A Discrete Choice Conjoint Experiment to Evaluate Parent Preferences for Treatment of Young, Medication Naive Children with ADHD

    ERIC Educational Resources Information Center

    Waschbusch, Daniel A.; Cunningham, Charles E.; Pelham, William E., Jr.; Rimas, Heather L.; Greiner, Andrew R.; Gnagy, Elizabeth M.; Waxmonsky, James; Fabiano, Gregory A.; Robb, Jessica A.; Burrows-MacLean, Lisa; Scime, Mindy; Hoffman, Martin T.

    2011-01-01

    The current study examined treatment preferences of 183 parents of young (average age = 5.8 years, SD = 0.6), medication naive children with ADHD. Preferences were evaluated using a discrete choice experiment in which parents made choices between different combinations of treatment characteristics, outcomes, and costs. Latent class analysis…

  17. Subjective taste and smell changes in treatment-naive people with solid tumours.

    PubMed

    Spotten, L; Corish, C; Lorton, C; Dhuibhir, P Ui; O'Donoghue, N; O'Connor, B; Cunningham, M; El Beltagi, N; Gillham, C; Walsh, D

    2016-07-01

    Taste and smell changes (TSCs) are common in head and neck (H&N) cancer and during and after chemotherapy (CT) and radiotherapy (RT). It is an area that has been under-investigated, particularly in the treatment-naive, but can negatively impact nutritional status. This study examined the prevalence, severity and characteristics of TSCs in people with non-H&N solid tumours, before CT and RT, and their relationship with co-occurring symptoms. A prospective, observational study was conducted. Forty consecutive pre-treatment cancer patients, referred to radiation oncology outpatients over 6 weeks, were recruited. Data on TSCs, symptoms and nutritional status were obtained using the 'Taste and Smell Survey' and the 'abridged Patient-Generated Subjective Global Assessment' (abPG-SGA). BMI was measured. SPSS® was used for statistical analysis. Two-sided P values <0.05 were considered statistically significant. Most patients were newly diagnosed (n = 28; 70 %). Nineteen (48 %) reported TSCs; nine noted a stronger sweet and seven a stronger salt taste. Of these, four reported a stronger and four a weaker smell sensation. Those at nutritional risk reported more TSCs (n = 13/20). TSCs were significantly associated with dry mouth (P < 0.01), early satiety (P < 0.05) and fatigue (P < 0.05). TSCs preceded CT or RT in almost half of treatment-naive patients with solid tumours, notably stronger sweet and salt tastes. Half of the study group were at nutritional risk; the majority of these reported TSCs. TSCs were significantly associated with other symptoms. Future research and clinical guidelines, with a common terminology for assessment, diagnosis and management of cancer TSCs, are needed.

  18. Clinical role of obinutuzumab in the treatment of naive patients with chronic lymphocytic leukemia

    PubMed Central

    Cerquozzi, Sonia; Owen, Carolyn

    2015-01-01

    The introduction of targeted therapy against CD20+ with the monoclonal antibody rituximab has dramatically improved the survival of B-cell non-Hodgkin lymphoma including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. Unfortunately, CLL remains incurable with chemoimmunotherapy, with many patients having refractory or relapsing disease after rituximab-containing therapy. Obinutuzumab (GA101) is a novel humanized Type II anti-CD20 monoclonal antibody that has been investigated and compared to rituximab. Here, we provide an overview of obinutuzumab, including its mechanisms of action, preclinical data, and Phase I to III clinical studies. Preclinical data illustrate obinutuzumab’s higher potency compared to rituximab through antibody-dependent cellular cytotoxicity and direct cell death. Recently, the CLL11 study presented a significant benefit from obinutuzumab chemoimmunotherapy and supports its use for treatment-naive unfit CLL patients. Herein, we review that obinutuzumab is both a safe and effective alternative to rituximab. PMID:25733804

  19. Clinical role of obinutuzumab in the treatment of naive patients with chronic lymphocytic leukemia.

    PubMed

    Cerquozzi, Sonia; Owen, Carolyn

    2015-01-01

    The introduction of targeted therapy against CD20(+) with the monoclonal antibody rituximab has dramatically improved the survival of B-cell non-Hodgkin lymphoma including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. Unfortunately, CLL remains incurable with chemoimmunotherapy, with many patients having refractory or relapsing disease after rituximab-containing therapy. Obinutuzumab (GA101) is a novel humanized Type II anti-CD20 monoclonal antibody that has been investigated and compared to rituximab. Here, we provide an overview of obinutuzumab, including its mechanisms of action, preclinical data, and Phase I to III clinical studies. Preclinical data illustrate obinutuzumab's higher potency compared to rituximab through antibody-dependent cellular cytotoxicity and direct cell death. Recently, the CLL11 study presented a significant benefit from obinutuzumab chemoimmunotherapy and supports its use for treatment-naive unfit CLL patients. Herein, we review that obinutuzumab is both a safe and effective alternative to rituximab.

  20. Alemtuzumab improves neurological functional systems in treatment-naive relapsing-remitting multiple sclerosis patients.

    PubMed

    Fox, Edward J; Wynn, Daniel; Coles, Alasdair J; Palmer, Jeffrey; Margolin, David H

    2016-04-15

    Individual functional system scores (FSS) of the Expanded Disability Status Scale (EDSS) play a central role in determining the overall EDSS score in patients with early-stage multiple sclerosis (MS). Alemtuzumab treatment improves preexisting disability for many patients; however, it is unknown whether improvement is specific to certain functional systems. We assessed the effect of alemtuzumab on individual FSS of the EDSS. CAMMS223 was a 36-month, rater-blinded, phase 2 trial; treatment-naive patients with active relapsing-remitting MS, EDSS ≤3, and symptom onset within 3 years were randomized to annual courses of alemtuzumab or subcutaneous interferon beta-1a (SC IFNB-1a) 44 μg three times weekly. Alemtuzumab-treated patients had improved outcomes versus SC IFNB-1a patients on most FSS at Month 36; the greatest effect occurred for sensory, pyramidal, and cerebellar FSS. Among patients who experienced 6-month sustained accumulation of disability, clinical worsening occurred most frequently in the brainstem and sensory systems. For patients with 6-month sustained reduction in preexisting disability, pyramidal and sensory systems contributed most frequently to clinical improvement. Alemtuzumab demonstrated a broad treatment effect in improving preexisting disability. These findings may influence treatment decisions in patients with early, active relapsing-remitting MS displaying neurological deficits. ClinicalTrials.gov Identifier NCT00050778. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  1. HIV-1 Genetic Diversity and Drug Resistance Mutations Among Treatment-Naive Adult Patients in Suriname.

    PubMed

    Abdoel Wahid, Firoz; Sno, Rachel; Darcissac, Edith; Lavergne, Anne; Adhin, Malti R; Lacoste, Vincent

    2016-12-01

    The molecular epidemiologic profile of HIV-1 in Suriname was determined through protease (PR) and reverse transcriptase (RT) sequences obtained from HIV-1 strains collected from 100 drug-naive HIV-1-infected persons. Subtype determination revealed that most viruses were of subtype B (94.9%) in both PR and RT genomic regions, followed by B/D recombinants (5.1%). Analysis of drug resistance mutations showed only one transmitted dug resistance mutation (TDRM) (V75M) in a single strain. The genetic data obtained can serve as a baseline for Suriname to monitor emerging mutations. This study reveals that the HIV-1 epidemic in Suriname is still characterized by a low TDRM rate (1%) and a low level of subtype diversity. However, both genes display a high genetic polymorphism. This high polymorphism may ultimately lead to drug resistance. Continuous monitoring of the baseline resistance is therefore a prerequisite to safeguard effective long-term treatment for people living with HIV-1 in Suriname.

  2. Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies.

    PubMed

    Goedee, H Stephan; van der Pol, W Ludo; van Asseldonk, Jan-Thies H; Franssen, Hessel; Notermans, Nicolette C; Vrancken, Alexander J F E; van Es, Michael A; Nikolakopoulos, Stavros; Visser, Leo H; van den Berg, Leonard H

    2017-01-10

    To determine the diagnostic value of high-resolution ultrasound (HRUS) for detection of chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner syndrome (LSS), and multifocal motor neuropathy (MMN). Between January 2013 and January 2015, we enrolled 75 consecutive treatment-naive patients with chronic inflammatory neuropathies and 70 disease controls. We performed extensive nerve conduction and standardized HRUS studies bilaterally of large arm and leg nerves and brachial plexus. We determined optimal sonographic cutoff values of nerve size and used receiver operating characteristic analysis and logistic regression models to identify nerve combinations with optimal diagnostic performance. Enlargement of median nerve at forearm >10 mm(2), upper arm >13 mm(2), and any trunk of brachial plexus >8 mm(2) was 99% specific for chronic inflammatory neuropathies. A shortened HRUS protocol for detecting this abnormal nerve enlargement showed high sensitivity (83%-95%), positive predictive value (100%), and negative predictive value (98%) in discriminating CIDP, LSS, and MMN from clinical mimics. Sonographic enlargement of proximal median nerve segments in the arms and brachial plexus is a key feature of chronic inflammatory neuropathies, which helps to reliably distinguish them from axonal neuropathies and amyotrophic lateral sclerosis. This study provides Class II evidence that, in absence of clinical features that suggest a hereditary demyelinating neuropathy, sonographic enlargement of proximal median nerve segments and brachial plexus accurately identifies patients with chronic inflammatory neuropathies. © 2016 American Academy of Neurology.

  3. Experience of dolutegravir in HIV-infected treatment-naive patients from a tertiary care University Hospital in Ireland

    PubMed Central

    Waqas, Sarmad; O’Connor, Mairead; Levey, Ciara; Mallon, Paddy; Sheehan, Gerard; Patel, Anjali; Avramovic, Gordana; Lambert, John S

    2016-01-01

    Objective: Dolutegravir, an HIV integrase inhibitor, is a relatively new treatment option. To assess the tolerability, side effects, and time to viral decline to non-detectable in patients newly started on dolutegravir. Methods: Retrospective health care record of 61 consecutive HIV treatment-naive patients started on dolutegravir was reviewed and analysed on SPSS. Results: The mean initial viral load was 160826.05 copies/mL (range, 79–1,126,617 copies/mL). HIV viral load became non-detectable in 63.9% of patients on dolutegravir within 3 months. In all, 60.7% of patients reported no side effects on dolutegravir; 98.4% of the patients claimed full compliance to their antiretrovirals. Conclusion: Dolutegravir was found to be efficacious and well tolerated in HIV-infected treatment-naive patients. PMID:27826447

  4. Experience of dolutegravir in HIV-infected treatment-naive patients from a tertiary care University Hospital in Ireland.

    PubMed

    Waqas, Sarmad; O'Connor, Mairead; Levey, Ciara; Mallon, Paddy; Sheehan, Gerard; Patel, Anjali; Avramovic, Gordana; Lambert, John S

    2016-01-01

    Dolutegravir, an HIV integrase inhibitor, is a relatively new treatment option. To assess the tolerability, side effects, and time to viral decline to non-detectable in patients newly started on dolutegravir. Retrospective health care record of 61 consecutive HIV treatment-naive patients started on dolutegravir was reviewed and analysed on SPSS. The mean initial viral load was 160826.05 copies/mL (range, 79-1,126,617 copies/mL). HIV viral load became non-detectable in 63.9% of patients on dolutegravir within 3 months. In all, 60.7% of patients reported no side effects on dolutegravir; 98.4% of the patients claimed full compliance to their antiretrovirals. Dolutegravir was found to be efficacious and well tolerated in HIV-infected treatment-naive patients.

  5. Longitudinal study of urban American Indian 12-step attendance, attrition, and outcome.

    PubMed

    Tonigan, J Scott; Martinez-Papponi, Brenda; Hagler, Kylee J; Greenfield, Brenna L; Venner, Kamilla L

    2013-07-01

    Strong opinions have been voiced about the "fit" between 12-step treatment, community-based 12-step practices, and American Indian beliefs and values. Little is known, however, about the relative benefit of 12-step programs for urban American Indians, although they are the most widely accessed type of treatment by American Indians. This study investigated rates of 12-step attendance, attrition, and substance use outcomes for American Indians for 9 months relative to non-Hispanic White participants. This study compared urban American Indian (n = 63) and non-Hispanic White (n = 133) 12-step attendance, attrition, and substance use over 9 months. The sample was formed by merging data from two prospective single-group longitudinal studies investigating behavior change in community-based 12-step programs. Participants were interviewed at baseline and at 3-, 6-, and 9-month follow-ups. No intervention was provided. Participants were recruited from Alcoholics Anonymous meetings in the community and as they presented for outpatient substance use disorder treatment. Substance use and patterns of 12-step attendance were measured using the Form 90 calendar-based interview, and the General Alcoholics Anonymous Tools of Recovery was administered to assess the adoption of prescribed 12-step practices and beliefs. Trajectories in 12-step meeting attendance over 9 months did not differ between American Indian and non-Hispanic White participants. However, American Indian participants discontinued 12-step attendance significantly less often than non-Hispanic White participants. Higher rates of 12-step attendance predicted increased alcohol abstinence and decreased drinking intensity for both American Indian and non-Hispanic White participants. Twelve-step attendance was unrelated to later illicit drug use for both American Indian and non-Hispanic White participants. Community-based 12-step program attendance is associated with drinking reductions among urban American Indians.

  6. Genetic characterization and antiretroviral resistance mutations among treatment-naive HIV-infected individuals in Jiaxing, China.

    PubMed

    Guo, Jinlei; Yan, Yong; Zhang, Jiafeng; Ji, Jimei; Ge, Zhijian; Ge, Rui; Zhang, Xiaofei; Wang, Henghui; Chen, Zhongwen; Luo, Jianyong

    2017-03-14

    The aim of this study was to characterize HIV-1 genotypes and antiretroviral resistance mutations among treatment-naive HIV-infected individuals in Jiaxing, China. The HIV-1 partial polymerase (pol) genes in 93 of the 99 plasma samples were successfully amplified and analyzed. Phylogenetic analysis revealed the existence of five HIV-1 genotypes, of which the most prevalent genotype was CRF01_AE (38.7%), followed by CRF07_BC (34.4%), CRF08_BC (16.1%), subtype B/B' (5.4%), and CRF55_01B (2.1%). Besides, three types of unique recombination forms (URFs) were also observed, including C/F2/A1, CRF01_AE/B, and CRF08_BC/CRF07_BC. Among 93 amplicons, 46.2% had drug resistance-associated mutations, including 23.7% for protease inhibitors (PIs) mutations, 1.1% for nucleoside reverse transcriptase inhibitors (NRTIs) mutations, and 20.4% for non-nucleoside reverse transcriptase inhibitors (NNRTIs) mutations. Six (6.5%) out of 93 treatment-naive subjects were identified to be resistant to one or more NNRTIs, while resistance to NRTIs or PIs was not observed. Our study showed the genetic diversity of HIV-1 strains circulating in Jiaxing and a relative high proportion of antiretroviral resistance mutations among treatment-naive patients, indicating a serious challenge for HIV prevention and treatment program.

  7. Gait and Balance in Treatment-Naive Active Alcoholics with and without a Lifetime Drug Codependence

    PubMed Central

    Fein, George; Smith, Stan; Greenstein, David

    2012-01-01

    Background Disturbed gait and balance are among the most consistent sequelae of chronic alcoholism. However, although a majority of alcoholics have never sought treatment, most investigations showing ataxia in alcohol dependent individuals have relied on samples drawn from treated populations. In addition, few studies have addressed the associations of codependence on other drugs with alcoholic gait and balance disturbance. Methods The present study employed the Walk-a-line Ataxia Battery (Fregly et al. 1972) to assess gait and balance in treatment-naive, actively drinking alcohol dependent men and women (TNA; n = 69) who were dependent on alcohol only (ALC; n = 43), or who also had a lifetime drug dependence (ALC+DRG; n = 26; i.e., methamphetamine, cocaine, opiates, and/or marijuana), compared with non-substance abusing controls (NSAC; n = 74). We also examined associations between lifetime alcohol use and age with gait and balance measures. Results Our main findings were 1) no evidence of disturbed gait and balance in ALC vs. NSAC and 2) significantly disturbed gait and balance in ALC+DRG, relative to both NSAC and ALC, along with steeper age-associated decline in gait and balance performance in ALC vs. ALC+DRG. Conclusions Our results provide evidence consistent with previous studies that TNA (without a lifetime drug codependence) may represent a population that is different and less impaired (including in gait and balance) than treated alcoholics. Additionally, we provide evidence that ALC+DRG, with greater alcohol use and family drinking density than ALC, have an accelerated effect of age on gait and balance disturbance compared to both NSAC and ALC. The ALC+DRG group likely represents a subset of TNA with different characteristics than ALC. PMID:22390787

  8. Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD.

    PubMed

    Cherkasova, Mariya V; Faridi, Nazlie; Casey, Kevin F; O'Driscoll, Gillian A; Hechtman, Lily; Joober, Ridha; Baker, Glen B; Palmer, Jennifer; Dagher, Alain; Leyton, Marco; Benkelfat, Chawki

    2014-05-01

    Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.

  9. Comparative study of clozapine versus risperidone in treatment-naive, first-episode schizophrenia: A pilot study.

    PubMed

    Sahni, Sukhtej; Chavan, B S; Sidana, Ajeet; Kalra, Priyanka; Kaur, Gurjit

    2016-11-01

    Clozapine may be more useful in treatment-naive patients with first-episode schizophrenia for better symptoms control and improving quality of life. The current study was carried out to compare the efficacy and tolerability of clozapine versus risperidone in treatment-naive, first-episode patients of schizophrenia. This was a comparative, open-label, six months prospective study of treatment-naive, first-episode patients with schizophrenia between the age group of 18 and 40 yr diagnosed as per the International Classification of Diseases-10 (ICD-10) criteria. A total of 63 patients were recruited and randomly assigned to clozapine group or risperidone group using computer-generated random number tables. Eight patients were lost to follow up. The dosages of the respective drugs were kept in therapeutic range of 200-600 mg/day and 4-8 mg/day orally for clozapine and risperidone, respectively. On general psychopathology score, after six months of intervention, clozapine led to 60.32 per cent mean reduction in Positive and Negative Syndrome Scale (PANSS) for Schizophrenia total score while risperidone led to 56.35 per cent mean reduction in PANSS total score, which meant more improvement with clozapine. Clozapine group was found to have significant improvement in quality of life (P = 0.04339). On Glasgow Antipsychotic Side-effect Scale, clozapine was superior to risperidone. The most common side effects observed in clozapine group were oversedation (78.96%) and dizziness (55.23%), and in risperidone group, common side effects were rigidity (62.36%), sedation (38.69%), tremors (65.69%) and menstrual irregularities in 80.25 per cent of female patients. The findings of this preliminary study showed clozapine as a better choice than risperidone in terms of efficacy, tolerability and better quality of life in treatment-naive, first-episode schizophrenia. However, further studies need to be done on a larger group of patients to confirm the findings.

  10. 12-STEP FACILITATION FOR THE DUALLY DIAGNOSED: A RANDOMIZED CLINICAL TRIAL

    PubMed Central

    Bogenschutz, Michael P.; Rice, Samara L.; Tonigan, J. Scott; Vogel, Howard S.; Nowinski, Joseph; Hume, Donald; Arenella, Pamela B.

    2014-01-01

    There are few clinical trials of 12-step treatments for individuals with serious mental illness and alcohol or drug dependence. This randomized trial assessed the effects of adding a 12-session 12-step facilitation therapy (TSF), adapted from that used in Project MATCH, to treatment as usual in an outpatient dual diagnosis program. Participants were 121 individuals dually diagnosed with alcohol dependence and a serious mental disorder, followed during 12 weeks of treatment and 36 weeks post-treatment. Participants receiving TSF had greater participation in 12-step programs, but did not demonstrate greater improvement in alcohol and drug use. However, considered dimensionally, greater participation in TSF was associated with greater improvement in substance use, and greater 12-step participation predicted decreases in frequency and intensity of drinking. Findings suggest that future work with TSF in this population should focus on maximizing exposure to TSF, and maximizing the effect of TSF on 12-step participation. PMID:24462479

  11. Attentional Control and Subjective Executive Function in Treatment-Naive Adults with Attention Deficit Hyperactivity Disorder

    PubMed Central

    Grane, Venke Arntsberg; Endestad, Tor; Pinto, Arnfrid Farbu; Solbakk, Anne-Kristin

    2014-01-01

    We investigated performance-derived measures of executive control, and their relationship with self- and informant reported executive functions in everyday life, in treatment-naive adults with newly diagnosed Attention Deficit Hyperactivity Disorder (ADHD; n = 36) and in healthy controls (n = 35). Sustained attentional control and response inhibition were examined with the Test of Variables of Attention (T.O.V.A.). Delayed responses, increased reaction time variability, and higher omission error rate to Go signals in ADHD patients relative to controls indicated fluctuating levels of attention in the patients. Furthermore, an increment in NoGo commission errors when Go stimuli increased relative to NoGo stimuli suggests reduced inhibition of task-irrelevant stimuli in conditions demanding frequent responding. The ADHD group reported significantly more cognitive and behavioral executive problems than the control group on the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). There were overall not strong associations between task performance and ratings of everyday executive function. However, for the ADHD group, T.O.V.A. omission errors predicted self-reported difficulties on the Organization of Materials scale, and commission errors predicted informant reported difficulties on the same scale. Although ADHD patients endorsed more symptoms of depression and anxiety on the Achenbach System of Empirically Based Assessment (ASEBA) than controls, ASEBA scores were not significantly associated with T.O.V.A. performance scores. Altogether, the results indicate multifaceted alteration of attentional control in adult ADHD, and accompanying subjective difficulties with several aspects of executive function in everyday living. The relationships between the two sets of data were modest, indicating that the measures represent non-redundant features of adult ADHD. PMID:25545156

  12. Contrast-enhancing tumor growth dynamics of preoperative, treatment-naive human glioblastoma.

    PubMed

    Ellingson, Benjamin M; Nguyen, Huytram N; Lai, Albert; Nechifor, Ruben E; Zaw, Okkar; Pope, Whitney B; Yong, William H; Nghiemphu, Phioanh L; Liau, Linda M; Cloughesy, Timothy F

    2016-06-01

    Little is known about the natural growth characteristics of untreated glioblastoma before surgical or therapeutic intervention, because patients are rapidly treated after preliminary radiographic diagnosis. Understanding the growth characteristics of uninhibited human glioblastoma may be useful for characterizing changes in response to therapy. Thus, the objective of the current study was to explore tumor growth dynamics in a cohort of patients with untreated glioblastoma before surgical or therapeutic intervention. Ninety-five patients with glioblastoma who had measurable enhancing disease on >2 magnetic resonance imaging scans before surgery were identified. Tumor growth rates were quantified in 4 different ways (the percentage change per day, the absolute rate of change per day, the estimated volumetric doubling time, and the radial expansion rate) using 3 different approaches (bidirectional product, enhancing disease, and total lesion volume). The median volumetric doubling time was 21.1 days, the percentage change in tumor volume was 2.1% per day, and the rate of change in total lesion volume was 0.18 cc per day. The length of follow-up between magnetic resonance imaging examinations should be >28 days to detect progressive disease with high specificity. Small initial tumor sizes (<3 cm in greatest dimension) are biased toward a large percentage change at follow-up. Presurgical, treatment-naive glioblastoma growth dynamics can be estimated in a variety of ways with similar results. The percentage changes in tumor size and volume depend on baseline tumor size and the time interval between scans. Cancer 2016;122:1718-27. © 2016 American Cancer Society. © 2016 American Cancer Society.

  13. Do changes in selfishness explain 12-step benefit? : A prospective lagged analysis

    PubMed Central

    Tonigan, J. Scott; Rynes, Kristina; Toscova, Radka; Hagler, Kylee

    2017-01-01

    Objective 12-step attendance is associated with increased abstinence. A strong claim made in 12-step literature is that alcoholics are pathologically selfish and that working the 12 steps reduces this selfishness which, in turn, leads to sustained alcohol abstinence. This study tested this assumption by investigating the linkages between 12-step attendance, pathological narcissism, and drinking. Method 130 early AA affiliates with limited AA and treatment histories were recruited from treatment and community-based AA. A majority of the sample was alcohol dependent and reported illicit drug use before recruitment. Participants were interviewed at intake and at 3, 6, and 9 months. Results A majority of participants attended AA meetings throughout follow-up and such attendance predicted increased abstinence and reduced drinking intensity. 12-step affiliates were significantly higher on pathological narcissism (PN) relative to general population samples and their PN remained elevated. Contrary to predictions, PN was unrelated to 12-step meeting attendance and did not predict later abstinence or drinking intensity. Conclusion Findings did not support the hypothesis that reductions in PN explain 12-step benefit. An alternative function for the emphasis placed on pathological selfishness in 12-step programs is discussed and a recommendation is made to use unobtrusive measures of selfishness in future research. PMID:23327500

  14. Predictors of 12-Step Attendance and Participation for Individuals with Stimulant Use Disorders

    PubMed Central

    Hatch-Maillette, Mary; Wells, Elizabeth A.; Doyle, Suzanne R.; Brigham, Gregory S.; Daley, Dennis; DiCenzo, Jessica; Donovan, Dennis; Garrett, Sharon; Horigian, Viviana E.; Jenkins, Lindsay; Killeen, Therese; Owens, Mandy; Perl, Harold I.

    2017-01-01

    Objective Few studies have examined the effectiveness of 12-step peer recovery support programs with drug use disorders, especially stimulant use, and it is difficult to know how outcomes related to 12-step attendance and participation generalize to individuals with non-alcohol substance use disorders (SUDs). Method A clinical trial of 12-step facilitation (N=471) focusing on individuals with cocaine or methamphetamine use disorders allowed examination of four questions: Q1) To what extent do treatment-seeking stimulant users use 12-step programs and, which ones? Q2) Do factors previously found to predict 12-step participation among those with alcohol use disorders also predict participation among stimulant users? Q3) What specific baseline “12-step readiness” factors predict subsequent 12-step participation and attendance? And Q4) Does stimulant drug of choice differentially predict 12-step participation and attendance? Results The four outcomes variables, Attendance, Speaking, Duties at 12-step meetings, and other peer recovery support Activities, were not related to baseline demographic or substance problem history or severity. Drug of choice was associated with differential days of Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) attendance among those who reported attending, and cocaine users reported more days of attending AA or NA at 1-, 3- and 6-month follow-ups than did methamphetamine users. Pre-randomization measures of Perceived Benefit of 12-step groups predicted 12-step Attendance at 3- and 6-month follow-ups. Pre-randomization 12-step Attendance significantly predicted number of other Self-Help Activities at end-of-treatment, 3- and 6-month follow-ups. Pre-randomization Perceived Benefit and problem severity both predicted number of Self-Help Activities at end-of-treatment and 3-month follow-up. Pre-randomization Perceived Barriers to 12-step groups were negatively associated with Self-Help Activities at end-of-treatment and 3-month follow

  15. Youth Recovery Contexts: The Incremental Effects of 12-Step Attendance and Involvement On Adolescent Outpatient Outcomes

    PubMed Central

    Kelly, John F.; Urbanoski, Karen

    2011-01-01

    Background A major barrier to youth recovery is finding suitable sobriety-supportive social contexts. National studies reveal most adolescent addiction treatment programs link youths to community 12-step fellowships to help meet this challenge, but little is known empirically regarding the extent to which adolescents attend and benefit from 12-step meetings or whether they derive additional gains from active involvement in prescribed 12-step activities (e.g., contact with a sponsor and other fellowship members). Greater knowledge in this area would enhance the efficiency of clinical continuing care recommendations. Methods Adolescent outpatients (N=127; M age 16.7; 75% male; 87% White) enrolled in a naturalistic study of treatment effectiveness were assessed at intake and 3, 6, and 12 months later using standardized assessments. Mixed-effects models, controlling for static and time-varying confounds, examined the concurrent and lagged effects of 12-step attendance and active involvement on abstinence over time. Results The proportion attending 12-step meetings was relatively low across follow-up (24–29%), but more frequent attendance was independently associated with greater abstinence in concurrent and, to a lesser extent, lagged models. An 8-item composite measure of 12-step involvement did not enhance outcomes over and above attendance, but separate components did; specifically, greater contact with a 12-step sponsor outside of meetings and more verbal participation during meetings. Conclusions The benefits of 12-step participation observed among adult samples extend to adolescent outpatients. Community 12-step fellowships appear to provide a useful sobriety-supportive social context for youth seeking recovery, but evidence-based youth-specific 12-step facilitation strategies are needed to enhance outpatient attendance rates. PMID:22509904

  16. Cultural points of resistance to the 12-Step recovery process.

    PubMed

    Smith, D E; Buxton, M E; Bilal, R; Seymour, R B

    1993-01-01

    This article addresses some of the key issues in developing culturally relevant approaches to drug abuse treatment and recovery, using the HAFC/Glide African-American Extended Family Program as a positive example of effective cultural adaptability within recovery. Cultural points of resistance to the recovery process are also addressed, including the perception that 12-Step fellowships are exclusive and confused with religion, confusion over surrender versus powerlessness, and concerns about low self-esteem, dysfunctional family structure, communication difficulties, and institutionalized and internalized racism. The authors also focus on professional resistance in other countries, where different treatment approaches and philosophies block the acceptance of a recovery concept in general and the 12-Step process in particular. In explicating these issues, addiction is presented as a multicultural problem in need of multicultural solutions. The challenge is to adapt the process of recovery to all cultures and races, to counter stereotypes on all sides, and to eliminate the perception that recovery only works for addicts from the White mainstream.

  17. Change in choroidal thickness after intravitreal aflibercept in pretreated and treatment-naive eyes for neovascular age-related macular degeneration

    PubMed Central

    Mazaraki, Kyriaki; Fassnacht-Riederle, Heidi; Blum, Robert; Becker, Matthias; Michels, Stephan

    2015-01-01

    Aim Evaluation of effects of intravitreal aflibercept therapy on choroidal thickness (CT) in neovascular age-related macular degeneration. Methods Retrospective cohort study evaluating the change in CT following a loading dose of three intravitreal aflibercept injections at 4 weeks interval. Pretreated and treatment-naive eyes as well as untreated fellow eyes were evaluated at five retinal locations (subfoveal, 300 and 2500 µm nasal and temporal to the fovea) using spectral domain optical coherence tomography prior to and 4 weeks after a loading dose of three intravitreal aflibercept injections. Results A total of 84 treated eyes (61 pretreated, 23 treatment naive) and 48 fellow eyes were enrolled into the study. Treatment-naive and pretreated eyes showed a significant reduction in CT at all retinal locations. The effect was more pronounced in treatment-naive eyes. In the pretreated group, the mean reduction in CT was greatest at 2500 µm temporal to the fovea at 10.7 µm compared with 22.4 at 300 µm nasal to the fovea in the treatment-naive group. Only the fellow eyes in the treatment-naive group showed a significant CT reduction 12 weeks after initiation of therapy to the partner eye. Conclusions Aflibercept induces a reduction in CT in treatment-naive and pretreated eyes with neovascular age-related macular degeneration. There is some evidence of a systemic effect of aflibercept reflected by CT reduction in untreated fellow eyes. PMID:25877895

  18. Cost effectiveness of darunavir/ritonavir combination antiretroviral therapy for treatment-naive adults with HIV-1 infection in Canada.

    PubMed

    Brogan, Anita J; Smets, Erik; Mauskopf, Josephine A; Manuel, Sarah A L; Adriaenssen, Ines

    2014-09-01

    The AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) clinical trial examined the efficacy and safety of two ritonavir-boosted protease inhibitors (PI/r), darunavir/r 800/100 mg once daily (QD) and lopinavir/r 800/200 mg daily, both used in combination with tenofovir disoproxil fumarate/emtricitabine. This study aimed to assess the cost effectiveness of the darunavir/r regimen compared with the lopinavir/r regimen in treatment-naive adults with HIV-1 infection in Canada. A Markov model with a 3-month cycle time and six CD4 cell-count-based health states (>500, 351-500, 201-500, 101-200, 51-100, and 0-50 cells/mm(3)) followed a cohort of treatment-naive adults with HIV-1 infection through initial darunavir/r or lopinavir/r combination therapy and a common set of subsequent regimens over the course of their remaining lifetimes. Population characteristics and transition probabilities were estimated from the ARTEMIS clinical trial and other trials. Costs (in 2014 Canadian dollars), utilities, and mortality were estimated from Canadian sources and published literature. Costs and health outcomes were discounted at 5% per year. One-way and probabilistic sensitivity analyses were performed, including a simple indirect comparison of the darunavir/r initial regimen with an atazanavir/r-based regimen. In the base-case lifetime analysis, individuals receiving initial therapy with the darunavir/r regimen experienced 0.25 more quality-adjusted life-years (QALYs) with lower antiretroviral drug costs (-$14,246) and total costs (-$18,402) than individuals receiving the lopinavir/r regimen, indicating that darunavir/r dominated lopinavir/r. In an indirect comparison with an atazanavir/r-based regimen, the darunavir/r regimen remained the dominant choice, but with lower cost savings (-$2,303) and QALY gains (0.02). Results were robust to a wide range of other changes in input parameter values, population characteristics, and modeling assumptions. The

  19. DETECTION OF TREATMENT-NAIVE CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION BY SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

    PubMed

    Ahmed, Daniel; Stattin, Martin; Graf, Alexandra; Forster, Julia; Glittenberg, Carl; Krebs, Ilse; Ansari-Shahrezaei, Siamak

    2017-09-04

    To compare the detection rate of choroidal neovascularization (CNV) in treatment-naive neovascular age-related macular degeneration by swept source optical coherence tomography angiography (SS-OCTA, Topcon's DRI Triton) working at 1,050 nm wavelength versus fluorescence angiography. Cross-sectional analysis of 156 eyes (107 neovascular age-related macular degeneration and 49 dry AMD) in 98 patients, previously diagnosed by multimodal imaging using fluorescein (FA) and indocyanine green angiography (Heidelberg's Spectralis) in a tertiary retina center, evaluated by SS-OCTA 4.5 mm × 4.5 mm and 6 mm × 6 mm macular cubes. Main outcome measures were sensitivity and specificity of SS-OCTA in AMD. Potential factors influencing CNV detection rate were analyzed. Swept source optical coherence tomography angiography detected CNV in 81 of 107 eyes, resulting in a sensitivity of 75.7%. In 49 eyes with dry AMD, no CNV could be identified (specificity 100%). A statistical significance was calculated for nondetection of treatment-naive CNV by SS-OCTA in pigment epithelial detachment over 400 μm (P = 0.0238). Topcon's SS-OCTA was not able to detect all CNV lesions. Large pigment epithelial detachments were associated with signal loss. Fluorescence angiography still remains the gold standard, but the tested SS-OCTA device can be considered as a feasible additional diagnostic tool in AMD.

  20. Secondary effects of antipsychotic treatment in naive or quasi-naive children and adolescents: design of a follow-up protocol and baseline results.

    PubMed

    Merchán-Naranjo, Jessica; Tapia, Cecilia; Bailón, Concha; Moreno, Carmen; Baeza, Inmaculada; Calvo-Escalona, Rosa; Morer, Astrid; Martínez-Cantarero, Carmen; Nestares, Patricia Andrés; Alda, José Ángel; Muñoz, Daniel; Arango, Celso

    2012-01-01

    The prescribing of anti-psychotic drugs has become a normal clinical practice. This article presents a longitudinal, multicentre study of 12 months conducted on 266 children and adolescents who were prescribed a first or second generation antipsychotic drug for the first time, and the baseline results of the study. The follow-up protocol had as its purpose to detect the possible appearance of metabolic, cardiological, and motor changes. When the presence of side effects was evaluated using the UKU (clinical side-effects scale) statistically significant differences were found between naive (patients who had never taken an anti-psychotic drug) and quasi-naive patients (those who have taken anti-psychotic drugs for a period of less than 30 days), with a greater number of the latter showing symptoms of: anxiety/laxity/tiredness (P=.0049), drowsiness/sedation (P<.001), increase in dream duration (P<.001), increase in dreams (P=.0199), emotional indifference (P=.0194), hypokinesia/akinesia (P=.0224), paresthesias (P=.0049), accommodation disorder (P=.0254), increase in salivation (P<.001), polyuria/polydipsia (P=.0076), increase in sweating (P=.0076), increase in sexual desire (P=.0117), decrease in sexual desire (P=.0053), tension headaches (P=.0405). When the presence of extrapyramidal symptoms was assessed using the MPRC-IMS (Maryland Psychiatry Research Center-Involuntary Movements) Scale, it was observed that the quasi-naïve patients had a statistically higher number of dyskinesia (P=.002), Parkinsonism (P=.0004) and akathisia (P=.0437) symptoms compared to the naïve patients. These results show that, in the childhood-adolescent population, the presence of secondary effects begins to be observed from the first dose of the antipsychotic drug. Copyright © 2011 SEP y SEPB. Published by Elsevier España, S.L. All rights reserved.

  1. The importance of age composition of 12-step meetings as a moderating factor in the relation between young adults' 12-step participation and abstinence.

    PubMed

    Labbe, Allison K; Greene, Claire; Bergman, Brandon G; Hoeppner, Bettina; Kelly, John F

    2013-12-01

    Participation in 12-step mutual help organizations (MHO) is a common continuing care recommendation for adults; however, little is known about the effects of MHO participation among young adults (i.e., ages 18-25 years) for whom the typically older age composition at meetings may serve as a barrier to engagement and benefits. This study examined whether the age composition of 12-step meetings moderated the recovery benefits derived from attending MHOs. Young adults (n=302; 18-24 years; 26% female; 94% White) enrolled in a naturalistic study of residential treatment effectiveness were assessed at intake, and 3, 6, and 12 months later on 12-step attendance, age composition of attended 12-step groups, and treatment outcome (Percent Days Abstinent [PDA]). Hierarchical linear models (HLM) tested the moderating effect of age composition on PDA concurrently and in lagged models controlling for confounds. A significant three-way interaction between attendance, age composition, and time was detected in the concurrent (p=0.002), but not lagged, model (b=0.38, p=0.46). Specifically, a similar age composition was helpful early post-treatment among low 12-step attendees, but became detrimental over time. Treatment and other referral agencies might enhance the likelihood of successful remission and recovery among young adults by locating and initially linking such individuals to age appropriate groups. Once engaged, however, it may be prudent to encourage gradual integration into the broader mixed-age range of 12-step meetings, wherein it is possible that older members may provide the depth and length of sober experience needed to carry young adults forward into long-term recovery. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Comparison of abacavir/lamivudine and tenofovir/emtricitabine among treatment-naive HIV-infected patients initiating therapy.

    PubMed

    Tan, Darrell H S; Chan, Keith; Raboud, Janet; Cooper, Curtis; Montaner, Julio S G; Walmsley, Sharon; Hogg, Robert S; Klein, Marina B; Machouf, Nima; Rourke, Sean B; Tsoukas, Chris; Loutfy, Mona R

    2011-09-01

    Controversy about the relative performance of abacavir (ABC)/lamivudine (3TC) and tenofovir (TDF)/emtricitabine (FTC) in initial combination antiretroviral therapy (cART) exists. We compared the times to regimen failure (composite of virologic failure or switching/stopping nucleosides for any reason) according to nucleoside backbone in treatment-naive patients starting cART in a retrospective observational cohort study. Additional endpoints included virologic failure, switching/stopping nucleosides for nonvirologic reasons, and virologic suppression. Treatment-naive noninjection drug user individuals in the Canadian Observational Cohort initiating ABC/3TC-containing or TDF/FTC-containing cART with efavirenz, nevirapine, lopinavir/ritonavir, or atazanavir/ritonavir with ≥6 months follow-up were included. Multivariable proportional hazards regression models accounting for competing risks were used to model outcomes. One thousand seven hundred sixty-four individuals (588 ABC/3TC, 1176 TDF/FTC) were included. Median (interquartile range) follow-up times were 34 (23-50) and 20 (13-30) months, respectively. Time to regimen failure was similar for ABC/3TC versus TDF/FTC [adjusted hazard ratio, (aHR) = 0.96, 95% CI = 0.80 to 1.17] after adjusting for baseline viral load (VL), sex, province, third antiretroviral agent, year of cART initiation, HLA-B*5701 test availability, and rate of VL testing. No differences were observed in time to virologic failure (aHR = 0.84, 95% CI = 0.58 to 1.20), switching/stopping nucleosides for nonvirologic reasons (aHR = 1.02, 95% CI = 0.81 to 1.28), or virologic suppression (aHR = 0.96, 95% CI = 0.83 to 1.10). There was no statistical interaction between backbone and baseline VL for any outcome. Results were similar when stratified by baseline VL ≤ 100,000 or > 100,000 copies per milliliter. In our naive noninjection drug user HIV-infected patients starting cART, there was no difference in time to regimen failure, virologic failure

  3. Finger Tapping-Related Activation Differences in Treatment-Naive Pediatric Tourette Syndrome: A Comparison of the Preferred and Nonpreferred Hand

    ERIC Educational Resources Information Center

    Roessner, Veit; Wittfoth, Matthias; August, Julia M.; Rothenberger, Aribert; Baudewig, Jurgen; Dechent, Peter

    2013-01-01

    Background: Disturbances of motor circuitry are commonly encountered in Tourette syndrome (TS). The aim of this study was to investigate simple motor performance differences between boys with TS and healthy controls. Methods: We attempted to provide insight into motor network alterations by studying a group of treatment-naive patients suffering…

  4. Finger Tapping-Related Activation Differences in Treatment-Naive Pediatric Tourette Syndrome: A Comparison of the Preferred and Nonpreferred Hand

    ERIC Educational Resources Information Center

    Roessner, Veit; Wittfoth, Matthias; August, Julia M.; Rothenberger, Aribert; Baudewig, Jurgen; Dechent, Peter

    2013-01-01

    Background: Disturbances of motor circuitry are commonly encountered in Tourette syndrome (TS). The aim of this study was to investigate simple motor performance differences between boys with TS and healthy controls. Methods: We attempted to provide insight into motor network alterations by studying a group of treatment-naive patients suffering…

  5. '12-Step' Strategy Boosts Success of Teen Drug Abuse Program

    MedlinePlus

    ... medlineplus.gov/news/fullstory_167650.html '12-Step' Strategy Boosts Success of Teen Drug Abuse Program Messages from recovering peers made an impact, study finds To use the sharing features on this ...

  6. Cost-effectiveness analysis of triple therapy with protease inhibitors in treatment-naive hepatitis C patients.

    PubMed

    Blázquez-Pérez, Antonio; San Miguel, Ramón; Mar, Javier

    2013-10-01

    Chronic hepatitis C is the leading cause of chronic liver disease, representing a significant burden in terms of morbidity, mortality and costs. A new scenario of therapy for hepatitis C virus (HCV) genotype 1 infection is being established with the approval of two effective HCV protease inhibitors (PIs) in combination with the standard of care (SOC), peginterferon and ribavirin. Our objective was to estimate the cost effectiveness of combination therapy with new PIs (boceprevir and telaprevir) plus peginterferon and ribavirin versus SOC in treatment-naive patients with HCV genotype 1 according to data obtained from clinical trials (CTs). A Markov model simulating chronic HCV progression was used to estimate disease treatment costs and effects over patients' lifetimes, in the Spanish national public healthcare system. The target population was treatment-naive patients with chronic HCV genotype 1, demographic characteristics for whom were obtained from the published pivotal CTs SPRINT and ADVANCE. Three options were analysed for each PI based on results from the two CTs: universal triple therapy, interleukin (IL)-28B-guided therapy and dual therapy with peginterferon and ribavirin. A univariate sensitivity analysis was performed to evaluate the uncertainty of certain parameters: age at start of treatment, transition probabilities, drug costs, CT efficacy results and a higher hazard ratio for all-cause mortality for patients with chronic HCV. Probabilistic sensitivity analyses were also carried out. Incremental cost-effectiveness ratios (ICERs) of €2012 per quality-adjusted life-year (QALY) gained were used as outcome measures. According to the base-case analysis, using dual therapy as the comparator, the alternative IL28B-guided therapy presents a more favorable ICER (€18,079/QALY for boceprevir and €25,914/QALY for telaprevir) than the universal triple therapy option (€27,594/QALY for boceprevir and €33,751/QALY for telaprevir), with an ICER clearly below

  7. Clozapine v. chlorpromazine in treatment-naive, first-episode schizophrenia: 9-year outcomes of a randomised clinical trial.

    PubMed

    Girgis, Ragy R; Phillips, Michael R; Li, Xiaodong; Li, Kejin; Jiang, Huiping; Wu, Chengjing; Duan, Naihua; Niu, Yajuan; Lieberman, Jeffrey A

    2011-10-01

    The differential effects of so-called 'first- and second generation' antipsychotic medications, when given in the first episode, on the long-term outcome of schizophrenia remain to be elucidated. We compared the 9-year outcomes of individuals initially randomised to clozapine or chlorpromazine. One-hundred and sixty individuals with treatment-naive, first episode schizophrenia or schizophreniform disorder in a mental health centre in Beijing, China were randomised to clozapine or chlorpromazine treatment for up to 2 years,followed by up to an additional 7 years of naturalistic treatment. The primary outcome was remission status for individuals in each group. Individuals in both groups spent essentially equal amounts of time in each clinical state over the follow-up time period(remission, 78%; intermediate, 8%; relapse, 14%). There were no significant differences on other measures of illness severity. The clozapine group was more likely than the chlorpromazine group to remain on the medication to which they were originally assigned (26% v. 10%, P = 0.01). There were no significant differences between the two groups on other secondary efficacy outcomes. These findings support the comparability in effectiveness between antipsychotic medications but with slightly greater tolerability of clozapine in the treatment of first-episode psychosis.

  8. Efficacy and safety of peginterferon alpha-2a/ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C.

    PubMed

    Njouom, Richard; Sartre, Michèle Tagni; Timba, Isabelle; Nerrienet, Eric; Tchendjou, Patrice; Pasquier, Christophe; Rousset, Dominique

    2008-12-01

    Data were examined from a day-to-day clinical practice in Yaounde, Cameroon to evaluate the efficacy and safety of peginterferon alfa-2a and ribavirin in treatment-naive Cameroonian patients with chronic hepatitis C. Ninety adults with chronic hepatitis C (mean age, 53 +/- 8 years; 79% males; 37.8% genotype 1; 23.3% genotype 2; and 38.9% genotype 4) were given at least 12 weeks of combination therapy between February 2003 and August 2007. Of these, 54 completed the treatment and the 24-week follow up. Subsequently, 18 continued treatment and 18 (20%) discontinued the treatment, 6 (6.7%) due to adverse effects. An intention-to-treat analysis showed that 38 (52.8%) had an end-of-treatment virologic response and 34 (47.2%) had a sustained virologic response. Sustained virologic response were significantly higher among patients with hepatitis C virus (HCV) genotype 2 (83.4%) than in those with genotype 1 (31%) or genotype 4 (42.3%) (P < 0.05). Non HCV-2 genotype, pretreatment fibrosis score >2, HCV RNA level >8.0 x 10(5) IU/ml and a non-virologic response at 12 weeks of treatment were associated with poor sustained virologic response (P < 0.05). Thus, HCV can be treated in a Sub-Saharan African country. It indicates that Cameroonian HCV-1 and -4 patients have a poorer sustained virologic response than the published results for Western and Middle-East countries. Virus subtype may influence the treatment outcome, since there is a great genetic diversity within Cameroonian HCV-1 and -4 genotypes.

  9. Prevalence of Intestinal Parasitic Infection among HIV Positive Persons Who Are Naive and on Antiretroviral Treatment in Hiwot Fana Specialized University Hospital, Eastern Ethiopia

    PubMed Central

    Teklemariam, Zelalem; Abate, Degu; Mitiku, Habtamu; Dessie, Yadeta

    2013-01-01

    Background. Intestinal parasitic infection affects the health and quality of life of people living with HIV. This study was aimed to determine the prevalence of intestinal parasites among HIV positive individuals who are naive and who are on antiretroviral treatment (ART) in Hiwot Fana Specialized University Hospital, Eastern Ethiopia. Methods. A comparative cross-sectional study was conducted on 371 (112 ART-naive group and 259 on ART) HIV positive individuals. Stool specimens were collected and examined by direct wet mount, formol ether concentration technique, and modified ziehl-Neelsen methods. Results. The overall prevalence of intestinal parasitic infections was 33.7%; it was significantly higher among the study participants who were ART-naive group (45.5%) (AOR: 2.60(1.56,4.34)) and diarrheic (53.3%) (AOR: 2.30(1.34,3.96)) and with CD4 count <200 cells/μL (46%) (AOR: 2.07(1.06,4.04)). The most commonly identified parasites were Entamoeba histolytica/E. dispar (13.5%), Giardia lamblia (8.1%), Strongyloides stercoralis (4.0%), and Cryptosporidium species (2.2%). Conclusion. HIV positive individuals with diarrhea and low CD4 count and ART naive groups were more infected with intestinal parasites than their counterparts. Early stool examination and treatment of intestinal parasites for HIV/AIDS patients is essential. PMID:24052888

  10. Resistance Analyses of Integrase Strand Transfer Inhibitors within Phase 3 Clinical Trials of Treatment-Naive Patients

    PubMed Central

    White, Kirsten L.; Raffi, Francois; Miller, Michael D.

    2014-01-01

    The integrase (IN) strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens has attained remarkably high levels, reaching undetectable viral loads in 90% of patients by Week 48; however, there remain patients who require a change in regimen due to adverse events, virologic failure with emergent resistance or other issues of patient management. Large, randomized clinical trials conducted in antiretroviral treatment-naive individuals are required for drug approval in this population in the US, EU and other countries, with the primary endpoint for virologic success at Week 48. However, there are differences in the definition of virologic failure and the evaluation of drug resistance among the trials. This review focuses on the methodology and tabulation of resistance to INSTIs in phase 3 clinical trials of first-line regimens and discusses case studies of resistance. PMID:25054884

  11. Cost-effectiveness of dolutegravir/abacavir/lamivudine in HIV-1 treatment-Naive (TN) patients in France.

    PubMed

    Pialoux, Gilles; Marcelin, Anne-Geneviève; Cawston, Hélène; Guilmet, Caroline; Finkielsztejn, Laurent; Laurisse, Audrey; Aubin, Céline

    2017-07-31

    To evaluate the cost-effectiveness of an integrase inhibitor (INI), dolutegravir (DTG), in combination with abacavir (ABC)/lamivudine (3TC) in France, in treatment-naive (TN) HIV adult patients. The ARAMIS microsimulation Markov model, evaluates costs and effects of DTG vs. first-line ARVs options including INIs (raltegravir, elvitegravir/c), protease inhibitors (PIs) (darunavir/r, atazanavir/r, lopinavir/r), non-nucleoside reverse transcriptase inhibitors (efavirenz and rilpivirine). Efficacy and safety data were derived from phase III studies and network meta-analysis. Treatment algorithms were based on French guidelines and experts opinion. Costs included routine HIV and opportunistic infection care, and death. The model showed the fixed-dose combination DTG/ABC/3TC was more effective than all other recommended regimens: patients stayed longer on first-line, and lived longer and healthier. With the exception of EFV, DTG/ABC/3TC was more efficacious and less costly compared to all strategies. The cost per QALY gained (ICER) for DTG compared to EFV was €6,939. DTG/ABC/3TC was more efficacious and less costly compared to INIs and PIs in all deterministic sensitivity analyses. DTG/ABC/3TC was cost-effective in the management of HIV TN patients in France. These results are mainly explained by its lower price compared to other INIs and PIs, DTG's superior efficacy and high barrier to resistance.

  12. HIV type 1 integrase polymorphisms in treatment-naive and treatment-experienced HIV type 1-infected patients in Thailand where HIV type 1 subtype A/E predominates.

    PubMed

    Phuphuakrat, Angsana; Pasomsub, Ekawat; Kiertiburanakul, Sasisopin; Chantratita, Wasun; Sungkanuparph, Somnuek

    2012-08-01

    Integrase inhibitor (INI) is a novel antiretroviral drug recommended for both treatment-naive and treatment-experienced HIV-1-infected patients. Limited data are available on INI resistance in Thailand, where HIV-1 subtype A/E predominates. We aimed to investigate INI resistance-associated mutations (RAMs) among treatment-naive patients and patients who experienced treatment failure with NNRTI-based or PI-based antiretroviral therapy (ART) in Thailand. One hundred and eight plasma samples of 58 treatment-naive and 50 treatment-experienced HIV-1-infected individuals were collected. The HIV-1 integrase coding region was sequenced. Polymorphisms were compared between subtype A/E and B circulating in Thailand and between treatment-naive and treatment-experienced groups. Resulting amino acids were interpreted for drug resistance according to Stanford algorithms. Ninety-seven samples were HIV-1 subtype A/E, 10 were subtype B, and one was subtype C. Age, gender, and CD4 cell counts were similar between treatment-naive and treatment-experienced groups, while the treatment-failure group showed a statistically significant longer awareness time of HIV-1 infection and lower viral load than the treatment-naive group. Major INI-RAM was not found in this study, but some minor INI-RAMs, such asV54I, L68I, L74M, T97A, and S230N, were found. Comparing INI-RAMs between subtype A/E and B, the prevalence of V54I and V72I was higher in subtype B than subtype E, while V201I was found in all sequences of subtype A/E. In subtype A/E, integrase polymorphisms were not different between treatment-naive and treatment-experienced groups. However, the number of amino acid substitutions was significantly higher in the treatment-experienced group (p=0.009). One NNRTI-based ART-treated patient was found to have potential low-level INI-RAMs. INI-RAMs are rare in both treatment-naive and treatment-experienced patients in Thailand. This suggested that INI should be active in patients who are naive to

  13. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials

    PubMed Central

    Raffi, François; Rachlis, Anita; Brinson, Cynthia; Arasteh, Keikawus; Górgolas, Miguel; Brennan, Clare; Pappa, Keith; Almond, Steve; Granier, Catherine; Nichols, W. Garrett; Cuffe, Robert Liam; Jr, Joseph Eron; Walmsley, Sharon

    2015-01-01

    Objectives: Dolutegravir (DTG) has been studied in three trials in HIV treatment-naive participants, showing noninferiority compared with raltegravir (RAL), and superiority compared with efavirenz and ritonavir-boosted darunavir. We explored factors that predicted treatment success, the consistency of observed treatment differences across subgroups and the impact of NRTI backbone on treatment outcome. Design: Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO. Methods: We examined the efficacy of DTG in HIV-infected participants with respect to relevant demographic and HIV-1-related baseline characteristics using the primary efficacy endpoint from the studies (FDA snapshot) and secondary endpoints that examine specific elements of treatment response. Regression models were used to analyze pooled data from all three studies. Results: Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4+ cell count, and HIV-1 RNA and by third agent. Differences between DTG and other third agents were generally consistent across these subgroups. There was no evidence of a difference in snapshot response between abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) overall [ABC/3TC 86%, TDF/FTC 85%, difference 1.1%, confidence interval (CI) −1.8, 4.0 percentage points, P = 0.61] or at high viral loads (difference −2.5, 95% CI −8.9, 3.8 percentage points, P = 0.42). Conclusions: DTG is a once-daily, unboosted integrase inhibitor that is effective in combination with either ABC/3TC or TDF/FTC for first-line antiretroviral therapy in HIV-positive individuals with a variety of baseline characteristics. PMID:25387312

  14. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naive HIV-infected individuals in three randomized trials.

    PubMed

    Raffi, François; Rachlis, Anita; Brinson, Cynthia; Arasteh, Keikawus; Górgolas, Miguel; Brennan, Clare; Pappa, Keith; Almond, Steve; Granier, Catherine; Nichols, W Garrett; Cuffe, Robert Liam; Eron, Joseph; Walmsley, Sharon

    2015-01-14

    Dolutegravir (DTG) has been studied in three trials in HIV treatment-naive participants, showing noninferiority compared with raltegravir (RAL), and superiority compared with efavirenz and ritonavir-boosted darunavir. We explored factors that predicted treatment success, the consistency of observed treatment differences across subgroups and the impact of NRTI backbone on treatment outcome. Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO. We examined the efficacy of DTG in HIV-infected participants with respect to relevant demographic and HIV-1-related baseline characteristics using the primary efficacy endpoint from the studies (FDA snapshot) and secondary endpoints that examine specific elements of treatment response. Regression models were used to analyze pooled data from all three studies. Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4⁺ cell count, and HIV-1 RNA and by third agent. Differences between DTG and other third agents were generally consistent across these subgroups. There was no evidence of a difference in snapshot response between abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) overall [ABC/3TC 86%, TDF/FTC 85%, difference 1.1%, confidence interval (CI) -1.8, 4.0 percentage points, P = 0.61] or at high viral loads (difference -2.5, 95% CI -8.9, 3.8 percentage points, P = 0.42). DTG is a once-daily, unboosted integrase inhibitor that is effective in combination with either ABC/3TC or TDF/FTC for first-line antiretroviral therapy in HIV-positive individuals with a variety of baseline characteristics.

  15. Development of a Prognostic Naive Bayesian Classifier for Successful Treatment of Nonunions

    DTIC Science & Technology

    2011-01-25

    Benjamin Kyle Potter, John Eberhardt, Scott B. Shawen, Romney C. Andersen, Treatment of Nonunions Development of a Prognostic Naïve Bayesian...Prognostic Naı̈ve Bayesian Classifier for Successful Treatment of Nonunions By Alexander Stojadinovic, MD, Benjamin Kyle Potter, MD, John Eberhardt...amedd.army.mil John Eberhardt, BA Clay Shwery, MS DecisionQ Corporation, 1010 Wisconsin Avenue, N.W., Suite 310, Washington, DC 20007 Scott B. Shawen, MD

  16. Human immunodeficiency virus type 1 gp 41 mutations in proviral DNA among antiretroviral treatment-naive individuals from India.

    PubMed

    Sen, Sourav; Tripathy, S P; Sahni, A K; Gupta, R M; Kapila, K; Chopra, G S; Chimanpure, Vaishali M; Patil, Ajit A; Paranjape, R S

    2009-05-01

    The HIV-1 gp41 has been identified as an important target for the immune response, for the development of antiviral and vaccine strategies, and for epidemiologic studies. This study describes the HIV-1 env gp41 region mutations, associated with enfuvirtide (ENF) resistance, in proviral DNA from PBMCs in antiretroviral treatment-naive individuals from Pune, India. Twenty-one antiretroviral drug-naive chronically HIV-1-infected individuals were enrolled. The study sequences belonged to subtype C (n = 17), subtype A1 (n = 2), and CRF_AE (n = 2). In subtype B-infected individuals, the various HR1 region substitutions in env gp41 that have been associated with ENF resistance include A30V, L33S/T/V, L34M, G36D/E/S/V, I37T/K/V, V38A/M/E/G, Q39R, Q40H, N42T/D, N43D/K/S, L44M, L45M, R46M, L54M, and Q56K/R as well as N126K and S138A in the HR2 region. The study sequences did not reveal any ENF resistance-associated mutations at env gp41 amino acid positions: 36 to 45. The presence of L54M and Q56K in combination is associated with 5-fold reduced sensitivity to inhibition by ENF. The mutation L54M was seen in seven subtype C and two CRF_AE study sequences. Q56K was observed in a subtype A1 sequence. All the study sequences harbored N42S, a natural polymorphism associated with increased susceptibility to ENF. Of the mutations V38A and N140I, known to provide immunologic gain, the latter was observed in four subtype C sequences. This is the first study from India highlighting the presence of certain mutations in Indian subtype C env gp41, which may play a role in the evolution of subtype-specific variations in the resistance to ENF and associated immune response.

  17. Picturing neuroscience research through a human rights lens: Imaging first-episode schizophrenic treatment-naive individuals

    PubMed Central

    Eijkholt, Marleen; Anderson, James A.; Illes, Judy

    2012-01-01

    In this paper we examine imaging research involving first-episode schizophrenic treatment-naive individuals (FESTNIs) through a legal human rights lens; in particular, the lens of the Additional Protocol to the Convention on Human Rights and Biomedicine Concerning Biomedical Research. We identify a number of ethical and legal hot spots highlighted by the Protocol, and offer a series of recommendations designed to ensure the human rights compatibility of this research. Subsequently, we argue that the lack of reporting on design elements related to ethical concerns frustrates commitments at the heart of the human rights approach, namely, transparency and openness to international scrutiny. To redress this problem, we introduce two norms for the first time: ethical transparency, and ethical reproducibility. When concluding, we offer a set of reporting guidelines designed to operationalize these norms in the context of imaging research involving FESTNIs. Though we will not make this case here, we believe that parallel reporting guidelines should be incorporated into other areas of research involving human subjects. PMID:22304987

  18. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.

    PubMed

    Scholz, Alexander; Harter, Patrick N; Cremer, Sebastian; Yalcin, Burak H; Gurnik, Stefanie; Yamaji, Maiko; Di Tacchio, Mariangela; Sommer, Kathleen; Baumgarten, Peter; Bähr, Oliver; Steinbach, Joachim P; Trojan, Jörg; Glas, Martin; Herrlinger, Ulrich; Krex, Dietmar; Meinhardt, Matthias; Weyerbrock, Astrid; Timmer, Marco; Goldbrunner, Roland; Deckert, Martina; Braun, Christian; Schittenhelm, Jens; Frueh, Jochen T; Ullrich, Evelyn; Mittelbronn, Michel; Plate, Karl H; Reiss, Yvonne

    2016-01-01

    Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti-angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin-2 (Ang-2) as a potential target in both naive and bevacizumab-treated glioblastoma. Ang-2 expression was absent in normal human brain endothelium, while the highest Ang-2 levels were observed in bevacizumab-treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang-2, whereas the combined inhibition of VEGF and Ang-2 leads to extended survival, decreased vascular permeability, depletion of tumor-associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206(+) (M2-like) macrophages were identified as potential novel targets following anti-angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang-2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang-2 may potentially overcome resistance to bevacizumab therapy.

  19. Brain Gray Matter Abnormalities in First-Episode, Treatment-Naive Children with Obsessive-Compulsive Disorder

    PubMed Central

    Cheng, Bochao; Cai, Wu; Wang, Xiuli; Lei, Du; Guo, Yingkun; Yang, Xun; Wu, Qizhu; Gong, Jianping; Gong, Qiyong; Ning, Gang

    2016-01-01

    Although several magnetic resonance imaging (MRI) studies have been conducted in children with obsessive-compulsive disorder (OCD), the brain structural abnormalities in OCD, especially in children, are not yet well characterized. We aimed to identify gray matter (GM) abnormalities in the early stage of pediatric OCD and examine the relationship between these structural abnormalities with clinical characteristics. Examinations of 30 first-episode, treatment-naive pediatric OCD patients without any comorbidities and 30 matched healthy controls (HCs) were performed with 3.0 T magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) following Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) was used to conduct voxel-wise tests for group differences in regional gray matter volume (GMV). Compared to HCs, the patient group exhibited more GMV in the bilateral putamen and left orbitofrontal cortex (OFC) and less GMV in the left inferior parietal lobule (IPL). The GMV alternation in the right putamen of OCD patients was positively correlated with Hamilton Anxiety Rating Scale (HAM-A) scores, while the GMV alternation in the left IPL exhibited a trend to negatively correlate with HAM-A scores. Our current results suggest that the GM abnormalities were defined in the early stage of pediatric OCD. Moreover, these findings provided further evidence of brain GM abnormalities that are not only present in the classical fronto–striatal–thalamic circuit but also in the default mode network (DMN), which may represent the interaction of abnormally functional organization of both network in pediatric OCD. PMID:27445736

  20. Reduced white matter integrity and its correlation with clinical symptom in first-episode, treatment-naive generalized anxiety disorder.

    PubMed

    Wang, Wei; Qian, Shaowen; Liu, Kai; Li, Bo; Li, Min; Xin, Kuolin; Sun, Gang

    2016-11-01

    The purpose of this study was to explore white matter microstructural alterations in the patients with generalized anxiety disorder (GAD) using diffusion tensor imaging (DTI) technique, and to assess neural associations with the symptom severity. Twenty-eight first-episode, treatment-naive GAD patients without co-morbidities and 28 matched healthy controls underwent DTI acquisition and clinical symptom assessments. Tract-based spatial statistics (TBSS) was used to analyze white matter microstructural abnormalities in patients with GAD, as well as their associations with clinical symptom scores in a voxel-wise manner. Compared to controls, patients showed decreased fractional anisotropy (FA) values in 7 clusters of white matter in bilateral uncinate fasciculus, body of corpus callosum, left middle cingulum (cingulate gyrus), bilateral anterior thalamic radiation and corona radiate, right anterior limb of internal capsule, bilateral inferior frontal-occipital fasciculus, bilateral superior and inferior longitudinal fasciculus, and increased mean diffusivity and radial diffusivity in widespread white matter regions. Reduced FA values in right uncinate fasciculus, left cingulum bundle showed significantly negative correlations with clinical symptom severity for Hamilton anxiety Rating Scale scores. Our findings suggest microstructural abnormalities in uncinate fasciculus and cingulum bundle play key roles in the underlying neural basis of GAD.

  1. Interferon γ-induced protein 10 kinetics in treatment-naive versus treatment-experienced patients receiving interferon-free therapy for hepatitis C virus infection: implications for the innate immune response.

    PubMed

    Lin, Jennifer C; Habersetzer, François; Rodriguez-Torres, Maribel; Afdhal, Nezam; Lawitz, Eric J; Paulson, Matthew S; Zhu, Yanni; Subramanian, Gangadharan Mani; McHutchison, John G; Sulkowski, Mark; Wyles, David L; Schooley, Robert T

    2014-12-15

    We measured interferon γ-induced protein 10 (IP-10) levels in 428 patients at baseline, week 1, and week 2 of all-oral treatment for hepatitis C virus (HCV) infection. An increased baseline IP-10 level was associated with a T allele in the IL28B gene, an increased alanine aminotransferase level in treatment-naive but not experienced patients, and an increased body mass index. At week 1, the mean decline in plasma IP-10 levels was the same in treatment-naive and treatment-experienced patients (-49%), whereas during week 2 the mean decline in IP-10 levels in treatment-naive patients (-14%) was significantly larger than in treatment-experienced patients (-2%; P = .0176). IP-10 thus may be a surrogate marker of the rate of intracellular viral replication complex decay.

  2. Long-term efficacy of imepitoin in the treatment of naive dogs affected by idiopathic epilepsy.

    PubMed

    Gallucci, A; Gagliardo, T; Menchetti, M; Bianchi, E; Bucci, D; Gandini, G

    2017-08-05

    The purpose of this study was to evaluate the long-term (12 months) efficacy and tolerability of imepitoin as first-choice treatment in 56 dogs suffering from idiopathic epilepsy and identify possible factors affecting the outcome. Primary treatment success (PTS) was defined as the achievement of a seizure-free interval three times longer than the pretreatment interictal interval (at least three months). Secondary treatment success (STS) was achieved by a decrease in seizure frequency ≥50 per cent compared with the pretreatment frequency. In the long-term follow-up, PTS was recorded in 14 (25 per cent) dogs and responder-dogs (PTS+STS) were 30 (54 per cent) showing significant reduction in the monthly average number of seizures (P<0.001). Median seizure frequency per month was 1.69 pretreatment and 0.3 at 12-month follow-up. Dogs with cluster seizures were significantly reduced (P=0.02). PTS at three and six months was associated with PTS (P=0.006 and <0.001, respectively) and with the status of responder dogs (P=0.002) at 12-month follow-up. Dogs aged >36 months at the start of imepitoin treatment had a positive association to become responder dogs (P<0.001) and achieve PTS (P=0.004). 16 dogs (29 per cent) discontinued imepitoin due to its inefficacy. The receiver operator curve highlighted ≥19 mg/kg twice a day as the most effective minimal dosage. Mild and transient side effects were observed in 16 dogs (29 per cent). British Veterinary Association.

  3. Development of a prognostic naive bayesian classifier for successful treatment of nonunions.

    PubMed

    Stojadinovic, Alexander; Kyle Potter, Benjamin; Eberhardt, John; Shawen, Scott B; Andersen, Romney C; Forsberg, Jonathan A; Shwery, Clay; Ester, Eric A; Schaden, Wolfgang

    2011-01-19

    predictive models permitting individualized prognostication for patients with fracture nonunion are lacking. The objective of this study was to train, test, and cross-validate a Bayesian classifier for predicting fracture-nonunion healing in a population treated with extracorporeal shock wave therapy. prospectively collected data from 349 patients with delayed fracture union or a nonunion were utilized to develop a naïve Bayesian belief network model to estimate site-specific fracture-nonunion healing in patients treated with extracorporeal shock wave therapy. Receiver operating characteristic curve analysis and tenfold cross-validation of the model were used to determine the clinical utility of the approach. predictors of fracture-healing at six months following shock wave treatment were the time between the fracture and the first shock wave treatment, the time between the fracture and the surgery, intramedullary stabilization, the number of bone-grafting procedures, the number of extracorporeal shock wave therapy treatments, work-related injury, and the bone involved (p < 0.05 for all comparisons). These variables were all included in the naïve Bayesian belief network model. a clinically relevant Bayesian classifier was developed to predict the outcome after extracorporeal shock wave therapy for fracture nonunions. The time to treatment and the anatomic site of the fracture nonunion significantly impacted healing outcomes. Although this study population was restricted to patients treated with shock wave therapy, Bayesian-derived predictive models may be developed for application to other fracture populations at risk for nonunion. prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

  4. Incidence of HIV-1 drug resistance among antiretroviral treatment-naive individuals starting modern therapy combinations.

    PubMed

    von Wyl, Viktor; Yerly, Sabine; Böni, Jürg; Shah, Cyril; Cellerai, Cristina; Klimkait, Thomas; Battegay, Manuel; Bernasconi, Enos; Cavassini, Matthias; Furrer, Hansjakob; Hirschel, Bernard; Vernazza, Pietro L; Ledergerber, Bruno; Günthard, Huldrych F

    2012-01-01

    Estimates of drug resistance incidence to modern first-line combination antiretroviral therapies against human immunodeficiency virus (HIV) type 1 are complicated by limited availability of genotypic drug resistance tests (GRTs) and uncertain timing of resistance emergence. Five first-line combinations were studied (all paired with lamivudine or emtricitabine): efavirenz (EFV) plus zidovudine (AZT) (n = 524); EFV plus tenofovir (TDF) (n = 615); lopinavir (LPV) plus AZT (n = 573); LPV plus TDF (n = 301); and ritonavir-boosted atazanavir (ATZ/r) plus TDF (n = 250). Virological treatment outcomes were classified into 3 risk strata for emergence of resistance, based on whether undetectable HIV RNA levels were maintained during therapy and, if not, whether viral loads were >500 copies/mL during treatment. Probabilities for presence of resistance mutations were estimated from GRTs (n = 2876) according to risk stratum and therapy received at time of testing. On the basis of these data, events of resistance emergence were imputed for each individual and were assessed using survival analysis. Imputation was repeated 100 times, and results were summarized by median values (2.5th-97.5th percentile range). Six years after treatment initiation, EFV plus AZT showed the highest cumulative resistance incidence (16%) of all regimens (<11%). Confounder-adjusted Cox regression confirmed that first-line EFV plus AZT (reference) was associated with a higher median hazard for resistance emergence, compared with other treatments: EFV plus TDF (hazard ratio [HR], 0.57; range, 0.42-0.76), LPV plus AZT (HR, 0.63; range, 0.45-0.89), LPV plus TDF (HR, 0.55; range, 0.33-0.83), ATZ/r plus TDF (HR, 0.43; range, 0.17-0.83). Two-thirds of resistance events were associated with detectable HIV RNA level ≤500 copies/mL during treatment, and only one-third with virological failure (HIV RNA level, >500 copies/mL). The inclusion of TDF instead of AZT and ATZ/r was correlated with lower rates of

  5. Enhancing the Referral-Making Process to 12-Step Programs: Strategies for Social Workers

    ERIC Educational Resources Information Center

    Dennis, Cory B.; Davis, Thomas D.

    2017-01-01

    Objectives: This study examines three preparatory strategies that can be used during treatment sessions to bridge the gap between clinician recommendations for client participation in 12-step programs (TSPs) and client adherence to such recommendations. Methods: A sample of 284 clinicians completed an online survey. Clinicians responded to items…

  6. Functional characterization and multimodal imaging of treatment-naive "quiescent" choroidal neovascularization.

    PubMed

    Querques, Giuseppe; Srour, Mayer; Massamba, Nathalie; Georges, Anouk; Ben Moussa, Naima; Rafaeli, Omer; Souied, Eric H

    2013-10-21

    To investigate the multimodal morphological and functional characteristics of treatment-naïve "quiescent" choroidal neovascularization (CNV) secondary to AMD. Eleven patients with treatment-naïve "quiescent" CNV that consecutively presented over a 6-month period, underwent multimodal morphological and functional assessment (including indocyanine green angiography [ICGA], spectral-domain optical coherence tomography [SD-OCT], microperimetry, and preferential hyperacuity perimeter [PHP]). For the purpose of this study, asymptomatic previously untreated CNVs showing absence of intraretinal/subretinal exudation in two consecutive visits (at least 6 months apart) were defined as treatment-naïve "quiescent" CNV. Eleven eyes of 11 patients (9 females; mean age 76.5 ± 8.5 years) were included. On fluorescein angiography (FA), "quiescent" CNVs appeared as late speckled hyperfluorescent lesions lacking well-demarcated borders. Mid-late phase ICGA allowed visualizing the hyperfluorescent "quiescent" CNV network and delineating the plaque. Mean lesion area (mid-late phase ICGA) appeared larger compared with earliest previous examination performed 23.8 ± 16.0 months before (3.24 ± 2.51 mm(2) vs. 3.52 ± 2.46 mm(2), respectively; P = 0.01). SD-OCT revealed, at the site of "quiescent" CNV, an irregularly slightly elevated RPE, without hyporeflective intraretinal/subretinal fluid, showing a major axis in the horizontal plane, which was characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane. Hypergeometric distribution revealed a significant correlation between microperimetry and PHP with respect to locations of "affected areas" (P = 0.001). "Quiescent" CNVs are sub-RPE CNVs secondary to AMD, showing absence of intraretinal/subretinal exudation on repeated OCT. "Quiescent" CNVs enlarge over time and may contribute to local reduced retinal sensitivity and metamorphopsia.

  7. The treatment-naive microbiome in new-onset Crohn's disease.

    PubMed

    Gevers, Dirk; Kugathasan, Subra; Denson, Lee A; Vázquez-Baeza, Yoshiki; Van Treuren, Will; Ren, Boyu; Schwager, Emma; Knights, Dan; Song, Se Jin; Yassour, Moran; Morgan, Xochitl C; Kostic, Aleksandar D; Luo, Chengwei; González, Antonio; McDonald, Daniel; Haberman, Yael; Walters, Thomas; Baker, Susan; Rosh, Joel; Stephens, Michael; Heyman, Melvin; Markowitz, James; Baldassano, Robert; Griffiths, Anne; Sylvester, Francisco; Mack, David; Kim, Sandra; Crandall, Wallace; Hyams, Jeffrey; Huttenhower, Curtis; Knight, Rob; Xavier, Ramnik J

    2014-03-12

    Inflammatory bowel diseases (IBDs), including Crohn's disease (CD), are genetically linked to host pathways that implicate an underlying role for aberrant immune responses to intestinal microbiota. However, patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies. Using samples from multiple gastrointestinal locations collected prior to treatment in new-onset cases, we studied the microbiome in the largest pediatric CD cohort to date. An axis defined by an increased abundance in bacteria which include Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with disease status. Microbiome comparison between CD patients with and without antibiotic exposure indicates that antibiotic use amplifies the microbial dysbiosis associated with CD. Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal-associated microbiome offers unique potential for convenient and early diagnosis of CD.

  8. Step by Step: Avoiding Spiritual Bypass in 12-Step Work

    ERIC Educational Resources Information Center

    Cashwell, Craig S.; Clarke, Philip B.; Graves, Elizabeth G.

    2009-01-01

    With spirituality as a cornerstone, 12-step groups serve a vital role in the recovery community. It is important for counselors to be mindful, however, of the potential for clients to be in spiritual bypass, which likely will undermine the recovery process.

  9. Real-world outcomes of ledipasvir/sofosbuvir in treatment-naive patients with hepatitis C.

    PubMed

    Younossi, Zobair M; Park, Haesuk; Gordon, Staurt C; Ferguson, John R; Ahmed, Aijaz; Dieterich, Douglas; Saab, Sammy

    2016-05-01

    Studies of hepatitis C virus (HCV) regimens have documented substantially reduced effectiveness in sustained virologic response (SVR) in the context of real-world clinical practice compared with clinical trials. Real-world and clinical trial SVR and cost-per-SVR data have not been reported for the all-oral, peginterferon-free and ribavirin (RBV)-free ledipasvir/sofosbuvir (LDV/SOF) regimen. Our objective was to compare the rates of SVR achievement and cost per SVR between pooled data from clinical studies of LDV/SOF and from real-world clinical practice. Data were derived from the Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET), a real-world, multicenter, prospective, observational study; and from the TRIO Network, a retrospective database of HCV-treated patients. The 1-year cost per SVR was calculated as the total cost of an SVR ([cost of treatment regimen, adverse events, and monitoring costs] per SVR) during the first year of treatment. After 12 weeks, the SVR rates obtained in real-world studies ranged from 94% to 98%, comparing favorably with the SVRs achieved in the ION-1 and ION-3 trials (94% and 95%-99% with 8 and 12 weeks of RBV-free therapy, respectively). A single SVR, on average, cost $84,989 among patients enrolled in the ION-3 trial, with higher costs ($101,204) among patients with compensated cirrhosis compared with noncirrhotic patients ($81,668). In the pooled TARGET/TRIO population, the average cost of an SVR was $84,770, with costs of $101,380 and $81,368 in patients with compensated cirrhosis and patients without cirrhosis, respectively. Unlike the results obtained with prior HCV regimens, this study suggests that similar SVR rates are achieved with LDV/SOF in clinical trial-based studies and real-world studies. Further, achieving an SVR in real-world clinical practice was not associated with excess costs.

  10. Characteristics of Transmitted Drug-Resistant HIV-1 in Recently Infected Treatment-Naive Patients in Japan.

    PubMed

    Hattori, Junko; Shiino, Teiichiro; Gatanaga, Hiroyuki; Mori, Haruyo; Minami, Rumi; Uchida, Kazue; Sadamasu, Kenji; Kondo, Makiko; Sugiura, Wataru

    2016-04-01

    Progress in antiretroviral treatment has led to fewer virological failure cases, but 10%-20% of treatment-naive HIV/AIDS cases are reported to harbor drug-resistant strains, suggesting transmission of drug-resistant HIV. We aimed to determine the trend in prevalence of transmitted drug-resistant (TDR) HIV in Japan, particularly in recently infected patients. Drug-resistance test was performed on 3904 HIV-1-infected cases newly diagnosed between 2007 and 2012. The number of cases infected within 6 months [recent seroconverters (RS)] was estimated by BED assay of 2700 plasma samples. Characteristics of RS cases were further analyzed. The overall prevalence of TDR was 9.1%, ranging from 7.3% in 2008% to 12.5% in 2010. Among 1403 subtype B/E/D cases with >50 CD4 T cell counts and >1000 HIV copies per milliliter, 468 (33.4%) were estimated to be RS. The prevalence of RS was significantly higher among cases who were male, Japanese, and men who have sex with men. The prevalence of TDR did not differ significantly between recent and long-term seroconverters (8.5% vs. 9.2%, respectively, P = 0.68). Common mutations in both groups were M46I/L and T215 revertants. Furthermore, sequences with these mutations, K103N and D30N/N88D formed clusters on phylogenetic trees. Our study clarified an increase in prevalence of TDR in Japan from 2007 to 2012. The phylogenetic clustering of cases with M46I/L or T215 revertants suggests that HIV with these mutations have become circulating strains. Furthermore, detailed analyses showed that Japanese men who have sex with men are more aware of their risk of HIV infection.

  11. Stimulant Abuser Groups to Engage in 12-Step (STAGE-12): A Multisite Trial in the NIDA Clinical Trials Network

    PubMed Central

    Donovan, Dennis M.; Daley, Dennis C.; Brigham, Gregory S.; Hodgkins, Candace C.; Perl, Harold I.; Garrett, Sharon; Doyle, Suzanne; Floyd, Anthony S.; Knox, Patricia C.; Botero, Christopher; Kelly, Thomas; Killeen, Therese; Hayes, Carole; Baumhofer, Nicole Kau’i; Seamans, Cindy; Zammarelli, Lucy

    2012-01-01

    Aims The study evaluated the effectiveness of an 8-week combined group plus individual 12-step facilitative intervention on stimulant drug use and 12-step meeting attendance and service. Design Multisite randomized controlled trial, with assessments at baseline, mid-treatment, end of treatment, and 3- and 6-month post-randomization follow-ups (FU). Setting Intensive outpatient substance treatment programs. Participants Individuals with stimulant use disorders (n = 471) randomly assigned to treatment as usual (TAU) or TAU into which the STAGE-12 intervention was integrated. Measurements Urinalysis and self-reports of substance use and 12-step attendance and activities. Intervention Group sessions focused on increasing acceptance of 12-step principles; individual sessions incorporated an intensive referral procedure connecting participants to 12-step volunteers. Findings Compared to TAU, STAGE-12 participants had significantly greater odds of self-reported stimulant abstinence during the active 8-week treatment phase; however, among those who had not achieved abstinence during this period, STAGE-12 participants had more days of use. STAGE-12 participants had lower ASI Drug Composite scores at and a significant reduction from baseline to the 3-month FU, attended 12-step meetings on a greater number of days during the early phase of active treatment, engaged in more other types of 12-step activities throughout the active treatment phase and the entire FU period, and had more days of self-reported service at meetings from mid-treatment through the 6-month FU. Conclusions The present findings are mixed with respect to the impact of integrating the STAGE-12 intervention into intensive outpatient drug treatment compared to TAU on stimulant drug use. However, the results more clearly indicate that individuals in STAGE-12 had higher rates of 12-step meeting attendance and were engaged in more related activities throughout both the active treatment phase and the entire 6

  12. Regional variation in histopathologic features of tumor specimens from treatment-naive glioblastoma correlates with anatomic and physiologic MR Imaging

    PubMed Central

    Barajas, Ramon F.; Phillips, Joanna J.; Parvataneni, Rupa; Molinaro, Annette; Essock-Burns, Emma; Bourne, Gabriela; Parsa, Andrew T.; Aghi, Manish K.; McDermott, Michael W.; Berger, Mitchel S.; Cha, Soonmee; Chang, Susan M.; Nelson, Sarah J.

    2012-01-01

    Histopathologic evaluation of glioblastoma multiforme (GBM) at initial diagnosis is typically performed on tissue obtained from regions of contrast enhancement (CE) as depicted on gadolinium-enhanced, T1-weighted images. The non-enhancing (NE) portion of the lesion, which contains both reactive edema and infiltrative tumor, is only partially removed due to concerns about damaging functioning brain. The purpose of this study was to evaluate histopathologic and physiologic MRI features of image-guided tissue specimens from CE and NE regions to investigate correlations between imaging and histopathologic parameters. One hundred nineteen tissue specimens (93 CE and 26 NE regions) were acquired from 51 patients with newly diagnosed GBM by utilizing stereotactic image-guided sampling. Variables of anatomic, diffusion-weighted imaging (DWI), and dynamic susceptibility–weighted, contrast-enhanced perfusion imaging (DSC) from each tissue sample location were obtained and compared with histopathologic features such as tumor score, cell density, proliferation, architectural disruption, hypoxia, and microvascular hyperplasia. Tissue samples from CE regions had increased tumor score, cellular density, proliferation, and architectural disruption compared with NE regions. DSC variables such as relative cerebral blood volume, peak height, and recovery factor were significantly higher, and the percentage of signal intensity recovery was significantly lower in the CE compared with the NE regions. DWI variables were correlated with histopathologic features of GBM within NE regions. Image-guided tissue acquisition and assessment of residual tumor from treatment-naive GBM should be guided by DSC in CE regions and by DWI in NE regions. PMID:22711606

  13. Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment.

    PubMed

    Zeng, Botao; Ardekani, Babak A; Tang, Yingying; Zhang, Tianhong; Zhao, Shanshan; Cui, Huiru; Fan, Xiaoduo; Zhuo, Kaiming; Li, Chunbo; Xu, Yifeng; Goff, Donald C; Wang, Jijun

    2016-04-01

    Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent. Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8 weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons. At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018). White matter deficits were validated in the present study by a relatively large sample of medication naïve and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may

  14. HIV-1 genetic diversity and transmitted drug resistance frequency among Iranian treatment-naive, sexually infected individuals.

    PubMed

    Vahabpour, Rouhollah; Bokharaei-Salim, Farah; Kalantari, Saeed; Garshasbi, Saba; Monavari, Seyed Hamidreza; Esghaei, Maryam; Memarnejadian, Arash; Fakhim, Atousa; Keyvani, Hossein

    2017-02-08

    In recent years, the patterns of human immunodeficiency virus 1 (HIV-1) transmission in Iran have been changing gradually from drug injection to unprotected sexual contact. This study sought to investigate the phylogenetic trends and characteristics of transmitted drug resistance (TDR) mutations of HIV-1 in a population that is mainly infected through homo/heterosexual contacts. Sixty newly diagnosed antiretroviral-naive individuals with HIV infection living in Tehran were recruited to this survey, and among them, 42 subjects were established to be infected through sexual intercourse. Following amplification and sequencing of the main part of the HIV-1 pol region, phylogenetic and drug-resistance mutation (DRM) analysis was successfully performed on these 42 patients. Phylogenetic analysis showed that the majority of the subjects were infected with subtype CRF35_AD (88%), followed by subtype B, with 7.1%, and subtype CRF01_AE, with 4.7%. A total of 7.1% of the subjects were found to be infected with HIV-1 variants with surveillance drug-resistant mutations (SDRMs) according to the last world health organisation (WHO) algorithm. All of the identified SDRMs belonged to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) class, including K103 N and V106A, which were found in three patients. Two minor HIV protease-inhibitor-related mutations (L10I and G73S) were detected in two patients, but these mutations are not included in the WHO SDRMs list. The dominance of HIV-1 subtype CRF35_AD was observed among subjects of this study who were infected through sexual contact. The moderate prevalence of SDRMs (7.1%) in this population emphasises the fact that the risk of treatment failure in HIV-infected individuals might increase in the future, and preventive measures should be considered by health authorities.

  15. Is there a cerebellar compensatory effort in first-episode, treatment-naive major depressive disorder at rest?

    PubMed

    Guo, Wenbin; Liu, Feng; Liu, Jianrong; Yu, Liuyu; Zhang, Zhikun; Zhang, Jian; Chen, Huafu; Xiao, Changqing

    2013-10-01

    This study was undertaken to explore whether there is a cerebellar compensatory response in patients with first-episode, treatment-naive major depressive disorder (MDD). The cerebellar compensatory response is defined as a cerebellar hyperactivity which would be inversely correlated with both the activation of the functionally connected cerebral regions and the depression severity. Resting-state functional magnetic resonance imaging (fMRI) data of 24 patients with MDD and 24 healthy subjects were analyzed with the fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity (FC) methods. The structural images were processed with the voxel-based morphometry (VBM) method. Compared to healthy controls, depressed patients had significantly increased fALFF in the left Crus I and the left cerebellar lobule VI. FC analysis of these two seeded regions found that depressed patients had increased FC between the left Crus I and the right hippocampus, but had decreased FC between the left Crus I and the left inferior parietal lobule (IPL), and between the left cerebellar lobule VI and bilateral inferior temporal gyrus. No correlation was observed between the abnormal fALFF of the seeds and their connected regions and the depression severity or the executive function. The VBM results did not show significant reduction in gray or white matter volume in any above-mentioned region. Our findings suggest that increased cerebellar activity at resting state may be a disease state phenomenon but not a compensatory response to the dysfunction of the default mode network (DMN) in MDD. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication.

    PubMed

    Kumarasinghe, Nishantha; Beveridge, Natalie J; Gardiner, Erin; Scott, Rodney J; Yasawardene, Surangi; Perera, Antoinette; Mendis, Jayan; Suriyakumara, Kanishka; Schall, Ulrich; Tooney, Paul A

    2013-08-01

    Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.

  17. Pre-Existing Mutations in Reverse Transcriptase of Hepatitis B Virus in Treatment-Naive Chinese Patients with Chronic Hepatitis B

    PubMed Central

    Wang, Jing-Hui; Huang, Ling; Wang, Deng-yu; Zhao, Ling; Zhao, Guo-ping; Wang, Ying

    2015-01-01

    High rate of viral replication and lacking of proofreading activity in hepatitis B virus (HBV) polymerase lead to the generation of mutations in HBV virus. Mutations in the reverse transcriptase (RT) region of HBV polymerase are demonstrated to be strongly associated with drug resistance during antiviral treatment. However, the presence of mutations as well as its clinical significance in treatment-naïve hepatitis patients (defined as pre-existing mutations) need to be further investigated. In the present study, a total of 168 serum samples from treatment-naive chronic hepatitis B (CHB) patients were collected, and the RT region of HBV polymerase was sequenced. The results showed that pre-existing mutations in the RT region of HBV polymerase were detected in 43 of 168 (25.6%) treatment-naive CHB patients within which there were no well-characterized primary nucleotide analogs (NAs) resistance sites. Three dominant sites at rt191, rt207 and rt226 were found mutant in 7(16.28%), 8(18.60%), and 14(32.56%) samples respectively among these 43 patients. No significant correlation was found between pre-existing mutations and gender, age, HBV genotype, ALT, HBeAg or HBV DNA loads. However, patients with pre-existing RT mutations under HBeAg sero-negative status exhibited decreased HBV DNA loads, which contributed to the decreased HBV DNA loads in the total HBeAg sero-negative patients. The above investigation indicated that there was a prevalence of pre-existing mutations in RT region of HBV polymerase which might affect the serum HBV DNA level in treatment-naive CHB patients. Its effects on the occurrence of NAs resistance and the prognosis after treatment need to be further investigated. PMID:25821965

  18. Viremia Copy-Years Predicts Mortality Among Treatment-Naive HIV-Infected Patients Initiating Antiretroviral Therapy

    PubMed Central

    Napravnik, Sonia; Cole, Stephen R.; Eron, Joseph J.; Lau, Bryan; Crane, Heidi M.; Kitahata, Mari M.; Willig, James H.; Moore, Richard D.; Deeks, Steven G.; Saag, Michael S.

    2011-01-01

    Background. Cross-sectional plasma human immunodeficiency virus (HIV) viral load (VL) measures have proven invaluable for clinical and research purposes. However, cross-sectional VL measures fail to capture cumulative plasma HIV burden longitudinally. We evaluated the cumulative effect of exposure to HIV replication on mortality following initiation of combination antiretroviral therapy (ART). Methods. We included treatment-naive HIV-infected patients starting ART from 2000 to 2008 at 8 Center for AIDS Research Network of Integrated Clinical Systems sites. Viremia copy-years, a time-varying measure of cumulative plasma HIV exposure, were determined for each patient using the area under the VL curve. Multivariable Cox models were used to evaluate the independent association of viremia copy-years for all-cause mortality. Results. Among 2027 patients contributing 6579 person-years of follow-up, the median viremia copy-years was 5.3 log10 copy × y/mL (interquartile range: 4.9–6.3 log10 copy × y/mL), and 85 patients (4.2%) died. When evaluated separately, viremia copy-years (hazard ratio [HR] = 1.81 per log10 copy × y/mL; 95% confidence interval [CI], 1.51–2.18 per log10 copy × y/mL), 24-week VL (1.74 per log10 copies/mL; 95% CI, 1.48–2.04 per log10 copies/mL), and most recent VL (HR = 1.89 per log10 copies/mL; 95% CI: 1.63–2.20 per log10 copies/mL) were associated with increased mortality. When simultaneously evaluating VL measures and controlling for other covariates, viremia copy-years increased mortality risk (HR = 1.44 per log10 copy × y/mL; 95% CI, 1.07–1.94 per log10 copy × y/mL), whereas no cross-sectional VL measure was independently associated with mortality. Conclusions. Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional VL measures and time-updated CD4+ T-lymphocyte count in ART-treated patients, suggesting cumulative HIV replication causes harm independent of its effect on the degree of

  19. Methadone Anonymous: A 12-Step Program for Methadone Maintained Heroin Addicts.

    PubMed

    Gilman, Stephen M.; Galanter, Marc; Dermatis, Helen

    2001-12-01

    Methadone Anonymous (MA) is a new 12-step fellowship developed for methadone maintained heroin addicts. A total of 53 MA members completed a survey assessing factors related to methadone maintenance treatment program (MMTP) entry, drug use, MA participation, beliefs concerning effectiveness of MMTP and MA, and level of social cohesiveness. Length of time in MA was associated with a decreased use of alcohol, cocaine, and marijuana. Clients rated components of MA to be significantly more helpful to recovery than MMTP treatment components. Affiliation to five MA members known best by the respondents was significantly greater than affiliation to non-MA members. Length of time in MA was positively associated with MA affiliation. Social affiliation and endorsement of 12-step principles were positively correlated. These findings suggest that MA participation has benefits not available in professionally driven MMTP, and should be further studied.

  20. Molecular characterization of HBV strains circulating among the treatment-naive HIV/HBV co-infected patients of eastern India.

    PubMed

    Saha, Debraj; Pal, Ananya; Biswas, Avik; Panigrahi, Rajesh; Sarkar, Neelakshi; Das, Dipanwita; Sarkar, Jayeeta; Guha, Subhasish Kamal; Saha, Bibhuti; Chakrabarti, Sekhar; Chakravarty, Runu

    2014-01-01

    Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant.

  1. Molecular Characterization of HBV Strains Circulating among the Treatment-Naive HIV/HBV Co-Infected Patients of Eastern India

    PubMed Central

    Saha, Debraj; Pal, Ananya; Biswas, Avik; Panigrahi, Rajesh; Sarkar, Neelakshi; Das, Dipanwita; Sarkar, Jayeeta; Guha, Subhasish Kamal; Saha, Bibhuti; Chakrabarti, Sekhar; Chakravarty, Runu

    2014-01-01

    Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant. PMID:24587360

  2. Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug.

    PubMed

    Glenthoj, Andreas; Glenthoj, Birte Y; Mackeprang, Torben; Pagsberg, Anne K; Hemmingsen, Ralf P; Jernigan, Terry L; Baaré, William F C

    2007-04-15

    The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.

  3. Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients.

    PubMed

    Rosen, Michael J; Karns, Rebekah; Vallance, Jefferson E; Bezold, Ramona; Waddell, Amanda; Collins, Margaret H; Haberman, Yael; Minar, Phillip; Baldassano, Robert N; Hyams, Jeffrey S; Baker, Susan S; Kellermayer, Richard; Noe, Joshua D; Griffiths, Anne M; Rosh, Joel R; Crandall, Wallace V; Heyman, Melvin B; Mack, David R; Kappelman, Michael D; Markowitz, James; Moulton, Dedrick E; Leleiko, Neal S; Walters, Thomas D; Kugathasan, Subra; Wilson, Keith T; Hogan, Simon P; Denson, Lee A

    2017-05-01

    There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5

  4. Spirituality as a change mechanism in 12-step programs: a replication, extension, and refinement.

    PubMed

    Tonigan, J Scott; Rynes, Kristina N; McCrady, Barbara S

    2013-09-01

    This National Institutes of Health funded study investigated spiritual growth as a change mechanism in 12-step programs. A total of 130 people, early 12-step affiliates with limited Alcoholics Anonymous (AA) histories, were recruited from 2007 to 2008 from AA, treatment, and community centers in a Southwestern city in the United States. A majority of the sample was alcohol dependent. Participants were interviewed at baseline and at 3, 6, and 9 months. Lagged General Linear Modeling analyses indicated that spiritual change as measured by the Religious Background and Behavior (RBB) self-report questionnaire were predictive of increased abstinence and decreased drinking intensity, and that the magnitude of this effect varied across different RBB scoring algorithms. Future research should address study limitations by recruiting participants with more extensive AA histories and by including assessments of commitment to, and practice of, AA prescribed activities. The study's limitations are noted.

  5. Spirituality as a Change Mechanism in 12-Step Programs: A Replication, Extension, and Refinement

    PubMed Central

    Tonigan, J. Scott; Rynes, Kristina N.; McCrady, Barbara S.

    2016-01-01

    This National Institutes of Health funded study investigated spiritual growth as a change mechanism in 12-step programs. A total of 130 people, early 12-step affiliates with limited Alcoholics Anonymous (AA) histories, were recruited from 2007 to 2008 from AA, treatment, and community centers in a Southwestern city in the United States. A majority of the sample was alcohol dependent. Participants were interviewed at baseline and at 3, 6, and 9 months. Lagged General Linear Modeling analyses indicated that spiritual change as measured by the Religious Background and Behavior (RBB) self-report questionnaire were predictive of increased abstinence and decreased drinking intensity, and that the magnitude of this effect varied across different RBB scoring algorithms. Future research should address study limitations by recruiting participants with more extensive AA histories and by including assessments of commitment to, and practice of, AA prescribed activities. The study’s limitations are noted. PMID:24041178

  6. Independent levels of cell-free and cell-associated human immunodeficiency virus-1 in genital-tract secretions of clinically asymptomatic, treatment-naive African women.

    PubMed

    Andréoletti, Laurent; Chomont, Nicolas; Grésenguet, Gérard; Matta, Mathieu; de Dieu Longo, Jean; Carreno, Marie-Paule; Si-Mohamed, Ali; Legoff, Jérôme; Kazatchkine, Michel D; Bélec, Laurent

    2003-08-15

    Using ultrasensitive polymerase chain reaction-based techniques, we assessed levels of cell-free and cell-associated human immunodeficiency virus (HIV)-1 in paired blood and genital samples of 30 clinically asymptomatic, treatment-naive women. Levels of HIV-1 RNA in cervicovaginal-lavage samples were positively correlated with those in plasma samples (r=.50; P=.008), whereas levels of HIV-1 DNA in genital samples were loosely correlated with those in blood samples (r=.31; P=.041). In plasma of peripheral blood, levels of HIV-1 DNA were positively correlated with those of HIV-1 RNA (r=.64; P<.001), whereas no correlation between HIV-1 DNA and HIV-1 RNA was evident in genital secretions. Our results indicate that levels of HIV-1 RNA and HIV-1 DNA are unrelated in the genital tracts of treatment-naive women and suggest that the level of genital HIV-1 RNA is influenced by systemic viral replication-in contrast to genital HIV-1 provirus, which may be influenced as well by local cofactors triggering the migration of HIV-infected cells originating from the cervicovaginal submucosa. These features may be relevant for an understanding of HIV-1 transmission in heterosexual individuals.

  7. The General Alcoholics Anonymous Tools of Recovery: The Adoption of 12-Step Practices and Beliefs

    PubMed Central

    Greenfield, Brenna L.; Tonigan, J. Scott

    2013-01-01

    Working the 12 steps is widely prescribed for Alcoholics Anonymous (AA) members although the relative merits of different methods for measuring step-work have received minimal attention and even less is known about how step-work predicts later substance use. The current study (1) compared endorsements of step-work on an face-valid or direct measure, the Alcoholics Anonymous Inventory (AAI), with an indirect measure of step-work, the General Alcoholics Anonymous Tools of Recovery (GAATOR), (2) evaluated the underlying factor structure of the GAATOR and changes in step-work over time, (3) examined changes in the endorsement of step-work over time, and (4) investigated how, if at all, 12-step-work predicted later substance use. New AA affiliates (N = 130) completed assessments at intake, 3, 6, and 9 months. Significantly more participants endorsed step-work on the GAATOR than on the AAI for nine of the 12 steps. An exploratory factor analysis revealed a two-factor structure for the GAATOR comprising Behavioral Step-Work and Spiritual Step-Work. Behavioral Step-Work did not change over time, but was predicted by having a sponsor, while Spiritual Step-Work decreased over time and increases were predicted by attending 12-step meetings or treatment. Behavioral Step-Work did not prospectively predict substance use. In contrast, Spiritual Step-Work predicted percent days abstinent, an effect that is consistent with recent work on the mediating effects of spiritual growth, AA, and increased abstinence. Behavioral and Spiritual Step-Work appear to be conceptually distinct components of step-work that have distinct predictors and unique impacts on outcomes. PMID:22867293

  8. [Real life visual and anatomic outcomes of aflibercept treatment for treatment-naive patients with exudative age-related macular degeneration].

    PubMed

    Duval, M-V; Rougier, M-B; Delyfer, M-N; Combillet, F; Korobelnik, J-F

    2017-04-01

    Anti-VEGF therapies have revolutionized the treatment of neovascular age-related macular degeneration (AMD). The goal of this study was to evaluate the "real life" visual and anatomical outcomes of aflibercept treatment for treatment-naive patients with exudative AMD. This was a retrospective study of patients treated with aflibercept in the department of Ophthalmology at the University Hospital of Bordeaux between November 2013 and July 2015. The follow-up period varied from 3months to 2years. All patients received an induction phase with 3monthly intravitreal injections (IVT) followed by personalized monitoring. ETDRS best-corrected visual acuity (BCVA), fundus examination and OCT were performed at each visit. Data were collected at day 0, 3 months, 6, 9, 12months, 18 and 24months. Forty-three eyes of forty patients, mean age 77.7years, were included, with a minimum of 3months follow-up. Twenty-five eyes were followed for 1year; 5 eyes for two years. At baseline, the mean BCVA was 55.7 letters. Patients received 7.5 injections on average the first year and 2.6 the 2nd year. The mean gain of visual acuity was +7.3 letters at 3 months, +6.2 letters at 12 months, and +6.8 letters at 2years. Anatomically, the OCT data showed a decline of all parameters. The central macular thickness decreased by 118.3μm at 3months, 136.4μm at 12months and 65.5μm at 2years. Aflibercept can achieve effective visual and anatomical outcomes with results, which approach the pivotal studies, despite the use of personalized protocols and longer monitoring intervals. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Mediational relations between 12-Step attendance, depression and substance use in patients with comorbid substance dependence and major depression.

    PubMed

    Worley, Matthew J; Tate, Susan R; Brown, Sandra A

    2012-11-01

    Among patients with substance dependence and comorbid major depressive disorder (MDD) receiving treatment in a controlled trial, we examined if group differences in depression were mediated by 12-Step involvement, and if the effects of 12-Step involvement on future alcohol and drug use were mediated by reductions in depression. Controlled trial of Twelve-Step facilitation (TSF) and integrated cognitive-behavioral therapy (ICBT), delivered in out-patient groups for 6 months with adjunct pharmacotherapy. Out-patient dual diagnosis clinic in Veteran's Affairs Healthcare Center. Veterans (n = 209) diagnosed with alcohol, stimulant or marijuana dependence and substance-independent MDD. Twelve-Step attendance and affiliation, depression severity, percentage of days drinking and percentage of days using drugs assessed at baseline and months 3, 6 and 9. In multi-level analyses greater 12-Step meeting attendance predicted lower depression and mediated the superior depression outcomes of the TSF group, explaining 24.3% of the group difference in depression. Independent of treatment group, lower depression severity predicted lower future alcohol use and mediated the effects of 12-Step meetings, explaining 15.7% of their effects on future drinking. Controlled, lagged models indicated these effects were not confounded by current substance use, suggesting that depression had unique associations with 12-Step meeting attendance and future drinking. For patients with substance dependence and major depressive disorder, attendance at 12-Step meetings is associated with mental health benefits that extend beyond substance use, and reduced depression could be a key mechanism whereby 12-Step meetings reduce future drinking in this population. © 2012 The Authors. Addiction © 2012 Society for the Study of Addiction.

  10. The Trouble with Morality: The Effects of 12-Step Discourse on Addicts’ Decision-Making

    PubMed Central

    Frank, David

    2016-01-01

    Since its development in the 1960s, researchers have extensively scrutinized methadone maintenance treatment (MMT) as a medical response to heroin addiction. Studies consistently find that MMT is more successful than other treatment models in the reduction of opiate/opioid misuse, the transmission of diseases like HIV/AIDS and hepatitis C, and criminal arrest and conviction rates. Nonetheless, a significant portion of active and former heroin addicts view MMT negatively and—perhaps as a result—MMT is vastly underused. This study examines the effects of 12-Step discourses on the opinions and treatment decisions of active heroin addicts, addicts in MMT, and addicts in 12-Step treatment programs. The study finds the abstinence/morality based discourse of drug addiction and treatment is pervasive among addicts and their non-drug using relations and peers alike; moreover, addicts have internalized this narrative, oftentimes despite their own knowledge of MMT’s success and positive personal experiences. The findings suggest that the dominance of abstinence/morality narratives contributes to MMT’s poor reputation among, and low use rate by current and former heroin addicts and that the power of the dominant discourse is such that it produces a desire to buy into its values and tenets even when it is against the individual’s interests to do so. PMID:22111408

  11. The trouble with morality: the effects of 12-step discourse on addicts' decision-making.

    PubMed

    Frank, David

    2011-01-01

    Since its development in the 1960s, researchers have extensively scrutinized methadone maintenance treatment (MMT) as a medical response to heroin addiction. Studies consistently find that MMT is more successful than other treatment models in the reduction of opiate/opioid misuse, the transmission of diseases like HIV/AIDS and hepatitis C, and criminal arrest and conviction rates. Nonetheless, a significant portion of active and former heroin addicts view MMT negatively and-perhaps as a result-MMT is vastly underused. This study examines the effects of 12-Step discourses on the opinions and treatment decisions of active heroin addicts, addicts in MMT, and addicts in 12-Step treatment programs. The study finds the abstinence/morality based discourse of drug addiction and treatment is pervasive among addicts and their non-drug using relations and peers alike; moreover, addicts have internalized this narrative, oftentimes despite their own knowledge of MMT's success and positive personal experiences. The findings suggest that the dominance of abstinence/morality narratives contributes to MMT's poor reputation among, and low use rate by current and former heroin addicts and that the power of the dominant discourse is such that it produces a desire to buy into its values and tenets even when it is against the individual's interests to do so.

  12. Factors associated with mental health clinicians’f referrals to 12-step groups

    PubMed Central

    Rosenblum, Andrew; Fong, Chunki; Laudet, Alexandre; Uttaro, Thomas; Magura, Stephen

    2012-01-01

    As substance use and mental illness services are increasingly integrated, mental health professionals are presented with opportunities to refer greater numbers of dually-diagnosed clients to 12-step groups. This study examined the relationships among clinicians’ 12-step experiences, attitudes and referral practices in 6 NYC mental health clinics. A path analysis model showed that greater interest in learning about 12-step (12-step interest) directly predicted 12-step referral practices and that 12-step interest was predicted both by clinicians’ perception of the helpfulness of 12-Step groups and the severity of their patients’ problems with substance abuse. Clinicians’ responses to open-ended questions supported this model. Didactic and experiential education for clinicians in substance abuse and mutual aid would likely increase patient referrals to 12-step groups. PMID:22873191

  13. Motivational Enhancement for 12-Step Involvement among Patients Undergoing Alcohol Detoxification

    ERIC Educational Resources Information Center

    Kahler, Christopher W.; Read, Jennifer P.; Ramsey, Susan E.; Stuart, Gregory L.; McCrady, Barbara S.; Brown, Richard A.

    2004-01-01

    Forty-eight patients undergoing inpatient detoxification for alcohol dependence were assigned to either brief advice (BA) to attend Alcoholics Anonymous or a motivational enhancement for 12-step involvement (ME-12) intervention that focused on increasing involvement in 12-step self-help groups. Attendance at 12-step groups did not differ…

  14. The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis.

    PubMed

    Manns, Michael P; Vierling, John M; Bacon, Bruce R; Bruno, Savino; Shibolet, Oren; Baruch, Yaacov; Marcellin, Patrick; Caro, Luzelena; Howe, Anita Y M; Fandozzi, Christine; Gress, Jacqueline; Gilbert, Christopher L; Shaw, Peter M; Cooreman, Michael P; Robertson, Michael N; Hwang, Peggy; Dutko, Frank J; Wahl, Janice; Mobashery, Niloufar

    2014-08-01

    MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  15. Treatment-naive individuals are the major source of transmitted HIV-1 drug resistance in men who have sex with men in the Swiss HIV Cohort Study.

    PubMed

    Drescher, Sara M; von Wyl, Viktor; Yang, Wan-Lin; Böni, Jürg; Yerly, Sabine; Shah, Cyril; Aubert, Vincent; Klimkait, Thomas; Taffé, Patrick; Furrer, Hansjakob; Battegay, Manuel; Ambrosioni, Juan; Cavassini, Matthias; Bernasconi, Enos; Vernazza, Pietro L; Ledergerber, Bruno; Günthard, Huldrych F; Kouyos, Roger D

    2014-01-01

    Human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) can compromise antiretroviral therapy (ART) and thus represents an important public health concern. Typically, sources of TDR remain unknown, but they can be characterized with molecular epidemiologic approaches. We used the highly representative Swiss HIV Cohort Study (SHCS) and linked drug resistance database (SHCS-DRDB) to analyze sources of TDR. ART-naive men who have sex with men with infection date estimates between 1996 and 2009 were chosen for surveillance of TDR in HIV-1 subtype B (N = 1674), as the SHCS-DRDB contains pre-ART genotypic resistance tests for >69% of this surveillance population. A phylogeny was inferred using pol sequences from surveillance patients and all subtype B sequences from the SHCS-DRDB (6934 additional patients). Potential sources of TDR were identified based on phylogenetic clustering, shared resistance mutations, genetic distance, and estimated infection dates. One hundred forty of 1674 (8.4%) surveillance patients carried virus with TDR; 86 of 140 (61.4%) were assigned to clusters. Potential sources of TDR were found for 50 of 86 (58.1%) of these patients. ART-naive patients constitute 56 of 66 (84.8%) potential sources and were significantly overrepresented among sources (odds ratio, 6.43 [95% confidence interval, 3.22-12.82]; P < .001). Particularly large transmission clusters were observed for the L90M mutation, and the spread of L90M continued even after the near cessation of antiretroviral use selecting for that mutation. Three clusters showed evidence of reversion of K103N or T215Y/F. Many individuals harboring viral TDR belonged to transmission clusters with other Swiss patients, indicating substantial domestic transmission of TDR in Switzerland. Most TDR in clusters could be linked to sources, indicating good surveillance of TDR in the SHCS-DRDB. Most TDR sources were ART naive. This, and the presence of long TDR transmission chains, suggests

  16. Brief Report: Geographical Variation in Prevalence of Cryptococcal Antigenemia Among HIV-Infected, Treatment-Naive Patients in Nigeria: A Multicenter Cross-Sectional Study.

    PubMed

    Ezeanolue, Echezona E; Nwizu, Chidi; Greene, Gregory S; Amusu, Olatilewa; Chukwuka, Chinwe; Ndembi, Nicaise; Smith, Rachel M; Chiller, Tom; Pharr, Jennifer; Kozel, Thomas R

    2016-09-01

    Worldwide, HIV-associated cryptococcal meningitis affects approximately 1 million persons and causes 600,000 deaths each year mostly in sub-Saharan Africa. Limited data exist on cryptococcal meningitis and antigenemia in Nigeria, and most studies are geographically restricted. We determined the prevalence of cryptococcal antigenemia (CrAg) among HIV-infected, treatment-naive individuals in Nigeria. This was a retrospective, cross-sectional study across 4 geographic regions in Nigeria. We performed CrAg testing using a lateral flow immunoassay on archived whole-blood samples collected from HIV-infected participants at US President's Emergency Plan for AIDS Relief (PEPFAR)-supported sites selected to represent the major geographical and ethnic diversity in Nigeria. Eligible samples were collected from consenting patients (>15 years) naive to antiretroviral therapy with CD4 count less than 200 cells per cubic millimeter and were stored in an -80°C freezer. A total of 2752 stored blood samples were retrospectively screened for CrAg. Most of the samples were from participants aged 30-44 years (57.6%), and 1570 (57.1%) were from women. The prevalence of CrAg positivity in specimens with CD4 <200 cells per cubic millimeter was 2.3% (95% confidence interval: 1.8% to 3.0%) and varied significantly across the 4 regions (P < 0.001). At 4.4% (3.2% to 5.9%), the South East contained the highest prevalence. The significant regional variation in CrAg prevalence found in Nigeria should be taken into consideration as plans are made to integrate routine screening into clinical care for HIV-infected patients.

  17. Naive Conceptions of Motion.

    ERIC Educational Resources Information Center

    McCloskey, Michael

    Two experiments were conducted to characterize the system of beliefs that make up the naive impetus theory of motion and to determine what effects physics instruction has on students' conceptions of motion. Thirteen college students were asked to solve several quantitative problems and were interviewed about their answers in the first experiment.…

  18. Naive Conceptions of Motion.

    ERIC Educational Resources Information Center

    McCloskey, Michael

    Two experiments were conducted to characterize the system of beliefs that make up the naive impetus theory of motion and to determine what effects physics instruction has on students' conceptions of motion. Thirteen college students were asked to solve several quantitative problems and were interviewed about their answers in the first experiment.…

  19. Skill training versus 12-step facilitation for parents of substance-abusing teens.

    PubMed

    McGillicuddy, Neil B; Rychtarik, Robert G; Papandonatos, George D

    2015-03-01

    Distressed parents (N=85) with a substance-abusing adolescent not receiving treatment were randomized to 12 weeks of coping skill training (CST), 12-step facilitation (TSF), or delayed treatment control (DTC). At the end of treatment/delay, CST showed greater coping skillfulness than TSF, and both CST and TSF were more skillful than DTC. The percentage of parent problem days (PPD)-days when the adolescent's substance use caused a problem-also was reduced in CST and TSF, relative to DTC. Both CST and TSF reported significantly reduced monthly PPD by the end of a 12-month follow-up. Skill training and TSF interventions appear equally effective for this underserved parent population. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

    PubMed

    Kantarjian, Hagop M; Roboz, Gail J; Kropf, Patricia L; Yee, Karen W L; O'Connell, Casey L; Tibes, Raoul; Walsh, Katherine J; Podoltsev, Nikolai A; Griffiths, Elizabeth A; Jabbour, Elias; Garcia-Manero, Guillermo; Rizzieri, David; Stock, Wendy; Savona, Michael R; Rosenblat, Todd L; Berdeja, Jesus G; Ravandi, Farhad; Rock, Edwin P; Hao, Yong; Azab, Mohammad; Issa, Jean-Pierre J

    2017-10-01

    The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m(2) guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m(2) on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m(2) in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock

  1. Genotypes and Transmitted Drug Resistance among Treatment-Naive HIV-1-Infected Patients in a Northwestern Province, China: Trends from 2003 to 2013

    PubMed Central

    Liu, Qingquan; Li, Yuan; Liu, Qing; Jiang, Wei; Zhuang, Yan; Guo, Zisheng; Yu, Zhuoran; Li, Xinhong; Wang, Chunfu; Yao, Na; Sun, Yongtao

    2014-01-01

    Background Transmitted drug resistance (TDR) reduces the efficacy of initial antiretroviral treatment and has become a public health concern. Little information is available regarding the genetic diversity of HIV-1 and the prevalence of TDR among treatment-naïve patients in a northwestern province of China since the implementation of national free antiretroviral therapy (ART). Methods Blood samples from 372 HIV-1 treatment-naive patients were collected between 2003 and 2013 in Shaanxi province. Viral RNA was extracted for nested PCR, and phylogenetic reconstruction and recombination analyses were performed to characterize patterns of the HIV-1 subtypes. Genotypic drug resistance testing was performed using an in-house assay to determine trends in the prevalence of HIV-1 transmitted drug resistance. Results Multiple genotypes were identified among the patients in Shaanxi, including B (25.0%), C (0.3%), G (0.3%), and CRF01_AE (39.2%), CRF07_BC (32.7%), CRF08_BC (0.8%), CRF55_01B (1.1%), and URFs (0.6%). The subtypes were associated with the transmission routes (χ2 = 77.113, p<0.01). In this study, a low baseline CD4+ T cell count and a high viral load were found among CRF01_AE-infected patients compared with patients who were infected with non-CRF01_AE (p<0.01) through sexual transmission; however, the CRF01_AE subtype was not associated with a low baseline CD4+ T cell count or a high viral load in Chinese patients infected through blood transmission (p = 0.249). The overall TDR rate in this population was 4.4% between 2003 and 2013. A univariate logistic regression model revealed that a low CD4 T cell count (≤100 cells/µL) was associated with the development of drug-resistant strains. Conclusion Our work revealed diverse HIV-1 subtype distributions in Shaanxi province. We identified a low and stable TDR time trend among ART-naive patients. These findings enhance our understanding of HIV-1 genetic diversity and provide some guidelines for the improvement

  2. Structural equation modelling of viral tropism reveals its impact on achieving viral suppression within 6 months in treatment-naive HIV-1-infected patients after combination antiretroviral therapy.

    PubMed

    Mengoli, Carlo; Andreis, Samantha; Scaggiante, Renzo; Cruciani, Mario; Bosco, Oliviero; Ferretto, Roberto; Leoni, Davide; Maffongelli, Gaetano; Basso, Monica; Torti, Carlo; Sarmati, Loredana; Andreoni, Massimo; Palù, Giorgio; Parisi, Saverio Giuseppe

    2017-01-01

    To evaluate the role of pre-treatment co-receptor tropism of plasma HIV on the achievement of viral suppression (plasma HIV RNA 1.69 log10 copies/mL) at the sixth month of combination antiretroviral therapy (cART) in a cohort of naive patients using, for the first time in this context, a path analysis (PA) approach. Adult patients with chronic infection by subtype B HIV-1 were consecutively enrolled from the start of first-line cART (T0). Genotypic analysis of viral tropism was performed on plasma and interpreted using the bioinformatic tool Geno2pheno, with a false positive rate of 10%. A Bayesian network starting from the viro-immunological data at T0 and at the sixth month of treatment (T1) was set up and this model was evaluated using a PA approach. A total of 262 patients (22.1% bearing an X4 virus) were included; 178 subjects (67.9%) achieved viral suppression. A significant positive indirect effect of bearing X4 virus in plasma at T0 on log10 HIV RNA at T1 was detected (P = 0.009), the magnitude of this effect was, however, over 10-fold lower than the direct effect of log10 HIV RNA at T0 on log10 HIV RNA at T1 (P = 0.000). Moreover, a significant positive indirect effect of bearing an X4 virus on log10 HIV RNA at T0 (P = 0.003) was apparent. PA overcame the limitations implicit in common multiple regression analysis and showed the possible role of pre-treatment viral tropism at the recommended threshold on the outcome of plasma viraemia in naive patients after 6 months of therapy. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Age-dependent effects of acute methylphenidate on amygdala reactivity in stimulant treatment-naive patients with Attention Deficit/Hyperactivity Disorder.

    PubMed

    Bottelier, Marco A; Schrantee, Anouk; Ferguson, Bart; Tamminga, Hyke G H; Bouziane, Cheima; Kooij, J J Sandra; de Ruiter, Michiel B; Reneman, Liesbeth

    2017-09-12

    In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant treatment-naive patients with ADHD (N = 35 boys; N = 46 men) and 23 healthy control subjects (N = 11 boys; N = 12 men). In ADHD patients, we also measured amygdala reactivity 90min after an acute oral challenge with MPH (0.5mg/kg). Mean amygdala reactivity was analyzed for all subjects using a repeated measures analysis of variance (ANOVA). Whole-brain maps were analyzed for the patients only. At baseline, we found a age*diagnosis effect approaching significance (p = 0.05) in the right amygdala due to lower reactivity in children with Attention Deficit/Hyperactivity Disorder (ADHD) vs. controls (-31%), but higher reactivity in adults with ADHD vs. controls (+31%). MPH significantly reduced right amygdala reactivity in all patients, resulting in further reductions in children. In the left amygdala, reduction of amygdala reactivity was confined to adult ADHD patients whereas there was no change in children with ADHD. MPH-induced decrease of amygdala reactivity in adults might be a promising avenue for managing emotional dysregulation when replicated for chronic MPH treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. The effect of 12-step based fellowship participation on abstinence among dually diagnosed persons: a two-year longitudinal study.

    PubMed

    Laudet, Alexandre B; Magura, Stephen; Cleland, Charles M; Vogel, Howard S; Knight, Edward L; Rosenblum, Andrew

    2004-06-01

    A large percentage of individuals are dually-diagnosed with a psychiatric disorder and a substance use disorder. Such persons typically face more difficulties and have poorer outcomes than do single disorder substance users. Among noncomorbid substance users, treatment and participation in 12-Step groups have been shown to enhance the likelihood of abstinence from substance misuse. Specialized 12-Step based fellowships have recently emerged to address the recovery needs of dually-diagnosed persons. The present study is a longitudinal investigation of the effect of such 12-Step based groups on abstinence among dually-diagnosed persons. Participants were members of Double Trouble in Recovery (DTR) who were recruited at community-based meetings in New York City and reinterviewed twice at yearly intervals. Generalized estimating equation analysis indicated that, over the two-year study period, ongoing DTR attendance was significantly associated with a greater likelihood of abstinence after controlling for other pertinent variables, such as mental health symptoms. For clinicians, these findings underline the importance of fostering stable affiliation with specialized 12-Step based groups among their clients.

  5. Genetic diversity and drug resistance among newly diagnosed and antiretroviral treatment-naive HIV-infected individuals in western Yunnan: a hot area of viral recombination in China

    PubMed Central

    2012-01-01

    Background The emergence of an HIV-1 epidemic in China was first recognized in Dehong, western Yunnan. Due to its geographic location, Dehong contributed greatly in bridging HIV-1 epidemics in Southeast Asia and China through drug trafficking and injection drug use; and also extensively to the HIV genetic diversity in Yunnan and China. We attempt to monitor HIV-1 in this area by studying the HIV-1 genetic distribution and transmitted drug resistance (TDR) in various at-risk populations. Methods Blood samples from a total of 320 newly HIV-1 diagnosed individuals, who were antiretroviral therapy (ART)-naive, were collected from January 2009 to December 2010 in 2 counties in Dehong. HIV-1 subtypes and pol gene drug resistance (DR) mutations were genotyped. Results Among 299 pol sequences successfully genotyped (93.4%), subtype C accounted for 43.1% (n=129), unique recombinant forms (URFs) for 18.4% (n=55), CRF01_AE for 17.7% (n=54), B for 10.7% (n=32), CRF08_BC for 8.4% (n=25) and CRF07_BC for 1.7% (n=5). Subtype distribution in patients infected by different transmission routes varied. In contract to the previous finding of CRF01_AE predominance in 2002-2006, subtype C predominated in both injecting drug users (IDUs) and heterosexually transmitted populations in this study. Furthermore, we found a high level of BC, CRF01_AE/C and CRF01_AE/B/C recombinants suggesting the presence of active viral recombination in the area. TDR associated mutations were identified in 4.3% (n=13) individuals. A total of 1.3% of DR were related to protease inhibitors (PIs), including I85IV, M46I and L90M; 0.3% to nucleoside reverse transcriptase inhibitors (NRTIs), including M184I; and 2.7% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), including K103N/S, Y181C, K101E and G190A. Conclusion Our work revealed diverse HIV-1 subtype distributions and intersubtype recombinations. We also identified a low but significant TDR mutation rate among ART-naive patients. These findings

  6. Prevalence of antiretroviral drug resistance among treatment-naive and treated HIV-infected patients in Venezuela.

    PubMed

    Rangel, Héctor Rafael; Garzaro, Domingo José; Torres, Jaime Rafael; Castro, Julio; Suarez, Jose Antonio; Naranjo, Laura; Ossenkopp, John; Martinez, Nahír; Gutierrez, Cristina; Pujol, Flor Helene

    2009-05-01

    An in-house, low-cost method was developed to determine the genotypic resistance of immunodeficiency virus type 1 (HIV-1) isolates. All 179 Venezuelan isolates analysed belonged to subtype B. Primary drug resistance mutations were found in 11% of 63 treatment-naïve patients. The prevalence of resistance in isolates from 116 HIV-positive patients under antiretroviral treatment was 47% to protease inhibitors, 65% to nucleoside inhibitors and 38% to non-nucleoside inhibitors, respectively. Around 50% of patients in the study harboured viruses with highly reduced susceptibility to the three classical types of drugs after only five years from their initial diagnoses.

  7. Lithium Monotherapy Increases ACTH and Cortisol Response in the Dex/CRH Test in Unipolar Depressed Subjects. A Study with 30 Treatment-Naive Patients

    PubMed Central

    Bschor, Tom; Ritter, Dirk; Winkelmann, Patricia; Erbe, Sebastian; Uhr, Manfred; Ising, Marcus; Lewitzka, Ute

    2011-01-01

    Background Distorted activity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the most robustly documented biological abnormalities in major depression. Lithium is central to the treatment of affective disorders, but little is known about its effects on the HPA system of depressed subjects. Objective To assess the effects of lithium monotherapy on the HPA system of patients with major depression by means of the combined DEX/CRH test. Method Thirty drug-naive outpatients with major depression (single episode or unipolar recurrent; SCID I- and II-confirmed) were treated with lithium monotherapy for four weeks. The DEX/CRH test was conducted directly before intake of the first lithium tablet and four weeks thereafter. Weekly ratings with the HDRS21 were used to determine response (≥50% symptom reduction) and remission (HDRS ≤7). Results Lithium levels within the therapeutic range were achieved rapidly. Tolerability was good; no patient terminated the treatment prematurely. Response and remission rates were 50% and 33% respectively. Compared to the DEX/CRH test before the start of the treatment, a considerable and significant increase in all CRH-stimulated ACTH and cortisol parameters could be detected in the second DEX/CRH test. When analysed with particular regard to responders and non-responders, that significant increase was only present in the responders. Conclusions We were able to demonstrate that lithium leads to a significant activation of the HPA system. This is possibly connected to stimulation of hypothalamic arginine vasoporessin (AVP), to direct intracellular effects of lithium on pituitary cells and to an induction of gene expression. Trial Registration drks-nue.uniklinik-freiburg.de DRKS00003185 PMID:22132117

  8. Comparison of antiretroviral drug resistance among treatment-naive and treated HIV-infected individuals in Shiraz, Iran.

    PubMed

    Davarpanah, Mohammad Ali; Motazedian, Nasrin; Joulaei, Hassan; Aghasadeghi, Mohammad Reza; Faramarzi, Hossein; Aghah, Ehsan

    2017-10-06

    The use of anti-retroviral therapy has been effective in controlling the spread of HIV-1, and has prolonged life expectancy, but this success can be affected by the emergence of drug resistance. The main goal of this study was to investigate drug resistance in the reverse transcriptase (RT), and protease (PR) genes among HIV-1 infected individuals. We systematically selected 59 HIV-1 infected individuals from Shiraz Voluntary Counseling and Testing Center (29 treatment- naïve and 30 treated). In this study intravenous drug users older than 18 were included in this study. Using specific primers, nested RT-PCR was performed on RNA extracted from patient samples. The genes targeted for RT and PCR were successfully amplified and sequenced. The sequences of these two genes were compared with mutations related to drug resistance against nucleotide reverse transcriptase inhibitors (NRTI), non-nucleotide reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) using the latest database from the International AIDS society - USA, Stanford University, and the patterns were recorded. Among treatment-naïve, the detected NRTI and NNRTI resistance mutations were V179T, V75 M and E138A. V179T causes high level resistance to Efavirenze and Nevirapin. V75 M causes intermediate resistance to Stavudine. Regarding NRTI and NNRTI resistance mutations among treated patients, the most frequent mutation (7%) was M184 V, which causes high level resistance to zidovudin and emtricitabine. The interesting result from this study was the detection of NRTI and NNRTI resistance mutations before the initiation of treatment, which signifies the transmission of resistant strains of virus between individuals. This mutation highlights the importance of drug resistance HIV-1 genotyping before commencing treatment.

  9. Effects of Fluticasone Furoate on Clinical and Immunological Outcomes (IL-17) for Patients With Nasal Polyposis Naive to Steroid Treatment.

    PubMed

    Venkatesan, Narayanan; Lavigne, Philippe; Lavigne, Francois; Hamid, Qutayba

    2016-03-01

    We investigated the effect of topical steroids on clinical outcomes and related immune response of chronic rhinosinusitis with nasal polyp (CRSwNP) patients and in eradicating some polyps. We want to explore a new potential mechanism linked to Th-17 cells. Prospective, double-blind, placebo-controlled studies with 24 allergic and nonallergic patients were randomized to either placebo or fluticasone furoate for 12 weeks. Assessment of clinical response, endoscopic score with biopsies of the inferior turbinate, and polyps before and after treatment were performed. Biopsies were stained for T-cells, eosinophils, neutrophils, and IL-17A/F. Steroid treatment improved the mean symptoms scores from 7.12 to 4.02 (P < .01) and the polyp score from 5.13 to 3.31 (P < .05), but the comparison with placebo was not statistically significant in nonallergics due to insufficient study power. Steroid treatment decreased eosinophil counts on allergics but not neutrophils or T-cells. The IL-17A/F expression was higher in nonallergics with high neutrophil counts and was inclined by steroids. Compared to baselines, IL-17 cells were significantly less in allergic individuals and were not observed in allergics and with high neutrophil counts. Topical steroids were more effective on certain nasal polyp phenotypes. Identification of polyp phenotype might be essential to ensure a better therapeutic response to intranasal corticosteroids. © The Author(s) 2015.

  10. The 12 Steps of Addiction Recovery Programs as an Influence on Leadership Development: A Personal Narrative

    ERIC Educational Resources Information Center

    Friedman, Mitchell

    2016-01-01

    My participation in a 12-step addiction program based on the principles and traditions of Alcoholics Anonymous (AA) has been critical for my leadership development. As I worked to refrain from addictive behaviors and practiced 12-step principles, I experienced a shift from individualistic, self-centered leadership towards a servant leader…

  11. The 12 Steps of Addiction Recovery Programs as an Influence on Leadership Development: A Personal Narrative

    ERIC Educational Resources Information Center

    Friedman, Mitchell

    2016-01-01

    My participation in a 12-step addiction program based on the principles and traditions of Alcoholics Anonymous (AA) has been critical for my leadership development. As I worked to refrain from addictive behaviors and practiced 12-step principles, I experienced a shift from individualistic, self-centered leadership towards a servant leader…

  12. Antiretroviral activity and safety of once-daily etravirine in treatment-naive HIV-infected adults: 48-week results

    PubMed Central

    Floris-Moore, Michelle A; Mollan, Katie; Wilkin, Aimee M; Johnson, Marc A; Kashuba, Angela DM; Wohl, David A; Patterson, Kristine B; Francis, Owen; Kronk, Catherine; Eron, Joseph J

    2017-01-01

    Background Etravirine (ETR), an NNRTI approved for 200 mg BID dosing in conjunction with other antiretrovirals (ARVs), has pharmacokinetic properties which support once-daily dosing. Methods In this single arm, open-label study, 79 treatment-naïve HIV-infected adults were assigned to receive ETR 400 mg plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) 300/200mg once daily to assess antiviral activity, safety, and tolerability. Antiretroviral activity at 48 weeks was determined by proportion of subjects with HIV-1 RNA <50 copies/mL (intention-to-treat, missing = failure). Results Of 79 eligible subjects, 90% were men, 62% African-American and 29% Caucasian. At baseline, median (Q1, Q3) age was 29 years (23, 44) and HIV-1 RNA 4.52 log10 copies/mL (4.07, 5.04). Sixty-nine (87%) completed a week 48 visit and 61 (77%, 95% CI: 66 – 86%) achieved HIV-1 RNA <50 copies/mL at week 48. At time of virologic failure, genotypic resistance-associated mutations were detected in 3 participants, 2 with E138K (1 alone and 1 with additional mutations). Median (95% CI) CD4+ cell count increase was 163 (136, 203) cells/uL. Fifteen (19.0%) participants reported a new sign/symptom or lab abnormality ≥ Grade 3 and 3 participants (3.8 %) permanently discontinued ETR due to toxicity. Two participants had psychiatric symptoms of any grade. There were no deaths. Conclusions In this study of ARV-naïve HIV+ adults, once daily ETR with TDF/FTC had acceptable antiviral activity and was well-tolerated. Once daily ETR may be a plausible option as part of a combination ARV regimen for treatment-naïve individuals. PMID:26263403

  13. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks.

    PubMed

    Aberg, Judith A; Tebas, Pablo; Overton, Edgar Turner; Gupta, Samir K; Sax, Paul E; Landay, Alan; Falcon, Ron; Ryan, Robert; De La Rosa, Guy

    2012-10-01

    We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4(+) cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, -0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.

  14. Metabolic disorders and cardiovascular risk in treatment-naive HIV-infected patients of sub-saharan origin starting antiretrovirals: impact of westernized lifestyle.

    PubMed

    Eholié, Serge Paul; Lacombe, Karine; Krain, Alysa; Diallo, Zelica; Ouiminga, Mariama; Campa, Pauline; Bouchaud, Olivier; Bissagnene, Emmanuel; Girard, Pierre-Marie

    2015-04-01

    In a cohort of HIV-infected patients of sub-Saharan origin we describe the incidence of metabolic syndrome, insulin resistance, and lipodystrophy after 3 years of combined antiretroviral therapy, and model the 10-year risk of cardiovascular diseases, while taking into account environmental factors. This is a multinational, prospective cohort study conducted in HIV outpatient clinics from four tertiary care centers set in France and Côte d'Ivoire. The participants were HIV-infected, treatment-naive patients eligible to start antiretroviral treatment and were of sub-Saharan African origin. The main outcome measures were the incidence of metabolic syndrome, insulin resistance, and lipodystrophy, and the assessment of the 10-year risk of cardiovascular diseases using Framingham risk prediction, D.A.D. Cardiovascular Disease Risk, and WHO/ISH prediction charts. Of 245 patients followed for up to 3 years, the incidence of metabolic syndrome, insulin resistance, and lipodystrophy was 5.5, 8.5, and 6.8 per 100 person-years of follow-up (cumulative incidence: 14.4%, 19.2%, and 18.1%, respectively). Living in France as well as female gender and being overweight were risk factors for metabolic disorders as whole and only first generation protease inhibitors were marginally associated with metabolic syndrome. Cardiovascular risk as modeled through the three equations was high in all patients with the synergistic and deleterious effect of living in France compared to Côte d'Ivoire. This cohort study shows how the synergy between HIV, antiretroviral (ARV) exposure, and westernization of life style in a cohort of HIV-infected patients of sub-Saharan origin leads to a progressive increase in the risk of lipodystrophy, as well as metabolic syndrome and insulin resistance, all associated with increased cardiovascular risk.

  15. Sex-Specific Patterns of Aberrant Brain Function in First-Episode Treatment-Naive Patients with Schizophrenia.

    PubMed

    Lei, Wei; Li, Mingli; Deng, Wei; Zhou, Yi; Ma, Xiaohong; Wang, Qiang; Guo, Wanjun; Li, Yinfei; Jiang, Lijun; Han, Yuanyuan; Huang, Chaohua; Hu, Xun; Li, Tao

    2015-07-16

    Male and female patients with schizophrenia show significant differences in a number of important clinical features, yet the neural substrates of these differences are still poorly understood. Here we explored the sex differences in the brain functional aberrations in 124 treatment-naïve patients with first-episode schizophrenia (61 males), compared with 102 age-matched healthy controls (50 males). Maps of degree centrality (DC) and amplitude of low-frequency fluctuations (ALFF) were constructed using resting-state functional magnetic resonance imaging data and compared between groups. We found that: (1) Selective DC reduction was observed in the right putamen (Put_R) in male patients and the left middle frontal gyrus (MFG) in female patients; (2) Functional connectivity analysis (using Put_R and MFG as seeds) found that male and female patients have disturbed functional integration in two separate networks, i.e., the sensorimotor network and the default mode network; (3) Significant ALFF alterations were also observed in these two networks in both genders; (4) Sex specific brain functional alterations were associated with various symptoms in patients. These results suggested that sex-specific patterns of functional aberration existed in schizophrenia, and these patterns were associated with the clinical features both in male and female patients.

  16. Amplitude of Low-Frequency Oscillations in First-Episode, Treatment-Naive Patients with Major Depressive Disorder: A Resting-State Functional MRI Study

    PubMed Central

    Wang, Li; Dai, Wenji; Su, Yunai; Wang, Gang; Tan, Yunlong; Jin, Zhen; Zeng, Yawei; Yu, Xin; Chen, Wei; Wang, Xiaodong; Si, Tianmei

    2012-01-01

    Background Resting-state fMRI is a novel approach to measure spontaneous brain activity in patients with major depressive disorder (MDD). Although most resting-state fMRI studies have focused on the examination of temporal correlations between low-frequency oscillations (LFOs), few studies have explored the amplitude of these LFOs in MDD. In this study, we applied the approaches of amplitude of low-frequency fluctuation (ALFF) and fractional ALFF to examine the amplitude of LFOs in MDD. Methodology/Principal Findings A total of 36 subjects, 18 first-episode, treatment-naive patients with MDD matched with 18 healthy controls (HCs) completed the fMRI scans. Compared with HCs, MDD patients showed increased ALFF in the right fusiform gyrus and the right anterior and posterior lobes of the cerebellum but decreased ALFF in the left inferior temporal gyrus, bilateral inferior parietal lobule, and right lingual gyrus. The fALFF in patients was significantly increased in the right precentral gyrus, right inferior temporal gyrus, bilateral fusiform gyrus, and bilateral anterior and posterior lobes of the cerebellum but was decreased in the left dorsolateral prefrontal cortex, bilateral medial orbitofrontal cortex, bilateral middle temporal gyrus, left inferior temporal gyrus, and right inferior parietal lobule. After taking gray matter (GM) volume as a covariate, the results still remained. Conclusions/Significance These findings indicate that MDD patients have altered LFO amplitude in a number of regions distributed over the frontal, temporal, parietal, and occipital cortices and the cerebellum. These aberrant regions may be related to the disturbances of multiple emotion- and cognition-related networks observed in MDD and the apparent heterogeneity in depressive symptom domains. Such brain functional alteration of MDD may contribute to further understanding of MDD-related network imbalances demonstrated in previous fMRI studies. PMID:23119084

  17. Should we await IFN-free regimens to treat HCV genotype 1 treatment-naive patients? A cost-effectiveness analysis (ANRS 95141).

    PubMed

    Deuffic-Burban, Sylvie; Schwarzinger, Michaël; Obach, Dorothée; Mallet, Vincent; Pol, Stanislas; Pageaux, Georges-Philippe; Canva, Valérie; Deltenre, Pierre; Roudot-Thoraval, Françoise; Larrey, Dominique; Dhumeaux, Daniel; Mathurin, Philippe; Yazdanpanah, Yazdan

    2014-07-01

    In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015). A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3-4/F0-2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0-0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1-10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12weeks of IFN-based new DAAs and two times higher for IFN-free regimens. Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0-1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective. Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. Naive coadaptive cortical control.

    PubMed

    Gage, Gregory J; Ludwig, Kip A; Otto, Kevin J; Ionides, Edward L; Kipke, Daryl R

    2005-06-01

    The ability to control a prosthetic device directly from the neocortex has been demonstrated in rats, monkeys and humans. Here we investigate whether neural control can be accomplished in situations where (1) subjects have not received prior motor training to control the device (naive user) and (2) the neural encoding of movement parameters in the cortex is unknown to the prosthetic device (naive controller). By adopting a decoding strategy that identifies and focuses on units whose firing rate properties are best suited for control, we show that naive subjects mutually adapt to learn control of a neural prosthetic system. Six untrained Long-Evans rats, implanted with silicon micro-electrodes in the motor cortex, learned cortical control of an auditory device without prior motor characterization of the recorded neural ensemble. Single- and multi-unit activities were decoded using a Kalman filter to represent an audio "cursor" (90 ms tone pips ranging from 250 Hz to 16 kHz) which subjects controlled to match a given target frequency. After each trial, a novel adaptive algorithm trained the decoding filter based on correlations of the firing patterns with expected cursor movement. Each behavioral session consisted of 100 trials and began with randomized decoding weights. Within 7 +/- 1.4 (mean +/- SD) sessions, all subjects were able to significantly score above chance (P < 0.05, randomization method) in a fixed target paradigm. Training lasted 24 sessions in which both the behavioral performance and signal to noise ratio of the peri-event histograms increased significantly (P < 0.01, ANOVA). Two rats continued training on a more complex task using a bilateral, two-target control paradigm. Both subjects were able to significantly discriminate the target tones (P < 0.05, Z-test), while one subject demonstrated control above chance (P < 0.05, Z-test) after 12 sessions and continued improvement with many sessions achieving over 90% correct targets. Dynamic analysis of

  19. Impact of the Data Collection on Adverse Events of Anti-HIV Drugs cohort study on abacavir prescription among treatment-naive, HIV-infected patients in Canada.

    PubMed

    Antoniou, Tony; Gillis, Jennifer; Loutfy, Mona R; Cooper, Curtis; Hogg, Robert S; Klein, Marina B; Machouf, Nima; Montaner, Julio S G; Rourke, Sean B; Tsoukas, Chris; Raboud, Janet M

    2014-01-01

    To evaluate the trends in abacavir (ABC) prescription among antiretroviral (ARV) medication-naive individuals following the presentation of the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) cohort study. We conducted a retrospective cohort study of ARV medication-naive individuals in the Canadian Observational Cohort (CANOC). Between January 1, 2000, and February 28, 2010, a total of 7280 ARV medication-naive patients were included in CANOC. We observed a significant change in the proportion of new ABC prescriptions immediately following the release of DAD (-11%; 95% confidence interval [CI]: -20% to -2.4%) and in the months following the presentation of these data (-0.66% per month; 95% CI: -1.2% to -0.073%). A post-DAD presentation decrease in the odds of being prescribed ABC versus tenofovir (TDF) was observed (adjusted odds ratio, 0.72 per year, 95% CI: 0.54-0.97). Presentation of the DAD was associated with a significant decrease in ABC use among ARV medication-naive, HIV-positive patients initiating therapy.

  20. Safety and efficacy of tiotropium Respimat versus HandiHaler in patients naive to treatment with inhaled anticholinergics: a post hoc analysis of the TIOSPIR trial

    PubMed Central

    Wise, Robert; Calverley, Peter MA; Dahl, Ronald; Dusser, Daniel; Metzdorf, Norbert; Müller, Achim; Fowler, Andy; Anzueto, Antonio

    2015-01-01

    Background: Patients with chronic obstructive pulmonary disease (COPD) who were naive to anticholinergics before the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial may reflect patients seen in practice, in particular in primary care. In addition, investigating safety in these patients avoids the potential bias in patients who previously received anticholinergics and may be tolerant of their effects. Aims: The aim of this study was to evaluate whether patients naive to anticholinergic therapy who were treated with tiotropium Respimat 2.5 or 5 μg had different safety and efficacy outcomes than patients treated with tiotropium HandiHaler 18 μg. Methods: A post hoc analysis of patients who were not receiving anticholinergics before TIOSPIR (N=6,966/17,135) was conducted. Primary end points were risk of death from any cause and risk of COPD exacerbation. Secondary outcomes included severe exacerbation and major adverse cardiovascular events (MACE). Additional analysis of exacerbations was carried out in anticholinergic-naive patients with moderate (GOLD II) disease. Results: Anticholinergic-naive patients had less severe disease than the total TIOSPIR population. Discontinuations because of anticholinergic side effects were infrequent (0.9% overall). Similar to the primary study, patients in the tiotropium Respimat groups had no difference in the risk of death or risk of any or severe exacerbation than patients treated with tiotropium HandiHaler. Risk of MACE was similar across the Respimat and HandiHaler groups. Rates of exacerbations in the subgroup of patients with moderate disease were similar across the Respimat and HandiHaler groups. Conclusions: Tiotropium Respimat and HandiHaler have similar safety and efficacy profiles in patients who are naive to anticholinergic therapy. PMID:26540491

  1. Alcoholic Recovery and the 12 Steps: White Bison Presents a Native View.

    ERIC Educational Resources Information Center

    Simonelli, Richard

    1993-01-01

    Describes an alcohol recovery program offered by White Bison, Inc. (Colorado Springs), that integrates the 12 Steps of Alcoholics Anonymous with traditional Native American ceremonies and medicine wheel teachings symbolizing the life cycle. (LP)

  2. Alcoholic Recovery and the 12 Steps: White Bison Presents a Native View.

    ERIC Educational Resources Information Center

    Simonelli, Richard

    1993-01-01

    Describes an alcohol recovery program offered by White Bison, Inc. (Colorado Springs), that integrates the 12 Steps of Alcoholics Anonymous with traditional Native American ceremonies and medicine wheel teachings symbolizing the life cycle. (LP)

  3. Effectiveness of Making Alcoholics Anonymous Easier: a group format 12-step facilitation approach.

    PubMed

    Kaskutas, Lee Ann; Subbaraman, Meenakshi S; Witbrodt, Jane; Zemore, Sarah E

    2009-10-01

    Most treatment programs recommend clients attend 12-step groups, but many drop out posttreatment. The effectiveness of Making Alcoholics Anonymous [AA] Easier (MAAEZ ), a manual-guided intervention designed to help clients connect with individuals encountered in AA, was tested using an "OFF/ON" design (n = 508). MAAEZ effectiveness was determined by comparing abstinence rates of participants recruited during ON and OFF conditions and by studying the effect of the number of MAAEZ sessions attended. At 12 months, more clients in the ON condition (vs. OFF) reported past 30-day abstinence from alcohol (p = .012), drugs (p = .009), and both alcohol and drugs (p = .045). In multivariate analyses, ON condition participants had significantly increased odds of abstinence from alcohol (odds ratio [OR] = 1.85) and from drugs (OR = 2.21); abstinence odds also increased significantly for each additional MAAEZ session received. MAAEZ appeared especially effective for those with more prior AA exposure, severe psychiatric problems, and atheists/agnostics. MAAEZ represents an evidence-based intervention that is easily implemented in existing treatment programs.

  4. Antiretroviral Regimen Durability and Success in Treatment-Naive and Treatment-Experienced Patients by Year of Treatment Initiation, United States, 1996-2011.

    PubMed

    Sheth, Anandi N; Ofotokun, Ighovwerha; Buchacz, Kate; Armon, Carl; Chmiel, Joan S; Hart, Rachel L D; Baker, Rose; Brooks, John T; Palella, Frank J

    2016-01-01

    Although modern combination antiretroviral therapy (cART) regimens are better tolerated and less complex than earlier treatments, regimen modification or discontinuation remains a concern. We studied HIV Outpatient Study (HOPS) participants who initiated the first or second cART regimens during: 1996-1999, 2000-2003, 2004-2007, and 2008-2011. We analyzed regimen durability (time to regimen modification) and success (achieving undetectable plasma HIV RNA) for the first and second cART regimens using Kaplan-Meier curves and log-rank tests, and examined factors associated with durability and success of the first cART regimen using proportional hazards models. Durability of cART was progressively longer for cART regimens initiated in more recent periods: median first cART regimen durations were 1.0, 1.1, 2.1, and 4.6 years in 1996-1999, 2000-2003, 2004-2007, and 2008-2011, and the median second cART durations were 0.9, 1.2, 2.8, and 3.9 years, respectively (both P < 0.001). Comparing 1996-1999 and 2008-2011, the percentage of patients who achieved an undetectable HIV RNA within 6 months of first cART initiation increased from 65% to 81% and from 63% to 80% on second cART (both P < 0.001). Among patients initiating first cART during 2008-2011, black non-Hispanic/Latino race/ethnicity and ≥ twice-daily dosing were significantly associated with higher rates of regimen modification (P < 0.05), and higher baseline HIV RNA levels were associated with failure to achieve an undetectable HIV RNA (P < 0.001). Among HIV-infected U.S. adults in routine HIV care, durability of the first and second cART regimens and the likelihood of prompt virological suppression increased during 1996-2011, coincident with the availability of more tolerable, less complex cART options.

  5. Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks

    PubMed Central

    Tebas, Pablo; Overton, Edgar Turner; Gupta, Samir K.; Sax, Paul E.; Landay, Alan; Falcon, Ron; Ryan, Robert; De La Rosa, Guy

    2012-01-01

    Abstract We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted. PMID:22352336

  6. Coping Skills Training and 12-Step Facilitation for Women Whose Partner Has Alcoholism: Effects on Depression, the Partner's Drinking, and Partner Physical Violence

    ERIC Educational Resources Information Center

    Rychtarik, Robert G.; McGillicuddy, Neil B.

    2005-01-01

    Women (N = 171), distressed from their partners' untreated alcoholism, received either coping skills training (CST), 12-step facilitation (TSF), or delayed treatment (DTC). CST and TSF resulted in lower depression levels than DTC but did not differ from one another. Skill acquisition mediated the treatment effects of CST; Al-Anon attendance did…

  7. Coping Skills Training and 12-Step Facilitation for Women Whose Partner Has Alcoholism: Effects on Depression, the Partner's Drinking, and Partner Physical Violence

    ERIC Educational Resources Information Center

    Rychtarik, Robert G.; McGillicuddy, Neil B.

    2005-01-01

    Women (N = 171), distressed from their partners' untreated alcoholism, received either coping skills training (CST), 12-step facilitation (TSF), or delayed treatment (DTC). CST and TSF resulted in lower depression levels than DTC but did not differ from one another. Skill acquisition mediated the treatment effects of CST; Al-Anon attendance did…

  8. The meaning of suffering in drug addiction and recovery from the perspective of existentialism, Buddhism and the 12-Step program.

    PubMed

    Chen, Gila

    2010-09-01

    The aim of the current article was to examine the meaning of suffering in drug addiction and in the recovery process. Negative emotions may cause primary suffering that can drive an individual toward substance abuse. At the same time, drugs only provide temporary relief, and over time, the pathological effects of the addiction worsen causing secondary suffering, which is a motivation for treatment. The 12-Step program offers a practical way to cope with suffering through a process of surrender. The act of surrender sets in motion a conversion experience, which involves a self-change including reorganization of one's identity and meaning in life. This article is another step toward understanding one of the several factors that contribute to the addict's motivation for treatment. This knowledge may be helpful for tailoring treatment that addresses suffering as a factor that initiates treatment motivation and, in turn, treatment success.

  9. Periodontal disease is significantly higher in non-smoking treatment-naive rheumatoid arthritis patients: results from a case-control study.

    PubMed

    Potikuri, Damodaram; Dannana, Kalyan Chakravarthy; Kanchinadam, Suresh; Agrawal, Sumeet; Kancharla, Anuradha; Rajasekhar, Liza; Pothuraju, Shantakumari; Gumdal, Narsimulu

    2012-09-01

    To find the strength of association between periodontal disease (PD) and rheumatoid arthritis (RA) in non-smoking, disease modifying antirheumatic drug (DMARD)-naive RA patients in a case-control design. Patients of RA (DMARD-naive, non-smokers) satisfying the American college of Rheumatology 1987 criteria and healthy controls were included. PD was defined as present if the mean pocket depth (MPD) is ≥3 mm. Demographic data and disease specific variables were recorded for RA patients and healthy controls. Titres of immunoglobulin M-rheumatoid factor (IgM-RF) and anticitrullinated peptide antibodies (ACPAs) were measured using ELISA. Patients with RA (n=91) had a 4.28 (CI 2.35 to 7.38) higher odds of PD (64.8% vs 28%, p<0.001) compared with healthy controls (n=93). The MPD was 3.61±1.22 mm in cases and 2.46±0.74 mm in controls (p<0.001). IgM-RF titres (110.56±95.81 vs 66.53±70.29; p=0.02) and ACPA titres (753.05±1088.27 vs 145.15±613.16, p=0.001) were significantly higher in RA patients with PD than those without PD. The MPD positively correlated with titres of ACPAs in RA patients (r=0.24; p=0.02). PD is more frequent and severe in non-smoking DMARD-naive RA patients compared with healthy controls. PD in RA is associated with high titres of ACPAs.

  10. THE TWELVE PROMISES OF ALCOHOLICS ANONYMOUS: PSYCHOMETRIC MEASURE VALIDATION AND MEDIATIONAL TESTING AS A 12-STEP SPECIFIC MECHANISM OF BEHAVIOR CHANGE

    PubMed Central

    Kelly, John F.; Greene, M. Claire

    2013-01-01

    Background Empirical support for the recovery utility of 12-step mutual-help organizations (MHOs) has led to increased investigation of how such organizations confer benefit. The Twelve Promises of Alcoholics Anonymous (AA) feature prominently in 12-step philosophy and culture and are one of the few documented explications of the cognitive, affective, and behavioral benefits that members might accrue. This study investigated the psychometric properties of a measure of AA’s Twelve Promises and examined whether it mediated the effect of 12-step participation on abstinence. Method Young adults (N=302, M age 20.4 [1.6], range 18–25; 27% female; 95% White) enrolled in an addiction treatment effectiveness study completed assessments at intake and 3-, 6-, and 12-months post treatment including a 26-item, Twelve Promises Scale (TPS). Factor analyses examined the TPS’ psychometrics and lagged mediational analyses tested the TPS as a mechanism of behavior change. Results Robust principal axis factoring extraction with Varimax rotation revealed a 2-factor solution explaining 45–58% of the variance across three administrations (“Psychological Wellbeing” = 26–39%; “Freedom from Craving=17–21%); internal consistency was high (alpha = .83–.93). Both factors were found to increase in relation to greater 12-step participation, but significant mediation was found only for the Freedom from Craving factor explaining 21–34% of the effect of 12-step participation in increasing abstinence. Conclusions The TPS shows potential as a conceptually relevant, and psychometrically sound measure and may be useful in helping elucidate the extent to which the Twelve Promises emerge as an independent benefit of 12-step participation and/or explain SUD remission and recovery. PMID:24004905

  11. Religiosity, Emotional Responses, Perceived Pressure, and Start-Time Compliance among Individuals Who Are Court Mandated to Attend 12 Step Groups

    ERIC Educational Resources Information Center

    Tyce, Sue L.

    2009-01-01

    Research findings demonstrate that effective drug treatment often involves AA's 12 Step program. However, AA's religiosity can be seen as an important, perhaps significant emotional stimulus that either hinders or complicates attendance compliance. This study examined the individual's level of religiosity as a predictor of emotional responses,…

  12. Religiosity, Emotional Responses, Perceived Pressure, and Start-Time Compliance among Individuals Who Are Court Mandated to Attend 12 Step Groups

    ERIC Educational Resources Information Center

    Tyce, Sue L.

    2009-01-01

    Research findings demonstrate that effective drug treatment often involves AA's 12 Step program. However, AA's religiosity can be seen as an important, perhaps significant emotional stimulus that either hinders or complicates attendance compliance. This study examined the individual's level of religiosity as a predictor of emotional responses,…

  13. Social support and comfort in AA as mediators of "Making AA easier" (MAAEZ), a 12-step facilitation intervention.

    PubMed

    Subbaraman, Meenakshi Sabina; Kaskutas, Lee Ann

    2012-12-01

    A trial of "Making Alcoholics Anonymous Easier" (MAAEZ), a group-format 12-step facilitation program, showed significantly higher odds of past 30-day abstinence after 12 months among those who had been treated in MAAEZ compared to usual care, especially for clients with high prior AA/NA/CA meeting attendance (>90 prior meetings; OR = 2.94, p = .02). We examined whether MAAEZ effects for this group were mediated by social support for sobriety and comfort with the 12-step fellowship. Among those with high prior AA/NA/CA attendance, we performed tests of multiple mediation to estimate MAAEZ effects attributable to the combined effect of social network support for sobriety, comfort being at AA/NA/CA meetings, and comfort speaking at AA/NA/CA meetings. To gain some understanding of sustaining these behaviors, we also examined each potential mediating variable measured both prior to, and concurrent with, 12-month outcomes. Having support for sobriety at 6 months emerged as a mediator of 12-month MAAEZ effects, when controlling for comfort being and speaking at AA/NA/CA meetings at 6 months. The effect remained when controlling for mediator values at 12 months, and explained 44% of the MAAEZ effect. Results highlight the value of studying specific, modifiable 12-step activities, and demonstrate the importance of exploring subgroups to determine behaviors and attitudes to target for optimal treatment. For example, increasing support for sobriety among those with high prior AA/NA/CA attendance may be especially pertinent. 2013 APA, all rights reserved

  14. Optimal time for initiating antiretroviral therapy (ART) in HIV-infected, treatment-naive children aged 2 to 5 years old

    PubMed Central

    Siegfried, Nandi; Davies, Mary-Ann; Penazzato, Martina; Muhe, Lulu M; Egger, Matthias

    2014-01-01

    Background The use of combination antiretroviral therapy (cART) comprising three antiretroviral medications from at least two classes of drugs is the current standard treatment for HIV infection in adults and children. Current World Health Organization (WHO) guidelines for antiretroviral therapy recommend early treatment regardless of immunologic thresholds or the clinical condition for all infants (less than one years of age) and children under the age of two years. For children aged two to five years current WHO guidelines recommend (based on low quality evidence) that clinical and immunological thresholds be used to identify those who need to start cART (advanced clinical stage or CD4 counts ≤ 750 cells/mm3 or per cent CD4 ≤ 25%). This Cochrane review will inform the current available evidence regarding the optimal time for treatment initiation in children aged two to five years with the goal of informing the revision of WHO 2013 recommendations on when to initiate cART in children. Objectives To assess the evidence for the optimal time to initiate cART in treatment-naive, HIV-infected children aged 2 to 5 years. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the AEGIS conference database, specific relevant conferences, www.clinicaltrials.gov, the World Health Organization International Clinical Trials Registry platform and reference lists of articles. The date of the most recent search was 30 September 2012. Selection criteria Randomised controlled trials (RCTs) that compared immediate with deferred initiation of cART, and prospective cohort studies which followed children from enrolment to start of cART and on cART. Data collection and analysis Two review authors considered studies for inclusion in the review, assessed the risk of bias, and extracted data on the primary outcome of death from all causes and several secondary outcomes, including incidence of CDC category C and B clinical events and

  15. Cost-effectiveness of Early Treatment of Hepatitis C Virus Genotype 1 by Stage of Liver Fibrosis in a US Treatment-Naive Population

    PubMed Central

    Chahal, Harinder S.; Marseille, Elliot A.; Tice, Jeffrey A.; Pearson, Steve D.; Ollendorf, Daniel A.; Fox, Rena K.; Kahn, James G.

    2016-01-01

    IMPORTANCE Novel treatments for hepatitis C virus (HCV) infection are highly efficacious but costly. Thus, many insurers cover therapy only in advanced fibrosis stages. The added health benefits and costs of early treatment are unknown. OBJECTIVE To assess the cost-effectiveness of (1) treating all patients with HCV vs only those with advanced fibrosis and (2) treating each stage of fibrosis. DESIGN, SETTING, AND PARTICIPANTS This study used a decision-analytic model for the treatment of HCV genotype 1. The model used a lifetime horizon and societal perspective and was representative of all US patients with HCV genotype 1 who had not received previous treatment. Comparisons in the model included antiviral treatment of all fibrosis stages (METAVIR [Meta-analysis of Histological Data in Virial Hepatitis] stages F0 [no fibrosis] to F4 [cirrhosis]) vs treatment of stages F3 (numerous septa without cirrhosis) and F4 only and by specific fibrosis stage. Data were collected from March 1 to September 1, 2014, and analyzed from September 1, 2014, to June 30, 2015. INTERVENTIONS Six HCV therapy options (particularly combined sofosbuvir and ledipasvir therapy) or no treatment. MAIN OUTCOMES AND MEASURES Cost and health outcomes were measured using total medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), calculated as the difference in costs between strategies divided by the difference in QALYs. RESULTS We simulated 1000 individuals, but present the results normalized to a single HCV-infected person. In the base-case analysis, among patients receiving 8 or 12 weeks of sofosbuvir-ledipasvir treatment, treating all fibrosis stages compared with treating stages F3 and F4 adds 0.73 QALYs and $28 899, for an ICER of $39 475 per QALY gained. Treating at stage F2 (portal fibrosis with rare septa) costs $19 833 per QALY gained vs waiting until stage F3; treating at stage F1 (portal fibrosis without septa), $81 165 per QALY gained

  16. Cost-effectiveness of Early Treatment of Hepatitis C Virus Genotype 1 by Stage of Liver Fibrosis in a US Treatment-Naive Population.

    PubMed

    Chahal, Harinder S; Marseille, Elliot A; Tice, Jeffrey A; Pearson, Steve D; Ollendorf, Daniel A; Fox, Rena K; Kahn, James G

    2016-01-01

    Novel treatments for hepatitis C virus (HCV) infection are highly efficacious but costly. Thus, many insurers cover therapy only in advanced fibrosis stages. The added health benefits and costs of early treatment are unknown. To assess the cost-effectiveness of (1) treating all patients with HCV vs only those with advanced fibrosis and (2) treating each stage of fibrosis. This study used a decision-analytic model for the treatment of HCV genotype 1. The model used a lifetime horizon and societal perspective and was representative of all US patients with HCV genotype 1 who had not received previous treatment. Comparisons in the model included antiviral treatment of all fibrosis stages (METAVIR [Meta-analysis of Histological Data in Virial Hepatitis] stages F0 [no fibrosis] to F4 [cirrhosis]) vs treatment of stages F3 (numerous septa without cirrhosis) and F4 only and by specific fibrosis stage. Data were collected from March 1 to September 1, 2014, and analyzed from September 1, 2014, to June 30, 2015. Six HCV therapy options (particularly combined sofosbuvir and ledipasvir therapy) or no treatment. Cost and health outcomes were measured using total medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), calculated as the difference in costs between strategies divided by the difference in QALYs. We simulated 1000 individuals, but present the results normalized to a single HCV-infected person. In the base-case analysis, among patients receiving 8 or 12 weeks of sofosbuvir-ledipasvir treatment, treating all fibrosis stages compared with treating stages F3 and F4 adds 0.73 QALYs and $28,899, for an ICER of $39,475 per QALY gained. Treating at stage F2 (portal fibrosis with rare septa) costs $19,833 per QALY gained vs waiting until stage F3; treating at stage F1 (portal fibrosis without septa), $81,165 per QALY gained compared with waiting until stage F2; and treating at stage F0, $187,065 per QALY gained compared with

  17. Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial.

    PubMed

    Foley, J E; Bunck, M C; Möller-Goede, D L; Poelma, M; Nijpels, G; Eekhoff, E M; Schweizer, A; Heine, R J; Diamant, M

    2011-08-01

    Traditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2 years). Whether this effect persists after cessation of treatment remains unknown. Here, we assessed the insulin secretory capacity in drug-naive patients with type 2 diabetes after a 52 week treatment period with vildagliptin or placebo, and again after a 12 week washout period. This study was conducted at a single university medical centre, and was a double-blind, randomised clinical trial in 59 drug-naive patients with type 2 diabetes and mild hyperglycaemia to either vildagliptin 100 mg (n = 29) or placebo (n = 30). Randomisation was performed by a validated 1:1 system. Neither patient, nor caregiver, was informed about the assigned treatment. Inclusion criteria were drug-naive patients ≥30 years, with HbA(1c) ≤7.5% and BMI of 22-45 kg/m(2). The mildly hyperglycaemic patient population was chosen to minimise glucose toxicity as a confounding variable. Beta-cell function was measured during an arginine-stimulated hyperglycaemic clamp at week 0, week 52 and after a 12 week washout period. All patients with at least one post-randomisation measure were analysed (intent-to-treat). Fifty-two week vildagliptin 100 mg (n = 26) treatment increased the primary efficacy variable, combined hyperglycaemia and arginine-stimulated C-peptide secretion (AIR(arg)), by 5.0 ± 1.8 nmol/l × min, while it decreased by 0.8 ± 1.8 nmol/l × min with placebo (n = 25) (between-group difference p = 0.030). No significant between-group difference in AIR(arg) was seen after the 12 week washout period. The between-group difference adjusted mean 52 week changes from baseline was -0.19 ± 0.11, p = 0.098 and -0.22 ± 0.23%, p = 0.343 for HbA(1c) and fasting plasma glucose, respectively

  18. SILEN-C3, a Phase 2 Randomized Trial with Faldaprevir plus Pegylated Interferon α-2a and Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients

    PubMed Central

    Asselah, Tarik; Guyader, Dominique; Berg, Thomas; Schuchmann, Marcus; Mauss, Stefan; Ratziu, Vlad; Ferenci, Peter; Larrey, Dominique; Maieron, Andreas; Stern, Jerry O.; Ozan, Melek; Datsenko, Yakov; Böcher, Wulf Otto; Steinmann, Gerhard

    2014-01-01

    Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143–2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620). PMID:24709256

  19. Comparing Acceptance and Commitment Group Therapy and 12-Steps Narcotics Anonymous in Addict's Rehabilitation Process: A Randomized Controlled Trial.

    PubMed

    Azkhosh, Manoochehr; Farhoudianm, Ali; Saadati, Hemn; Shoaee, Fateme; Lashani, Leila

    2016-10-01

    Objective: Substance abuse is a socio-psychological disorder. The aim of this study was to compare the effectiveness of acceptance and commitment therapy with 12-steps Narcotics Anonymous on psychological well-being of opiate dependent individuals in addiction treatment centers in Shiraz, Iran. Method: This was a randomized controlled trial. Data were collected at entry into the study and at post-test and follow-up visits. The participants were selected from opiate addicted individuals who referred to addiction treatment centers in Shiraz. Sixty individuals were evaluated according to inclusion/ exclusion criteria and were divided into three equal groups randomly (20 participants per group). One group received acceptance and commitment group therapy (Twelve 90-minute sessions) and the other group was provided with the 12-steps Narcotics Anonymous program and the control group received the usual methadone maintenance treatment. During the treatment process, seven participants dropped out. Data were collected using the psychological well-being questionnaire and AAQ questionnaire in the three groups at pre-test, post-test and follow-up visits. Data were analyzed using repeated measure analysis of variance. Results: Repeated measure analysis of variance revealed that the mean difference between the three groups was significant (P<0.05) and that acceptance and commitment therapy group showed improvement relative to the NA and control groups on psychological well-being and psychological flexibility. Conclusion: The results of this study revealed that acceptance and commitment therapy can be helpful in enhancing positive emotions and increasing psychological well-being of addicts who seek treatment.

  20. Naive Theories of Social Groups

    ERIC Educational Resources Information Center

    Rhodes, Marjorie

    2012-01-01

    Four studies examined children's (ages 3-10, Total N = 235) naive theories of social groups, in particular, their expectations about how group memberships constrain social interactions. After introduction to novel groups of people, preschoolers (ages 3-5) reliably expected agents from one group to harm members of the other group (rather than…

  1. Using metaphors to explore the experiences of powerlessness among women in 12-step recovery.

    PubMed

    Matheson, Jennifer L; McCollum, Eric E

    2008-07-01

    12-Step programs of substance abuse(1) recovery are the most utilized mutual-help models in the United States. A pivotal aspect of 12-Step is the often-controversial idea of powerlessness. There is debate about the usefulness of the concept of powerlessness, especially for women in recovery. This study used a metaphor-elicitation interviewing technique to examine the experiences of powerlessness among 13 women of varied racial, ethnic, and socioeconomic backgrounds, ages 21 to 60, who had an average of 9.5 years of recovery. Interviews were conducted during a 6-month span between 2004 and 2005 in the Washington, DC metropolitan area. Open and axial coding was used to determine emergent themes. Concepts of powerlessness were found to be process oriented and developmental. Some metaphors indicated positive emotions around powerlessness such as relief, whereas others indicated negative emotions such as fear. Implications for future research and study strengths and limitations are included.

  2. The Touro 12-Step: A Systematic Guide to Optimizing Survey Research with Online Discussion Boards

    PubMed Central

    Ip, Eric J; Tenerowicz, Michael J; Perry, Paul J

    2010-01-01

    The Internet, in particular discussion boards, can provide a unique opportunity for recruiting participants in online research surveys. Despite its outreach potential, there are significant barriers which can limit its success. Trust, participation, and visibility issues can all hinder the recruitment process; the Touro 12-Step was developed to address these potential hurdles. By following this step-by-step approach, researchers will be able to minimize these pitfalls and maximize their recruitment potential via online discussion boards. PMID:20507843

  3. Do social networks explain 12-step sponsorship effects? A prospective lagged mediation analysis.

    PubMed

    Rynes, Kristina N; Tonigan, J Scott

    2012-09-01

    Sponsorship is a basic and important part of the 12-step approach to recovery from substance abuse (Alcoholics Anonymous, 2005) and research has shown that having a sponsor is associated with increased involvement in 12-step programs and improved outcomes (Bond, Kaskutas, & Weisner, 2003; Tonigan & Rice, 2010). However, little is known about how sponsorship improves outcomes. Given research demonstrating bivariate associations between sponsorship and social support for abstinence (Majer, Jason, Ferrari, Venable, & Olson, 2002), we hypothesized that the association between having a sponsor and increased abstinence outcomes would be explained by increases in one's abstinence-based social network. Prospective fully lagged mediational analyses did not support this hypothesis and these results ran counter to findings of five previous studies (cf. Groh, Jason, & Keys, 2008). A review of these studies showed that researchers often used cross-sectional or partially lagged methods to test mediation and the mediational effect of the social network was small in magnitude. Results suggest that the prospective association between sponsorship and abstinence is not explained by increases in the abstinence-based social network and demonstrate the need for future studies to use rigorous and time-lagged methods to test social support for abstinence as a mediator of the effects of 12-step involvement. PsycINFO Database Record (c) 2012 APA, all rights reserved.

  4. Do Social Networks Explain 12-Step Sponsorship Effects? A Prospective Lagged Mediation Analysis

    PubMed Central

    Rynes, Kristina N.; Tonigan, J. Scott

    2011-01-01

    Sponsorship is a basic and important part of the 12-step approach to recovery from substance abuse (Alcoholics Anonymous, 2005) and research has shown that having a sponsor is associated with increased involvement in 12-step programs and improved outcomes (Bond, Kaskutas, & Weisner, 2003; Tonigan & Rice, 2010). However, little is known about how sponsorship improves outcomes. Given research demonstrating bivariate associations between sponsorship and social support for abstinence (Majer, Jason, Ferrari, Venable, & Olson, 2002), we hypothesized that the association between having a sponsor and increased abstinence outcomes would be explained by increases in one’s abstinence-based social network. Prospective fully lagged mediational analyses did not support this hypothesis and these results ran counter to findings of five previous studies (cf. Groh, Jason, & Keys, 2008). A review of these studies showed that researchers often used cross-sectional or partially-lagged methods to test mediation and the mediational effect of the social network was small in magnitude. Results suggest that the prospective association between sponsorship and abstinence is not explained by increases in the abstinence-based social network and demonstrate the need for future studies to use rigorous and time-lagged methods to test social support for abstinence as a mediator of the effects of 12-step involvement. PMID:21895349

  5. 12-step participation and outcomes over 7 years among adolescent substance use patients with and without psychiatric comorbidity.

    PubMed

    Chi, Felicia W; Sterling, Stacy; Campbell, Cynthia I; Weisner, Constance

    2013-01-01

    This study examines the associations between 12-step participation and outcomes over 7 years among 419 adolescent substance use patients with and without psychiatric comorbidities. Although level of participation decreased over time for both groups, comorbid adolescents participated in 12-step groups at comparable or higher levels across time points. Results from mixed-effects logistic regression models indicated that for both groups, 12-step participation was associated with both alcohol and drug abstinence at follow-ups, increasing the likelihood of either by at least 3 times. Findings highlight the potential benefits of 12-step participation in maintaining long-term recovery for adolescents with and without psychiatric disorders.

  6. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.

    PubMed

    Roth, David; Nelson, David R; Bruchfeld, Annette; Liapakis, AnnMarie; Silva, Marcelo; Monsour, Howard; Martin, Paul; Pol, Stanislas; Londoño, Maria-Carlota; Hassanein, Tarek; Zamor, Philippe J; Zuckerman, Eli; Wan, Shuyan; Jackson, Beth; Nguyen, Bach-Yen; Robertson, Michael; Barr, Eliav; Wahl, Janice; Greaves, Wayne

    2015-10-17

    and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. Merck Sharp & Dohme Corp. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study).

    PubMed

    Nam, J L; Villeneuve, E; Hensor, E M A; Conaghan, P G; Keen, H I; Buch, M H; Gough, A K; Green, M J; Helliwell, P S; Keenan, A M; Morgan, A W; Quinn, M; Reece, R; van der Heijde, D M; Wakefield, R J; Emery, P

    2014-01-01

    In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction. In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6 months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50. The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) -1.45 (-3.35 to 0.45); p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61); p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00); p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68); p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen. In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.

  8. Efficacy and resistance in de novo combination lamivudine and adefovir dipivoxil therapy versus entecavir monotherapy for the treatment-naive patients with chronic hepatitis B: a meta-analysis

    PubMed Central

    2014-01-01

    Background Currently, there is no consensus on the efficacy and resistance of de novo combination therapy versus monotherapy for treatment naive patients of chronic hepatitis B (CHB). Objectives The aim of this study was to evaluate the effectiveness and resistance of de novo combination of lamivudine (LAM) and adefovir dipivoxil (ADV) compared with entecavir (ETV) monotherapy for nucleos(t)ide–naive patients with CHB. Study design Publications on the effectiveness and resistance of LAM plus ADV versus ETV monotherapy for nucleos(t)ide-naive patients with CHB were identified by a search of PubMed, Embase, the Cochrane Library, Web of science, OVID, and CBM (Chinese Biological Medical Literature) until May 1, 2013. Biochemical response, hepatitis B e antigen seroconversion, and viroligic response were extracted and combined to obtain an integrated result. Viral resistance and safety were reviewed. Results Five eligible studies (328 patients in total) were included in the analysis. LAM plus ADV combination therapy produced more rapid HBV DNA reduction rate at 12 weeks than that of ETV monotherapy. At 48 weeks, the combination group had superior viroligic response rates compared with ETV group (90.0% vs. 78.9%, P=0.01). The difference in the ALT normalization and HBeAg seroconversion rates was not found. At week 96, LAM + ADV was more effective than ETV in ALT normalization [RR = 1. 11, 95% CI (1.02, 1.21), P =0.01] and HBeAg seroconversion [RR = 2.00, 95% CI (1.26, 3.18, P=0.003)], and no significant difference was found in the virologic response (P =0.23). No viral resistance occurred in combination therapy and six patients in ETV group were experienced with viral breakthrough. Both groups were well tolerated. Conclusion The de novo LAM plus ADV combination therapy for treatment-naïve patients with CHB was greater than ETV monotherapy in both biochemical response and HBeAg seroconversion rate up to 96 weeks. The rate of emergence of viral

  9. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial.

    PubMed

    Walmsley, Sharon; Baumgarten, Axel; Berenguer, Juan; Felizarta, Franco; Florence, Eric; Khuong-Josses, Marie-Aude; Kilby, J Michael; Lutz, Thomas; Podzamczer, Daniel; Portilla, Joaquin; Roth, Norman; Wong, Deborah; Granier, Catherine; Wynne, Brian; Pappa, Keith

    2015-12-15

    The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + abacavir/lamivudine arm [dolutegravir + abacavir/lamivudine arm, 16 (4%); efavirenz/tenofovir/emtricitabine arm, 58 (14%)] through W144 [corrected]. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144.

  10. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial

    PubMed Central

    Walmsley, Sharon; Baumgarten, Axel; Berenguer, Juan; Felizarta, Franco; Florence, Eric; Khuong-Josses, Marie-Aude; Kilby, J. Michael; Lutz, Thomas; Podzamczer, Daniel; Portilla, Joaquin; Roth, Norman; Granier, Catherine; Wynne, Brian; Pappa, Keith

    2015-01-01

    Abstract: The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + abacavir/lamivudine arm [dolutegravir + abacavir/lamivudine arm, 13 (3%); efavirenz/tenofovir/emtricitabine arm, 48 (11%)] through W144. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144. PMID:26262777

  11. Rare damaging variants in DNA repair and cell cycle pathways are associated with hippocampal and cognitive dysfunction: a combined genetic imaging study in first-episode treatment-naive patients with schizophrenia.

    PubMed

    Yang, Z; Li, M; Hu, X; Xiang, B; Deng, W; Wang, Q; Wang, Y; Zhao, L; Ma, X; Sham, P C; Northoff, G; Li, T

    2017-02-14

    Schizophrenia is a complex neurodevelopmental disorder where changes in both hippocampus and memory-related cognitive functions are central. However, the exact relationship between neurodevelopmental-genetic factors and hippocampal-cognitive dysfunction remains unclear. The general aim of our study is to link the occurrence of rare damaging mutations involved in susceptibility gene pathways to the structure and function of hippocampus in order to define genetically and phenotypically based subgroups in schizophrenia. In the present study, by analyzing the exome sequencing and magnetic resonance imaging data in 94 first-episode treatment-naive schizophrenia patients and 134 normal controls, we identified that a cluster of rare damaging variants (RDVs) enriched in DNA repair and cell cycle pathways was present only in a subgroup including 39 schizophrenic patients. Furthermore, we found that schizophrenic patients with this RDVs show increased resting-state functional connectivity (rsFC) between left hippocampus (especially for left dentate gyrus) and left inferior parietal cortex, as well as decreased rsFC between left hippocampus and cerebellum. Moreover, abnormal rsFC was related to the deficits of spatial working memory (SWM; that is known to recruit the hippocampus) in patients with the RDVs. Taken together, our data demonstrate for the first time, to our knowledge, that damaging rare variants of genes in DNA repair and cell cycle pathways are associated with aberrant hippocampal rsFC, which was further relative to cognitive deficits in first-episode treatment-naive schizophrenia. Therefore, our data provide some evidence for the occurrence of phenotypic alterations in hippocampal and SWM function in a genetically defined subgroup of schizophrenia.

  12. Dual Therapy Treatment Strategies for the Management of Patients Infected with HIV: A Systematic Review of Current Evidence in ARV-Naive or ARV-Experienced, Virologically Suppressed Patients.

    PubMed

    Baril, Jean-Guy; Angel, Jonathan B; Gill, M John; Gathe, Joseph; Cahn, Pedro; van Wyk, Jean; Walmsley, Sharon

    2016-01-01

    We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection. A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations. Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels. The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the

  13. Complete response to nivolumab monotherapy in a treatment-naive, BRAF wild-type patient with advanced mucosal melanoma and elevated lactate dehydrogenase: a case report from a phase III trial.

    PubMed

    Ascierto, Paolo A; Vanella, Vito; Grimaldi, Antonio Maria; Lucia, Festino; Palla, Marco; Simeone, Ester; Mozzillo, Nicola

    2016-11-01

    The anti-PD-1 agent, nivolumab, has been approved both as monotherapy and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma in the USA and European Union. Here we present the case of a patient with treatment-naive, metastatic mucosal melanoma and baseline LDH approximately seven times the upper limit of normal. The patient was enrolled in a clinical trial (CheckMate 066) and achieved a partial response, followed by a durable complete response with nivolumab treatment. The patient's LDH levels were documented in each cycle and dropped markedly within 2 months, when partial response to treatment was already evident. LDH levels remained low for the rest of follow-up, consistent with the ongoing complete response to treatment. The patient experienced only mild immune-related adverse events (grade 1-2), which included vitiligo and rash. This exceptional response suggests that patients with high LDH levels at baseline should be considered for nivolumab treatment. LDH levels, however, should not serve as a predictive marker of response to nivolumab. Moreover, this case suggests the need to identify patients who will achieve the greatest benefit from nivolumab monotherapy.

  14. Applying an Ensemble Classification Tree Approach to the Prediction of Completion of a 12-Step Facilitation Intervention with Stimulant Abusers

    PubMed Central

    Doyle, Suzanne R.; Donovan, Dennis M.

    2014-01-01

    Aims The purpose of this study was to explore the selection of predictor variables in the evaluation of drug treatment completion using an ensemble approach with classification trees. The basic methodology is reviewed and the subagging procedure of random subsampling is applied. Methods Among 234 individuals with stimulant use disorders randomized to a 12-Step facilitative intervention shown to increase stimulant use abstinence, 67.52% were classified as treatment completers. A total of 122 baseline variables were used to identify factors associated with completion. Findings The number of types of self-help activity involvement prior to treatment was the predominant predictor. Other effective predictors included better coping self-efficacy for substance use in high-risk situations, more days of prior meeting attendance, greater acceptance of the Disease model, higher confidence for not resuming use following discharge, lower ASI Drug and Alcohol composite scores, negative urine screens for cocaine or marijuana, and fewer employment problems. Conclusions The application of an ensemble subsampling regression tree method utilizes the fact that classification trees are unstable but, on average, produce an improved prediction of the completion of drug abuse treatment. The results support the notion there are early indicators of treatment completion that may allow for modification of approaches more tailored to fitting the needs of individuals and potentially provide more successful treatment engagement and improved outcomes. PMID:25134038

  15. 48-Week Efficacy and Safety of Dolutegravir Relative to Commonly Used Third Agents in Treatment-Naive HIV-1–Infected Patients: A Systematic Review and Network Meta-Analysis

    PubMed Central

    Patel, Dipen A.; Snedecor, Sonya J.; Tang, Wing Yu; Sudharshan, Lavanya; Lim, Jessica W.; Cuffe, Robert; Pulgar, Sonia; Gilchrist, Kim A.; Camejo, Rodrigo Refoios; Stephens, Jennifer; Nichols, Garrett

    2014-01-01

    Background A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1–infected patients. Methods A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed. Results Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions. Conclusion Three clinical

  16. Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study.

    PubMed

    Rossetti, Giuseppe; Pizzocri, Samuele; Brasca, Francesco; Pozzi, Marta; Beltrami, Laura M; Bolla, Giovanni B; Famiani, Roberta; Caimi, Barbara; Omboni, Stefano; Magrini, Fabio; Carugo, Stefano

    2008-06-01

    Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140-179 mm Hg and diastolic BP of 90-109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, -10.3/-9.4 vs -16.6/-9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05). In this small sample of treatment-naive

  17. Antihypertensive effect of barnidipine 10 mg or amlodipine 5 to 10 mg once daily in treatment-naive patients with essential hypertension: A 24-week, randomized, open-label, pilot study

    PubMed Central

    Rossetti, Giuseppe; Pizzocri, Samuele; Brasca, Francesco; Pozzi, Marta; Beltrami, Laura M.; Bolla, Giovanni B.; Famiani, Roberta; Caimi, Barbara; Omboni, Stefano; Magrini, Fabio; Carugo, Stefano

    2008-01-01

    Background: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. Objective: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. Methods: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140–179 mm Hg and diastolic BP of 90–109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. Results: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, −10.3/−9.4 vs −16.6/−9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13

  18. Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial.

    PubMed

    Mizokami, Masashi; Yokosuka, Osamu; Takehara, Tetsuo; Sakamoto, Naoya; Korenaga, Masaaki; Mochizuki, Hitoshi; Nakane, Kunio; Enomoto, Hirayuki; Ikeda, Fusao; Yanase, Mikio; Toyoda, Hidenori; Genda, Takuya; Umemura, Takeji; Yatsuhashi, Hiroshi; Ide, Tatsuya; Toda, Nobuo; Nirei, Kazushige; Ueno, Yoshiyuki; Nishigaki, Yoichi; Betular, Juan; Gao, Bing; Ishizaki, Akinobu; Omote, Masa; Mo, Hongmei; Garrison, Kim; Pang, Phillip S; Knox, Steven J; Symonds, William T; McHutchison, John G; Izumi, Namiki; Omata, Masao

    2015-06-01

    Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label-ie, patients ≤60 kg received 600 mg daily, patients >60 kg to ≤80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL, creatinine clearance of at least 1·0 mL/s, and a platelet count of at least 50 × 10(9) per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained

  19. Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/maraviroc/raltegravir in treatment-naive HIV patients.

    PubMed

    Pradat, Pierre; Durant, Jacques; Brochier, Corinne; Trabaud, Mary-Anne; Cottalorda-Dufayard, Jacqueline; Izopet, Jacques; Raffi, François; Lucht, Frédéric; Gagnieu, Marie-Claude; Gatey, Caroline; Jacomet, Christine; Vassallo, Matteo; Dellamonica, Pierre; Cotte, Laurent

    2016-11-01

    We assessed the virological efficacy of a 6 month maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with maraviroc/raltegravir. HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA <50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA <50 copies/mL at W48. Thirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm(3) and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA < 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died. Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

    PubMed

    Molina, Jean-Michel; Clotet, Bonaventura; van Lunzen, Jan; Lazzarin, Adriano; Cavassini, Matthias; Henry, Keith; Kulagin, Valeriv; Givens, Naomi; de Oliveira, Carlos Fernando; Brennan, Clare

    2015-04-01

    The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7-20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). Once-daily dolutegravir is associated with a higher virological response rate

  1. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis

    PubMed Central

    Gupta, Ravindra K; Jordan, Michael R; Sultan, Binta J; Hill, Andrew; Davis, Daniel HJ; Gregson, John; Sawyer, Anthony W; Hamers, Raph L; Ndembi, Nicaise; Pillay, Deenan; Bertagnolio, Silvia

    2012-01-01

    Summary Background The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings. Methods We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models. Findings Study-level data were available for 26 102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (–0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region. Interpretation Our findings suggest a significant increase in prevalence

  2. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis.

    PubMed

    Gupta, Ravindra K; Jordan, Michael R; Sultan, Binta J; Hill, Andrew; Davis, Daniel H J; Gregson, John; Sawyer, Anthony W; Hamers, Raph L; Ndembi, Nicaise; Pillay, Deenan; Bertagnolio, Silvia

    2012-10-06

    The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings. We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models. Study-level data were available for 26,102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (-0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region. Our findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral

  3. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus

    PubMed Central

    Thompson, Melanie; Saag, Michael; DeJesus, Edwin; Gathe, Joseph; Lalezari, Jay; Landay, Alan L.; Cade, Jerry; Enejosa, Jeffrey; Lefebvre, Eric; Feinberg, Judith

    2016-01-01

    Objective: To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults. Design: A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico). Methods: Study participants (HIV-1 RNA ≥1000 copies/ml, CD4+ cell count ≥200 cells/μl, C-C chemokine receptor type 5-tropic virus) were randomized 2 : 2 : 1 to CVC 100 mg (CVC100), CVC 200 mg (CVC200), or EFV 600 mg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48. Results: A total of 143 patients were randomized (CVC100, n = 59; CVC200, n = 56; EFV, n = 28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all P > 0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all P > 0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8 ng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC. Conclusion: CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC

  4. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus.

    PubMed

    Thompson, Melanie; Saag, Michael; DeJesus, Edwin; Gathe, Joseph; Lalezari, Jay; Landay, Alan L; Cade, Jerry; Enejosa, Jeffrey; Lefebvre, Eric; Feinberg, Judith

    2016-03-27

    To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults. A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico). Study participants (HIV-1 RNA ≥1000 copies/ml, CD4 cell count ≥200 cells/μl, C-C chemokine receptor type 5-tropic virus) were randomized 2 : 2 : 1 to CVC 100 mg (CVC100), CVC 200 mg (CVC200), or EFV 600 mg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48. A total of 143 patients were randomized (CVC100, n = 59; CVC200, n = 56; EFV, n = 28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all P > 0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all P > 0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8 ng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC. CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC200 for phase 3 studies. NCT01338883.

  5. Clinical manifestations of treatment-naive patients with acquired immunodeficiency syndrome and responses to highly active antiretroviral therapy in the Taipei Veterans General Hospital: a 5-year prospective study.

    PubMed

    Hsu, Shih-Fen; Yang, Su-Pen; Chan, Yu-Jiun; Wang, Yung-Wei

    2011-06-01

    Taipei Veterans General Hospital, one of the medical centers in Taiwan, has provided highly active antiretroviral therapy (HAART) to human immunodeficiency virus/AIDS patients for more than 10 years. Five years ago, we began a prospective follow-up of our patients' clinical manifestations and responses to HAART by collecting their clinical data. In this study, we analyzed the morbidity, mortality, and responses to HAART of treatment-naive AIDS patients. The purpose was to provide local data that may be valuable in Taiwan. Study cases were enrolled from January 1, 2004, to February 28, 2009, with inclusion criteria of newly diagnosed AIDS during hospitalization and being naive to HAART. Antiretroviral therapy was initiated. To evaluate the clinical responses to HAART, we excluded patients who were pregnant, died within 1 month after confirmation of an AIDS diagnosis, failed to initiate HAART, or were lost to follow-up for more than 6 months. Plasma viral loads and CD4(+) counts were quantified by reverse-transcriptase polymerase chain reaction and flow cytometry, respectively. Statistical analysis was performed using SPSS statistical software. A total of 49 patients were enrolled and 45 patients fulfilled the inclusion criteria for evaluating the efficacy of HAART. At 3 months, 12 months, and 30 months after the initiation of HAART, 64.4% (29 of 45), 88.2% (30 of 34), and 93.8% (15 of 16) had undetectable plasma viral loads, respectively, and 37.8% (17 of 45), 73.5% (25 of 34), and 81.2% (13 of 16) had CD4(+) counts of more than 200 cells/μL, respectively. Median CD4(+) counts increased from baseline at Month 3 by 171 cells/μL and at Month 30 by 375 cells/μL. The overall mortality was 22.4% (11 of 49). The virologic and immunologic responses after initiating HAART in this study demonstrated our achievements in providing care and treatment for AIDS patients during this 5-year period, which provides a strong evidence of the efficacy of HAART. Copyright © 2011

  6. Similar Prevalence of Low-Abundance Drug-Resistant Variants in Treatment-Naive Patients with Genotype 1a and 1b Hepatitis C Virus Infections as Determined by Ultradeep Pyrosequencing

    PubMed Central

    Liu, Tommy F.; Shulman, Nancy; Shafer, Robert W.; Najera, Isabel

    2014-01-01

    Background and Objectives Hepatitis C virus (HCV) variants that confer resistance to direct-acting-antiviral agents (DAA) have been detected by standard sequencing technology in genotype (G) 1 viruses from DAA-naive patients. It has recently been shown that virological response rates are higher and breakthrough rates are lower in G1b infected patients than in G1a infected patients treated with certain classes of HCV DAAs. It is not known whether this corresponds to a difference in the composition of G1a and G1b HCV quasispecies in regards to the proportion of naturally occurring DAA-resistant variants before treatment. Methods We used ultradeep pyrosequencing to determine the prevalence of low-abundance (<25% of the sequence reads) DAA-resistant variants in 191 NS3 and 116 NS5B isolates from 208 DAA-naive G1-infected patients. Results A total of 3.5 million high-quality reads of ≥200 nucleotides were generated. The median coverage depth was 4150x and 4470x per NS3 and NS5B amplicon, respectively. Both G1a and G1b populations showed Shannon entropy distributions, with no difference between G1a and G1b in NS3 or NS5B region at the nucleotide level. A higher number of substitutions that confer resistance to protease inhibitors were observed in G1a isolates (mainly at amino acid 80 of the NS3 region). The prevalence of amino acid substitutions that confer resistance to NS5B non-nucleoside inhibitors was similar in G1a and G1b isolates. The NS5B S282T variant, which confers resistance to the polymerase inhibitors mericitabine and sofosbuvir, was not detected in any sample. Conclusion The quasispecies genetic diversity and prevalence of DAA-resistant variants was similar in G1a and G1b isolates and in both NS3 and NS5B regions, suggesting that this is not a determinant for the higher level of DAA resistance observed across G1a HCV infected patients upon treatment. PMID:25140696

  7. Personalized therapy for chronic viral hepatitis C in the naive patient: How can we optimize treatment duration as a function of viral genotype?

    PubMed

    Nguyen-Khac, Eric; Capron, Dominique; Castelain, Sandrine; François, Catherine; Braillon, Alain

    2007-11-01

    Pegylated interferon plus ribavirin is the standard treatment for chronic hepatitis C (CHC). It yields sustained virological response (SVR) rates of 42-52% for genotype 1, 66-72% for genotype 4, and 76-80% for genotypes 2 and 3. Hence, the patient's genotype appears to be a determining predictive factor for the SVR. We have reviewed the literature in order to determine whether a genotype-specific treatment duration should be envisaged. The largest study to date of patients infected with HCV genotype 2 or 3 confirmed the value of the standard treatment duration of 24 weeks. Shorter treatments exposed the patients to a greater risk of relapse. For genotype 1, it was possible to offer a shorter, 24-week course of treatment to the 35% of patients with an initial viral load below 600,000 IU/mL and an early virological response (EVR) at week 4 (negative PCR), resulting in an SVR of 89%. For the remaining two-thirds of genotype 1 patients with a high viral load, the treatment duration should remain at 48 weeks. A subgroup of patients - the "slow virological responders" (positive PCR at week 12 but with less than 6000 IU/mL; negative PCR at week 24) - benefited from the extension of the treatment to 72 weeks, with an SVR of 88%. For patients infected with genotype 4 virus, combination therapy should feature a ribavirin dose of more than 1000 mg/day for an optimal duration of 48 weeks.

  8. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.

    PubMed

    Manns, Michael; Marcellin, Patrick; Poordad, Fred; de Araujo, Evaldo Stanislau Affonso; Buti, Maria; Horsmans, Yves; Janczewska, Ewa; Villamil, Federico; Scott, Jane; Peeters, Monika; Lenz, Oliver; Ouwerkerk-Mahadevan, Sivi; De La Rosa, Guy; Kalmeijer, Ronald; Sinha, Rekha; Beumont-Mauviel, Maria

    2014-08-02

    Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. 209 (81%) of 257 patients in the simeprevir group and

  9. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial.

    PubMed

    Lawitz, Eric; Poordad, Fred F; Pang, Phillip S; Hyland, Robert H; Ding, Xiao; Mo, Hongmei; Symonds, William T; McHutchison, John G; Membreno, Fernando E

    2014-02-08

    Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen--a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin--in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen. For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329978. In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75-100) in group 1, by 21 (100%) of 21 patients (84-100) in group 2, and by 18 (95%) of 19 patients (74-100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74-100) in group 4 and by all 21 (100%) of 21 patients (84-100) in group 5. Two patients had viral relapse; one patient was

  10. Vitalism in naive biological thinking.

    PubMed

    Morris, S C; Taplin, J E; Gelman, S A

    2000-09-01

    Vitalism is the belief that internal bodily organs have agency and that they transmit or exchange a vital force or energy. Three experiments investigated the use of vitalistic explanations for biological phenomena by 5- and 10-year-old English-speaking children and adults, focusing on 2 components: the notion that bodily organs have intentions and the notion that some life force or energy is transmitted. The original Japanese finding of vitalistic thinking was replicated in Experiment 1 with English-speaking 5-year-olds. Experiment 2 indicated that the more active component of vitalism for these children is a belief in the transfer of energy during biological processes, and Experiment 3 suggested an additional, albeit lesser, role for organ intentionality. A belief in vital energy may serve a causal placeholder function within a naive theory of biology until a more precisely formulated mechanism is known.

  11. [Comparative cost-effectiveness analysis between darunavir/ritonavir and other protease inhibitors in treatment-naive human immunodeficiency syndrome type 1-infected patients in Spain].

    PubMed

    Smets, Erik; Brogan, Anita J; Hill, Andrew; Adriaenssen, Ines; Sawyer, Anthony W; Domingo-Pedrol, Pere; Gostkorzewicz, Joana; Ledesma, Francisco

    2013-01-01

    GESIDA (AIDS Study Group) has proposed preferred regimens of antiretroviral treatment as initial therapy in HIV infected patients. The objective of this analysis is to compare the costs and effectiveness of darunavir/r QD and other ritonavir-boosted (/r) protease inhibitors (PIs) currently recommended in GESIDA guidelines for treatment-naïve patients. A cost-efficacy model compared the boosted PIs recommended as preferred or alternative treatment choices, each used with a nucleoside reverse transcriptase inhibitor backbone. Efficacy was measured by 48-week virological response (viral load < 50 copies/mL) adjusted by baseline viral load and CD4 cell count. To generate efficiency frontiers and cost-efficacy ratios, one-year antiretroviral therapy costs in Spain, and 48-week efficacy values were used. The model estimated that starting treatment with darunavir/r QD was the most cost-effective choice compared with the other preferred PI/r based therapies. The average cost per patient with a virological response was lower for darunavir/r QD (13,420€) than for atazanavir/r QD (14,000€), or lopinavir/r BID (13,815€). Among the preferred PI/r-based therapies, darunavir/r QD also was estimated to be the most efficient option for treatment-naïve patients. Atazanavir/r QD and lopinavir/r BID were found to be «dominated» by darunavir/r) and, consequently, were outside the efficiency frontier of PI/r-based first-line treatment. Given a fixed budget of 10 million euros for PI/r-based first-line therapy, the model estimated that darunavir/r QD would yield more responders (745) than atazanavir/r QD (714), or lopinavir/r BID (724). At the same time, darunavir/r QD would reduce the number of individuals failing treatment (150) compared with atazanavir/r QD (172) and lopinavir/r BID (286). In this model, darunavir/r QD was found to be the most cost-effective choice, among the preferred PI/r-based therapies recommended in the Spanish guidelines for treatment-naïve patients

  12. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer.

    PubMed

    Altorki, Nasser; Lane, Maureen E; Bauer, Thomas; Lee, Paul C; Guarino, Michael J; Pass, Harvey; Felip, Enriqueta; Peylan-Ramu, Nili; Gurpide, Alfonso; Grannis, Frederic W; Mitchell, John D; Tachdjian, Sabrina; Swann, R Suzanne; Huff, Anne; Roychowdhury, Debasish F; Reeves, Anthony; Ottesen, Lone H; Yankelevitz, David F

    2010-07-01

    Patients with early-stage, resectable, non-small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC. Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients. Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction > or = 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment. Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned.

  13. Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection

    PubMed Central

    Al-Mahtab, Mamun; Bazinet, Michel; Vaillant, Andrew

    2016-01-01

    Previous in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2–7 log reductions of serum HBsAg, 3–9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10–1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which

  14. Covariation between motor signs and negative symptoms in drug-naive subjects with schizophrenia-spectrum disorders before and after antipsychotic treatment.

    PubMed

    Peralta, Victor; de Jalón, Elena García; Campos, María S; Cuesta, Manuel J

    2017-08-29

    Objective To examine the covariation between negative symptoms and motor signs in a broad sample of drug-naïve subjects with schizophrenia-spectrum psychoses before and after inception of antipsychotic medication. One-hundred and eighty-nine antipsychotic-naïve subjects with DSM-IV schizophrenia-spectrum psychoses were assessed for negative symptoms including affective flattening, alogia, avolition/apathy and anhedonia/associality, and motor signs including catatonia, parkinsonism and dyskinesia. We examined the association between negative and motor features at baseline, 4-weeks after inception of antipsychotic treatment and that of their mean change over the treatment period, such as their trajectories and treatment response pattern. At the drug-naïve state, motor signs were strongly related to affective flattening and alogia (p<0.01); at 4-weeks, most negative and motor features were significantly interrelated (p<0.01); mean change of motor signs and negative symptoms tended to be unrelated. This association pattern was irrespective of levels of positive symptoms. Ratings of negative symptoms, excepting affective flattening, improved after treatment (p<0.001) while motor ratings showed divergent trajectories with catatonia improving (p<0.001), parkinsonism worsening (p<0.001) and dyskinesia remaining unchanged (p>0.01). Although to a different extent, motor and negative features showed drug-responsive, drug-worsening, of drug-unchanged patterns of response to antipsychotic medication. The main predictors of negative and motor features in treated subjects were their corresponding baseline ratings (p<0.001). Negative and motor features are differentiated, but to some extent, overlapping domains that are meaningfully influenced by antipsychotic medication. At the drug-naïve state, motor signs and the diminished expression domain of negative symptoms may share underlying neurobiological mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Cost effectiveness of direct-acting antiviral therapy for treatment-naive patients with chronic HCV genotype 1 infection in the veterans health administration.

    PubMed

    Chan, Kee; Lai, Mai Ngan; Groessl, Erik J; Hanchate, Amresh D; Wong, John B; Clark, Jack A; Asch, Steven M; Gifford, Allen L; Ho, Samuel B

    2013-11-01

    The Veterans Health Administration (VHA) is the largest single provider of care for hepatitis C virus (HCV) infection in the United States. We analyzed the cost effectiveness of treatment with the HCV protease inhibitors boceprevir and telaprevir in a defined managed care population of 102,851 patients with untreated chronic genotype 1 infection. We used a decision-analytic Markov model to examine 4 strategies: standard dual-therapy with pegylated interferon-alfa and ribavirin (PR), the combination of boceprevir and PR triple therapy, the combination of telaprevir and PR, or no antiviral treatment. A sensitivity analysis was performed. Sources of data included published rates of disease progression, the census bureau, and VHA pharmacy and hospitalization cost databases. The estimated costs for treating each patient were $8000 for PR, $31,300 for boceprevir and PR, and $41,700 for telaprevir and PR. Assuming VHA treatment rates of 22% and optimal rates of sustained virologic response, PR, boceprevir and PR, and telaprevir and PR would reduce relative liver-related deaths by 5.2%, 10.9%, and 11.5%, respectively. Increasing treatment rates to 50% would reduce liver-related deaths by 12%, 24.7%, and 26.1%, respectively. The incremental cost-effectiveness ratios were $29,184/quality-adjusted life-years for boceprevir and PR and $44,247/quality-adjusted life-years for telaprevir and PR vs only PR. With the current 22% treatment rate, total system-wide costs to adopt boceprevir and PR or telaprevir and PR would range from $708 to $943 million. Despite substantial up-front costs of treating HCV-infected patients in the VHA with PR, or telaprevir and PR, each regimen improves quality of life and extends life expectancy by reducing liver-related morbidity and mortality, and should be cost effective. Further efforts to expand access to direct-acting antiviral therapy are warranted. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Role of vaginal pallor reaction in predicting late vaginal stenosis after high-dose-rate brachytherapy in treatment-naive patients with cervical cancer.

    PubMed

    Yoshida, Ken; Yamazaki, Hideya; Nakamura, Satoaki; Masui, Koji; Kotsuma, Tadayuki; Akiyama, Hironori; Tanaka, Eiichi; Yoshikawa, Nobuhiko; Uesugi, Yasuo; Shimbo, Taiju; Narumi, Yoshifumi; Yoshioka, Yasuo

    2015-07-01

    To assess actual rates of late vaginal stenosis and identify predisposing factors for complications among patients with previously untreated cervical cancer following high-dose-rate brachytherapy. We performed longitudinal analyses of 57 patients using the modified Dische score at 6, 12, 18, 24, 36, and 60 months after treatment, which consisted of 15 interstitial brachytherapys and 42 conventional intracavitary brachytherapys, with a median follow-up time of 36 months (range, 6 to 144 months). More than half of the patients developed grade 1 (mild) vaginal stenosis within the first year of follow-up, and grade 2 (97.5%, moderate) to grade 3 (severe) stenosis gradually increased with time. Actual stenosis rates for grade 1, 2, and 3 were 97.5% (95% confidence interval [CI], 92.7 to 97.5), 60.7% (95% CI, 42.2 to 79.3), and 7.4% (95% CI, 0 to 18.4) at 3 years after treatment. Pallor reaction grade 2-3 at 6 months was only a statistically significant predisposing factor for grade 2-3 late vaginal stenosis 3 years or later with a hazard ratio of 3.48 (95% CI, 1.32 to 9.19; p=0.018) by a multivariate Cox proportional hazard model. Patients with grade 0-1 pallor reaction at 6 months showed a grade ≥2 vaginal stenosis rate of 53%, whereas the grade 2-3 pallor reaction group achieved a grade ≥2 vaginal stenosis rate at 3 years at 100% (p=0.001). High-dose-rate brachytherapy was associated with high incidence of late vaginal stenosis. Pallor reaction grade 2-3 at 6 months was predictive of late grade 2-3 vaginal stenosis at 3 years after treatment. These findings should prove helpful for patient counseling and preventive intervention.

  17. Hippocampal and orbital inferior frontal gray matter volume abnormalities and cognitive deficit in treatment-naive, first-episode patients with schizophrenia.

    PubMed

    Guo, Xiaofeng; Li, Jun; Wang, Juan; Fan, Xiaoduo; Hu, Maorong; Shen, Yidong; Chen, Huafu; Zhao, Jingping

    2014-02-01

    Cognitive impairment is a core feature of schizophrenia. Some evidence suggests an association between cognition deficits and gray matter reductions. In this study, we investigated the relationship between cognitive performance and gray matter volumes in patients with treatment-naïve, first-episode schizophrenia. First-episode patients with treatment-naïve schizophrenia and healthy controls went through brain imaging scan using high resolution magnetic resonance imaging. A neuropsychological battery including 8 neurocognitive tests was used to assess cognitive function. Voxel-based methods were used for volumetric measure in the brain. Fifty-one patients and 41 healthy controls were included in the analysis. Patients exhibited a poorer performance on all 7 cognitive function tests compared with healthy controls (ps<0.006). There were significant gray matter volume differences between the two groups in bilateral hippocampus gyri, right superior temporal gyrus, left fusiform gyrus and orbital inferior frontal gyri (FDR, ps<0.05). Within the schizophrenia group, multiple regression analysis demonstrated that poorer performance on the working memory, verbal learning and visual learning was associated with smaller hippocampal gray matter volume, and poorer executive function was associated with smaller left orbital inferior frontal gray matter volume after controlling for potential confounding variables (β ≥ 0.420, ps ≤ 0.010). Our findings suggest that cognitive deficits are associated with hippocampal and orbital inferior frontal gray matter volume abnormalities in treatment-naïve, first-episode patients with schizophrenia. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Lateral and medial hypofrontality in first-episode schizophrenia: functional activity in a medication-naive state and effects of short-term atypical antipsychotic treatment.

    PubMed

    Snitz, Beth E; MacDonald, Angus; Cohen, Jonathan D; Cho, Raymond Y; Becker, Theresa; Carter, Cameron S

    2005-12-01

    The dorsolateral prefrontal cortex and the anterior cingulate cortex are critical components of the brain circuitry underlying executive control. The objective of this study was to investigate control-related dorsolateral prefrontal cortex functioning and conflict-related anterior cingulate cortex functioning in a group of never medicated first-episode schizophrenia patients to determine whether both regions show dysfunction at illness onset. A second objective was to assess short-term effects of atypical antipsychotic medication on dorsolateral prefrontal cortex and anterior cingulate cortex functioning. First-episode schizophrenia patients (N=23) and healthy comparison subjects (N=24) underwent event-related fMRI and performed a cognitive task designed to functionally dissociate the two regions. Four weeks after initiation of pharmacotherapy for patients, a subset of 11 patients and 16 comparison subjects underwent a repeat assessment. At baseline, patients exhibited hypoactivation in the dorsolateral prefrontal cortex and anterior cingulate cortex. After 4 weeks of antipsychotic treatment, the patients demonstrated improved functioning in the anterior cingulate cortex but not in the dorsolateral prefrontal cortex. These findings confirm the presence of dorsolateral prefrontal cortex dysfunction early in the course of schizophrenia and suggest that anterior cingulate cortex functioning may be altered at illness onset as well. Results also suggest that anterior cingulate cortex functioning may be especially sensitive to remedial antipsychotic treatment effects. These findings are consistent with an emerging literature documenting short-term benefits of atypical antipsychotic medication for the neural circuitry underlying cognitive deficits in schizophrenia.

  19. Effects of once-daily darunavir/ritonavir versus lopinavir/ritonavir on metabolic parameters in treatment-naive HIV-1-infected patients at week 96: ARTEMIS.

    PubMed

    Arathoon, E; Schneider, S; Baraldi, E; Lim, P L; Opravil, M; Van De Casteele, T; Lavreys, L

    2013-01-01

    In the ARTEMIS trial, 689 treatment-naïve, HIV-1-infected adults received darunavir/ritonavir (DRV/r) 800/100 mg every day or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose plus fixed-dose tenofovir/emtricitabine. Week 96 metabolic parameters are reported. Adverse events (AEs) classed as metabolism/nutrition disorders were observed in 14% of DRV/r and 22% of LPV/r patients. Lipid-related AEs were reported in fewer DRV/r (8%) than LPV/r (16%) patients. A small increase in glucose and insulin levels was observed at week 96 in both groups. Lipoma was the only lipodystrophy-related AE reported in >1% of patients (DRV/r, n = 1; LPV/r, n = 4) and no grade 3 or 4 lipodystrophy-related AEs were reported. No clinically relevant changes from baseline were seen in anthropometric measurements in either group. Median mid-waist/hip ratio at week 96 was comparable to baseline in both arms. Over 96 weeks, DRV/r had a similar effect on glucose and insulin levels but a more favourable lipid profile than LPV/r in treatment-naïve, HIV-infected patients.

  20. 12-Step Therapy and Women with and without Social Phobia: A Study of the Effectiveness of 12-Step Therapy to Facilitate AA Engagement

    PubMed Central

    Tonigan, J. Scott; Book, Sarah W.; Pagano, Maria E.; Randall, Patrick K.; Smith, Joshua P.; Randall, Carrie L.

    2011-01-01

    Alcoholism treatment often encourages involvement in Alcoholics Anonymous (AA). Little provision is made for women with social phobia (SP), who have been reported to have worse outcomes in twelve-step-facilitation (TSF) relative to cognitive behavioral therapy. This study examined whether SP moderated the effects of gender for these women in TSF. 133 SP alcoholics assigned to TSF (35 females and 98 males) in Project MATCH were compared to a non-SP control group. SP women drank earlier and more intensely than non-SP women and all males, had equivalent AA attendance and completion of Step 5, and were less likely to acquire a sponsor during TSF. PMID:21423569

  1. IFN-λ gene polymorphisms as predictive factors in chronic hepatitis C treatment-naive patients without access to protease inhibitors.

    PubMed

    Olmedo, Daniele Blasquez; Cader, Samária Ali; Porto, Luís Cristóvão

    2015-10-01

    The single nucleotides polymorphisms analyses in the regions near the IL28B gene in patients chronically infected with genotype 1 hepatitis C virus (HCV) are an important predictive factor for sustained virological response (SVR). The aim was to assess the predictive value of the polymorphisms of the IL28B/IFNL3 gene in patients chronically infected with genotype 1 for the viral clearance obtained after initial treatment including admixed populations. A systematic review was conducted, using a meta-analysis in the PubMed, Embase, LILACS, and SCIELO using MesH and DECS in 42 studies. The parameters were IL28B polymorphisms, rs12979860, rs8099917, and rs12980275, SVR ratio, and OR (odds ratio). OR and confidence Interval of 95% (95%CI), were calculated by fixed or random effects models. Heterogeneity, sensitivity analysis, and publication bias were also performed. Significant differences were noted between carriers groups with the major versus minor allele at rs12979860 CC versus CT/TT-genotype (OR = 4.18; 95%CI = 3.37-5.17), rs8099917 TT versus TG/GG-genotype (OR = 4.07; 95%CI = 2.94-5.63), and rs12980275 AA versus AA/AG-genotype (OR = 5.34; 95%CI = 1.60-17.82). There was selection bias in the rs8099917 analysis (Egger's regression P = 0.049), which reversed after performing a sensitivity analysis (P = 0.510). The incorporation of SNP analyses in IL28B/IFNL3 gene during the diagnosis process in Brazil should be used as a complementary tool to determine the appropriate treatment for HCV genotype 1. Here, we confirm that the rs12979860 CC, rs8099917 TT, and rs12980275 AA genotype-carriers have favorable responses to standard therapy, including two studies with Brazilian population, and this information should be considered.

  2. Effect of Linezolid on the 50% Lethal Dose and 50% Protective Dose in Treatment of Infections by Gram-Negative Pathogens in Naive and Immunosuppressed Mice and on the Efficacy of Ciprofloxacin in an Acute Murine Model of Septicemia

    PubMed Central

    Marra, Andrea; Lamb, Lucinda; Medina, Ivette; George, David; Gibson, Glenn; Hardink, Joel; Rugg, Jady; Van Deusen, Jeffrey

    2012-01-01

    Murine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD50s) and 50% protective doses (PD50s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD50 in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD50s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin. PMID:22710118

  3. Comparison of Genotypic and Phenotypic HIV Type 1 Tropism Assay: Results from the Screening Samples of Cenicriviroc Study 202, a Randomized Phase II Trial in Treatment-Naive Subjects

    PubMed Central

    Johnson, Erik P.; Siaw, Martin F.; Van Baelen, Ben; Ogden, Richard; Platt, Jamie L.; Pesano, Rick L.; Lefebvre, Eric

    2014-01-01

    Abstract Cenicriviroc is a once-daily oral CCR5/CCR2 antagonist in development for treatment of HIV infection. CVC Study 202 (652-2-202; NCT01338883) excluded treatment-naive subjects demonstrated to harbor non-R5 (CXCR4-tropic or dual-mixed) tropic HIV-1 by either genotypic or phenotypic tropism testing. Here we compare the results of genotypic and phenotypic tropism testing in Study 202. A total of 304 subjects screened had paired genotypic and phenotypic results. Genotypic tropism testing (GTT) incorporated triplicate population sequencing using the geno2pheno algorithm and the PSSM algorithm, followed by ultradeep sequencing (UDS) for samples with R5 results. All samples were further evaluated with a phenotypic test, the enhanced-sensitivity Trofile assay (ESTA). Concordance between GTT and ESTA was 80% and increased to 84% when only geno2pheno was used for triplicate population sequencing. GTT (geno2pheno) classified 18% of the samples as non-R5 compared to 16% by ESTA. Only one-third of samples with non-R5 results by either test were classified as non-R5 by both tests. Median CD4(+) cell counts were lower in patients with concordant non-R5 results by UDS and ESTA than in subjects with an R5 result by either assay (p=0.0004). UDS detected non-R5 virus in an additional 27/304 subjects (median 15% non-R5, interquartile range: 3.7–62%) with R5 results by ESTA. In conclusion, the geno2pheno algorithm improves concordance of GTT with a clinically validated phenotypic tropism assay as does the use of UDS. These findings provide support for recent guidelines indicating that genotypic tropism testing may be considered as an alternative to phenotypic testing. PMID:23875707

  4. Baseline CD4 cell counts and outcomes among adult treatment naive HIV patients after taking fixed dose combination GPO-VIR-S and GPO-VIR-Z in Thailand.

    PubMed

    Kyaw, Nyan Lin; Thanachartwet, Vipa; Kiertiburanakul, Sasisopin; Desakorn, Varunee; Chamnanchanunt, Supat; Chierakul, Wirongrong; Manosuthi, Weerawat; Pitisuttithum, Punnee; Sungkanuparph, Somnuek

    2013-03-01

    A retrospective study was conducted by reviewing 459 medical records of adult treatment naive HIV patients who received a fixed dose combination of GPO-VIR-S (stavudine, lamivudine and nevirapine) or GPO-VIR-Z (zidovudine, lamivudine and nevirapine) at Ramathibodi Hospital in Bangkok, Thailand during 2002-2009 following Thai National Treatment Guideline for adults with HIV. The aim of this study was to assess the association between the baseline CD4 cell count and outcome. The median CD4 cell count at baseline, 6, 12 and 102 months were 102 cells/microl, 213 cells/microl, 274 cells/microl and 423 cells/microl. The virologic response (p=0.327), virologic rebound (p=0.626), adverse effects of anti-retroviral therapy (ART) (p=0.976), switching to other ART (p=0.245), occurrence of immune reconstitution inflammatory syndrome (IRIS) (p>0.05) and occurrence of drug resistance (p=0.952) were not significantly associated with baseline CD4 count. The Kaplan-Meier estimate showed the median time (95% CI) to achieve virologic response was 10.4 (9.8-11.0) months and the median time to achieve virologic rebound was 30.0 (21.6-38.4) months after initiation of ART. Analysis showed the median time to achieved virologic response (p=0.401) and virologic rebound (p=0.562) were not significantly associated with the baseline CD4 count. This study shows the outcome after onset of ART did not vary by baseline CD4 cell count.

  5. Comparative changes of lipid levels in treatment-naive, HIV-1-infected adults treated with dolutegravir vs. efavirenz, raltegravir, and ritonavir-boosted darunavir-based regimens over 48 weeks.

    PubMed

    Quercia, Romina; Roberts, Jeremy; Martin-Carpenter, Louise; Zala, Carlos

    2015-03-01

    Long-term use of antiretroviral therapy (ART) to treat HIV infection has been associated with dyslipidemia and metabolic and cardiovascular complications. Available options for patients at risk of cardiovascular disease include antiretroviral drugs with improved lipid profiles. Dolutegravir is one of a new generation of HIV integrase inhibitors recently incorporated into the US Department of Health and Human Services, German, Spanish, and Italian HIV treatment guidelines as a preferred first-line third agent in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) backbone therapies. To understand the lipid profile of dolutegravir in the context of combination ART, we analyzed the lipid outcomes at 48 weeks in ART-naive participants in four phase IIb-IIIb clinical trials. Variables included in this analysis were total cholesterol (TC), low-density lipoprotein (LDL) cholesterol (LDL-C), high-density lipoprotein (HDL) cholesterol (HDL-C), TC/HDL ratio, and triglycerides at baseline and week 48. In a comparative analysis, dolutegravir demonstrated a broadly neutral effect on lipids versus efavirenz or ritonavir-boosted darunavir; in both comparisons, patients taking dolutegravir exhibited smaller increases in TC, LDL-C, and triglyceride levels. In comparison with raltegravir, dolutegravir exhibited a similar lipid profile, including small increases in TC, LDL-C, and triglyceride levels for both agents. In the pooled dolutegravir analysis, minimal increases in LDL-C and triglycerides were observed but mean values at 48 weeks remained below National Cholesterol Education Program target levels. HDL-C levels increased at 48 weeks, and the mean TC/HDL-C ratio was 0.6 at 48 weeks; these values are associated with a lower risk of cardiovascular disease. Together, these data show that dolutegravir has a safer lipid profile in combination ART and provides an important treatment option for older patients who may have other risk factors for metabolic syndrome

  6. Prevalence of drug resistance among HIV-1 treatment-naive patients in Greece during 2003-2015: Transmitted drug resistance is due to onward transmissions.

    PubMed

    Paraskevis, D; Kostaki, E; Magiorkinis, G; Gargalianos, P; Xylomenos, G; Magiorkinis, E; Lazanas, M; Chini, M; Nikolopoulos, G; Skoutelis, A; Papastamopoulos, V; Antoniadou, A; Papadopoulos, A; Psichogiou, M; Daikos, G L; Oikonomopoulou, M; Zavitsanou, A; Chrysos, G; Paparizos, V; Kourkounti, S; Sambatakou, H; Sipsas, N V; Lada, M; Panagopoulos, P; Maltezos, E; Drimis, S; Hatzakis, A

    2017-10-01

    The prevalence of HIV-1 drug resistance among treatment-naïve patients ranges between 8.3% and 15% in Europe and North America. Previous studies showed that subtypes A and B were the most prevalent in the Greek HIV-1 epidemic. Our aim was to estimate the prevalence of resistance among drug naïve patients in Greece and to investigate the levels of transmission networking among those carrying resistant strains. HIV-1 sequences were determined from 3428 drug naïve HIV-1 patients, in Greece sampled during 01/01/2003-30/6/2015. Transmission clusters were estimated by means of phylogenetic analysis including as references sequences from patients failing antiretroviral treatment in Greece and sequences sampled globally. The proportion of sequences with SDRMs was 5.98% (n=205). The most prevalent SDRMs were found for NNRTIs (3.76%), followed by N(t)RTIs (2.28%) and PIs (1.02%). The resistance prevalence was 22.2% based on all mutations associated with resistance estimated using the HIVdb resistance interpretation algorithm. Resistance to NNRTIs was the most common (16.9%) followed by PIs (4.9%) and N(t)RTIs (2.8%). The most frequently observed NNRTI resistant mutations were E138A (7.7%), E138Q (4.0%), K103N (2.3%) and V179D (1.3%). The majority of subtype A sequences (89.7%; 245 out of 273) with the dominant NNRTI resistance mutations (E138A, K103N, E138Q, V179D) were found to belong to monophyletic clusters suggesting regional dispersal. For subtype B, 68.1% (139 out of 204) of resistant strains (E138A, K103N, E138Q V179D) belonged to clusters. For N(t)RTI-resistance, evidence for regional dispersal was found for 27.3% and 21.6% of subtype A and B sequences, respectively. The TDR rate based on the prevalence of SDRM is lower than the average rate in Europe. However, the prevalence of NNRTI resistance estimated using the HIVdb approach, is high in Greece and it is mostly due to onward transmissions among drug-naïve patients. Copyright © 2017 Elsevier B.V. All rights

  7. Safety and Antiviral Activity of the HCV Entry Inhibitor ITX5061 in Treatment-Naive HCV-Infected Adults: A Randomized, Double-Blind, Phase 1b Study

    PubMed Central

    Sulkowski, Mark S.; Kang, Minhee; Matining, Roy; Wyles, David; Johnson, Victoria A.; Morse, Gene D.; Amorosa, Valerianna; Bhattacharya, Debika; Coughlin, Kristine; Wong-Staal, Flossie; Glesby, Marshall J.

    2014-01-01

    Background. Hepatitis C virus (HCV) entry involves scavenger receptor B1 (SRB1). In vitro, SRB1 inhibition by ITX5061 impedes HCV replication. Methods. Multicenter study to assess safety/activity of ITX5061 in previously untreated, noncirrhotic, HCV genotype 1 infected adults. Design included sequential cohorts of 10 subjects with ITX5061 (n = 8) or placebo (n = 2) to escalate duration (3 to 14 to 28 days) or deescalate dose (150 to 75 to 25 mg) based on predefined criteria for safety and activity (≥4 of 8 subjects with HCV RNA decline ≥1 log10 IU/mL). Results. Thirty subjects enrolled in 3 cohorts: ITX5061 150 mg/day by mouth for 3 (A150), 14 (B150), and 28 (C150) days. Six subjects had grade ≥3 adverse events (one in placebo); none were treatment related. One of the 7 C150 subjects (14.3%, 95% confidence interval [CI], .7%–55.4%) had ≥1 log10 IU/mL decline in HCV RNA (1.49 log10 IU/mL), whereas none of the 6 placebo, 8 A150 or 8 B150 subjects showed such decline. Conclusions. Oral ITX5061 150 mg/day for up to 28 days was safe and well tolerated. In the 28-day cohort, 1 of 7 subjects showed antiviral activity; however, predefined criteria for antiviral activity were not met at the doses and durations studied. PMID:24041792

  8. Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-Infected adults treated with rilpivirine or Efavirenz for 96 weeks in the ECHO and THRIVE trials.

    PubMed

    Tebas, Pablo; Sension, Michael; Arribas, José; Duiculescu, Dan; Florence, Eric; Hung, Chien-Ching; Wilkin, Timothy; Vanveggel, Simon; Stevens, Marita; Deckx, Henri

    2014-08-01

    Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials. We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1). Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t]RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV- than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it. Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid

  9. Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individuals

    PubMed Central

    Winand, Raf; Theys, Kristof; Eusébio, Mónica; Aerts, Jan; Camacho, Ricardo J.; Gomes, Perpetua; Suchard, Marc A.; Vandamme, Anne-Mieke; Abecasis, Ana B.

    2015-01-01

    Objectives: Surveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs. Design: This is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients. Methods: The prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility. Results: Prevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers – above (PRO: D30N, N88D/S, L90 M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads. Conclusion: The significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with

  10. The Naive Intuitive Statistician: A Naive Sampling Model of Intuitive Confidence Intervals

    ERIC Educational Resources Information Center

    Juslin, Peter; Winman, Anders; Hansson, Patrik

    2007-01-01

    The perspective of the naive intuitive statistician is outlined and applied to explain overconfidence when people produce intuitive confidence intervals and why this format leads to more overconfidence than other formally equivalent formats. The naive sampling model implies that people accurately describe the sample information they have but are…

  11. Comparing Acceptance and Commitment Group Therapy and 12-Steps Narcotics Anonymous in Addict’s Rehabilitation Process: A Randomized Controlled Trial

    PubMed Central

    Azkhosh, Manoochehr; Farhoudianm, Ali; Saadati, Hemn; Shoaee, Fateme; Lashani, Leila

    2016-01-01

    Objective: Substance abuse is a socio-psychological disorder. The aim of this study was to compare the effectiveness of acceptance and commitment therapy with 12-steps Narcotics Anonymous on psychological well-being of opiate dependent individuals in addiction treatment centers in Shiraz, Iran. Method: This was a randomized controlled trial. Data were collected at entry into the study and at post-test and follow-up visits. The participants were selected from opiate addicted individuals who referred to addiction treatment centers in Shiraz. Sixty individuals were evaluated according to inclusion/ exclusion criteria and were divided into three equal groups randomly (20 participants per group). One group received acceptance and commitment group therapy (Twelve 90-minute sessions) and the other group was provided with the 12-steps Narcotics Anonymous program and the control group received the usual methadone maintenance treatment. During the treatment process, seven participants dropped out. Data were collected using the psychological well-being questionnaire and AAQ questionnaire in the three groups at pre-test, post-test and follow-up visits. Data were analyzed using repeated measure analysis of variance. Results: Repeated measure analysis of variance revealed that the mean difference between the three groups was significant (P<0.05) and that acceptance and commitment therapy group showed improvement relative to the NA and control groups on psychological well-being and psychological flexibility. Conclusion: The results of this study revealed that acceptance and commitment therapy can be helpful in enhancing positive emotions and increasing psychological well-being of addicts who seek treatment. PMID:28050185

  12. Coping Skills Training and 12-Step Facilitation for Women Whose Partner Has Alcoholism: Effects on Depression, the Partner’s Drinking, and Partner Physical Violence

    PubMed Central

    Rychtarik, Robert G.; McGillicuddy, Neil B.

    2015-01-01

    Women (N = 171), distressed from their partners’ untreated alcoholism, received either coping skills training (CST), 12-step facilitation (TSF), or delayed treatment (DTC). CST and TSF resulted in lower depression levels than DTC but did not differ from one another. Skill acquisition mediated the treatment effects of CST; Al-Anon attendance did not mediate the TSF effect. Lower depression levels were maintained at 12 months with no differences between groups. Partner drinking decreased from pretreatment to follow-up in the CST and TSF conditions. However, for partners with a history of relationship violence, drinking improved across follow-up in the CST condition but worsened in the TSF condition. Partner relationship violence was less in the CST condition. CST may be particularly useful for women experiencing physical violence from a partner with alcoholism. PMID:15796632

  13. Humility and 12-Step Recovery: A Prolegomenon for the Empirical Investigation of a Cardinal Virtue in Alcoholics Anonymous

    PubMed Central

    Post, Stephen G.; Pagano, Maria E.; Lee, Matthew T.; Johnson, Byron R.

    2016-01-01

    Alcoholics Anonymous (AA) offers a live stage to study how humility is worn by thousands for another day of sobriety and more freedom from the bondage of self. It has been the coauthors’ intent to emphasize the significance of humility as a cardinal virtue across the 12-Step program and as essential to all its key elements. The coauthors have placed this emphasis in the context of a wider theological history of thought as this converged on Bill W. and AA. In addition, the coauthors have offered a constructive developmental interpretation of the 12 Steps that relies on a model of four modulations of humility. Finally, the coauthors have reviewed in brief some approaches to the measurement of humility in this context, and suggest several aims for future research. PMID:27429509

  14. Humility and 12-Step Recovery: A Prolegomenon for the Empirical Investigation of a Cardinal Virtue in Alcoholics Anonymous.

    PubMed

    Post, Stephen G; Pagano, Maria E; Lee, Matthew T; Johnson, Byron R

    Alcoholics Anonymous (AA) offers a live stage to study how humility is worn by thousands for another day of sobriety and more freedom from the bondage of self. It has been the coauthors' intent to emphasize the significance of humility as a cardinal virtue across the 12-Step program and as essential to all its key elements. The coauthors have placed this emphasis in the context of a wider theological history of thought as this converged on Bill W. and AA. In addition, the coauthors have offered a constructive developmental interpretation of the 12 Steps that relies on a model of four modulations of humility. Finally, the coauthors have reviewed in brief some approaches to the measurement of humility in this context, and suggest several aims for future research.

  15. Naive Optics: Acting on Mirror Reflections

    ERIC Educational Resources Information Center

    Hecht, Heiko; Bertamini, Marco; Gamer, Matthias

    2005-01-01

    It is known that naive observers have striking misconceptions about mirror reflections. In 5 experiments, this article systematically extends the findings to graphic stimuli, to interactive visual tasks, and finally to tasks involving real mirrors. The results show that the perceptual knowledge of nonexpert adults is far superior to their…

  16. Naive Optics: Acting on Mirror Reflections

    ERIC Educational Resources Information Center

    Hecht, Heiko; Bertamini, Marco; Gamer, Matthias

    2005-01-01

    It is known that naive observers have striking misconceptions about mirror reflections. In 5 experiments, this article systematically extends the findings to graphic stimuli, to interactive visual tasks, and finally to tasks involving real mirrors. The results show that the perceptual knowledge of nonexpert adults is far superior to their…

  17. Ten years of treating eating disorders: what have we learned? A personal perspective on the application of 12-step and wellness programs.

    PubMed

    McAleavey, Kristen

    2008-01-01

    Conventional therapy for eating disorders has focused on behavioral approaches, medical models, and combinations of both, with lesser emphasis on psychological and wellness models. Because eating disorders are often difficult to treat and the individuals who have them often exhibit significant comorbidities, the long-term success rate (3-5 years or more)-defined as recovery and abstinence from the disorder behaviors-is in the 40% to 50% range, at best. Moreover, if one examines randomized controlled trials (RCTs) that test the efficacy of the most commonly used behavioral approaches in a historical manner, as is described in this article, by assigning RCTs to 2 different time periods for the treatment of bulimia nervosa (BN), it is found that no progress has been made in the success rate of treating this disorder. Many reasons exist for this lack of progress, including comorbidities, failure of patient-therapist relationships to be dynamic, failure to appreciate that BN and binge eating disorder have addiction components that might require 12-step or multimodal approaches, and an absence of treating the whole person, which requires using a wellness model and elements such as body awareness exercises, yoga, and spirituality. Based on a review of the literature and my personal experience over the last 10 years, it is suggested that best practices for treating these disorders should include wellness and 12-step models that focus less on self-centeredness, highlighting the strengths of the person and helping individuals to find their true spirituality, which can be used as a focal point for all treatment. Conventional approaches can still be useful in treating eating disorders, but clinicians and psychiatrists should cease seeing eating disorders as "diseases" that should be treated by pharmacodynamics and consider that these are conditions that have taken many years to develop and that have many background psychological factors, often reaching back to childhood.

  18. Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients.

    PubMed

    Curtis, L; Nichols, G; Stainsby, C; Lim, J; Aylott, A; Wynne, B; Clark, A; Bloch, M; Maechler, G; Martin-Carpenter, L; Raffi, F; Min, S

    2014-01-01

    The efficacy of dolutegravir (DTG) has been demonstrated in 5 randomized studies in integrase inhibitor (INI)-naive adult populations. To date, a detailed safety review of DTG has not been provided in the literature. To describe the safety and tolerability profile of DTG in adults based on 5 randomized, controlled trials and comparison with drugs in 3 major antiretroviral (ARV) classes. Safety data from phase IIb/III/IIIb trials in ART-naive and ART-experienced, INI-naive adults were integrated. In 4 ART-naive (SPRING-1, SPRING-2, SINGLE, FLAMINGO) and 1 ART-experienced, INI-naive study (SAILING), 1,579 individuals received a DTG-containing regimen. The proportion of individuals from DTG treatment arms who withdrew due to adverse events (AEs) was low (≤2%) compared to raltegravir (RAL; 2% SPRING-2, 4% SAILING), efavirenz (EFV)-containing comparator arm (10% SINGLE), and darunavir + ritonavir (DRV/r; 4% FLAMINGO). The most frequently observed AEs (diarrhea, nausea, headache), typically grade 1 or 2 in severity, did not lead to study discontinuation. Psychiatric and nervous system disorders with DTG were comparable to RAL- and DRV/r-containing regimens and favorable to EFV-containing regimens. In hepatitis B and/or C coinfected ART-naive individuals, the incidence of transaminase elevations was lower with DTG versus RAL and EFV comparators, but was similar to DRV/r. In SAILING, transaminase elevations were more commonly observed with DTG, particularly in the setting of inadequate hepatitis B therapy or immune reconstitution. On DTG treatment, mild creatinine elevations occurred and stabilized early. Few cases of hypersensitivity reaction and/or severe rash were seen. Rates of these events were comparable to or lower than with RAL-, EFV-, and DRV/r-containing regimens. The safety profile for DTG 50 mg once daily in INI-naive individuals was comparable to RAL- and DRV/r-containing regimens and generally favorable compared with EFV-containing regimens.

  19. Construction of human naive antibody gene libraries.

    PubMed

    Hust, Michael; Frenzel, André; Meyer, Torsten; Schirrmann, Thomas; Dübel, Stefan

    2012-01-01

    Human antibodies are valuable tools for proteome research and diagnostics. Furthermore, antibodies are a rapidly growing class of therapeutic agents, mainly for inflammation and cancer therapy. The first therapeutic antibodies are of murine origin and were chimerized or humanized. The later-developed antibodies are fully human antibodies. Here, two technologies are competing the hybridoma technology using transgenic mice with human antibody gene loci and antibody phage display. The starting point for the selection of human antibodies against any target is the construction of an antibody phage display gene library.In this review we describe the construction of human naive and immune antibody gene libraries for antibody phage display.

  20. Comparison of predicted susceptibility between genotype and virtual phenotype HIV drug resistance interpretation systems among treatment-naive HIV-infected patients in Asia: TASER-M cohort analysis

    PubMed Central

    2012-01-01

    Background Accurate interpretation of HIV drug resistance (HIVDR) testing is challenging, yet important for patient care. We compared genotyping interpretation, based on the Stanford University HIV Drug Resistance Database (Stanford HIVdb), and virtual phenotyping, based on the Janssen Diagnostics BVBA’s vircoTYPE™ HIV-1, and investigated their level of agreement in antiretroviral (ARV) naive patients in Asia, where non-B subtypes predominate. Methods Sequences from 1301 ARV-naive patients enrolled in the TREAT Asia Studies to Evaluate Resistance – Monitoring Study (TASER-M) were analysed by both interpreting systems. Interpretations from both Stanford HIVdb and vircoTYPE™ HIV-1 were initially grouped into 2 levels: susceptible and non-susceptible. Discrepancy was defined as a discordant result between the susceptible and non-susceptible interpretations from the two systems for the same ARV. Further analysis was performed when interpretations from both systems were categorised into 3 levels: susceptible, intermediate and resistant; whereby discrepancies could be categorised as major discrepancies and minor discrepancies. Major discrepancy was defined as having a susceptible result from one system and resistant from the other. Minor discrepancy corresponded to having an intermediate interpretation in one system, with a susceptible or resistant result in the other. The level of agreement was analysed using the prevalence adjusted bias adjusted kappa (PABAK). Results Overall, the agreement was high, with each ARV being in “almost perfect agreement”, using Landis and Koch’s categorisation. Highest discordance was observed for efavirenz (75/1301, 5.8%), all arising from susceptible Stanford HIVdb versus non-susceptible vircoTYPE™ HIV-1 predictions. Protease Inhibitors had highest level of concordance with PABAKs all above 0.99, followed by Nucleoside Reverse Transcriptase Inhibitors with PABAKs above 0.97 and non-NRTIs with the lowest PABAK of 0.88. The

  1. The Preference for Symmetry in Flower-Naive and Not-so-Naive Bumblebees

    ERIC Educational Resources Information Center

    Plowright, C. M. S.; Evans, S. A.; Leung, J. Chew; Collin, C. A.

    2011-01-01

    Truly flower-naive bumblebees, with no prior rewarded experience for visits on any visual patterns outside the colony, were tested for their choice of bilaterally symmetric over asymmetric patterns in a radial-arm maze. No preference for symmetry was found. Prior training with rewarded black and white disks did, however, lead to a significant…

  2. The Preference for Symmetry in Flower-Naive and Not-so-Naive Bumblebees

    ERIC Educational Resources Information Center

    Plowright, C. M. S.; Evans, S. A.; Leung, J. Chew; Collin, C. A.

    2011-01-01

    Truly flower-naive bumblebees, with no prior rewarded experience for visits on any visual patterns outside the colony, were tested for their choice of bilaterally symmetric over asymmetric patterns in a radial-arm maze. No preference for symmetry was found. Prior training with rewarded black and white disks did, however, lead to a significant…

  3. Do the Naive Know Best? The Predictive Power of Naive Ratings of Couple Interactions

    ERIC Educational Resources Information Center

    Baucom, Katherine J. W.; Baucom, Brian R.; Christensen, Andrew

    2012-01-01

    We examined the utility of naive ratings of communication patterns and relationship quality in a large sample of distressed couples. Untrained raters assessed 10-min videotaped interactions from 134 distressed couples who participated in both problem-solving and social support discussions at each of 3 time points (pre-therapy, post-therapy, and…

  4. Do the Naive Know Best? The Predictive Power of Naive Ratings of Couple Interactions

    ERIC Educational Resources Information Center

    Baucom, Katherine J. W.; Baucom, Brian R.; Christensen, Andrew

    2012-01-01

    We examined the utility of naive ratings of communication patterns and relationship quality in a large sample of distressed couples. Untrained raters assessed 10-min videotaped interactions from 134 distressed couples who participated in both problem-solving and social support discussions at each of 3 time points (pre-therapy, post-therapy, and…

  5. Comparison of 12-step groups to mutual help alternatives for AUD in a large, national study: Differences in membership characteristics and group participation, cohesion, and satisfaction.

    PubMed

    Zemore, Sarah E; Kaskutas, Lee Ann; Mericle, Amy; Hemberg, Jordana

    2017-02-01

    Many studies suggest that participation in 12-step groups contributes to better recovery outcomes, but people often object to such groups and most do not sustain regular involvement. Yet, research on alternatives to 12-step groups is very sparse. The present study aimed to extend the knowledge base on mutual help group alternatives for those with an alcohol use disorder (AUD), sampling from large, active, abstinence-focused groups including Women for Sobriety (WFS), LifeRing, and SMART Recovery (SMART). This paper presents a cross-sectional analysis of this longitudinal study, using baseline data to describe the profile and participation characteristics of attendees of these groups in comparison to 12-step members. Data from participants 18 and over with a lifetime AUD (N=651) were collected using Web-based surveys. Members of alternative 12-step groups were recruited in collaboration with group directors, who helped publicize the study by emailing meeting conveners and attendees and posting announcements on social media. A comparison group of current (past-30-day) 12-step attendees was recruited from an online meeting hub for recovering persons. Interested parties were directed to a Webpage where they were screened, and eligible participants completed an online survey assessing demographic and clinical variables; in-person and online mutual help involvement; and group satisfaction and cohesion. Analyses involved comparing those identifying WFS, SMART, and LifeRing as their primary group to 12-step members on the above characteristics. Compared to 12-step members, members of the mutual help alternatives were less religious and generally higher on education and income. WFS and LifeRing members were also older, more likely to be married, and lower on lifetime drug and psychiatric severity; meanwhile, LifeRing and SMART members were less likely to endorse the most stringent abstinence goal. Finally, despite lower levels of in-person meeting attendance, members of all

  6. Investigation of the operating characteristics of a 12 stepped-cavity relativistic magnetron with axial extraction driven by an "F" transparent cathode using particle-in-cell simulations

    NASA Astrophysics Data System (ADS)

    Liu, M.; Schamiloglu, E.; Jiang, W.; Fuks, M.; Liu, C.

    2016-11-01

    We explore the performance of a 12 stepped-cavity relativistic magnetron with axial extraction (12 stepped-cavity RMDO) driven by an "F" transparent cathode (the "F" transparent cathode is a coaxial transparent cathode with two azimuthal periods of increased thickness and which looks like the letter "F," so we call it "F" transparent cathode) through particle-in-cell (PIC) simulations. It is shown that using the "F" transparent cathode, an electronic efficiency of 70% with gigawatt output power is obtained while reducing the axial leakage current by about 50% compared to using the usual transparent cathode. Further PIC simulations demonstrate that frequency bifurcation occurs and mode switching can be achieved using several hundred kilowatts input RF power in the 12 stepped-cavity RMDO driven by an "F" transparent cathode. For example, it was found that using an applied driver power of 180 kW for 10 ns, the operating TE31 mode can be switched to the TE41 mode. It is also found that the secondary electron and backscattered electron emission and axial leakage current were two disturbing factors for the 12 stepped-cavity RMDO when it works at a stable operation mode but when the 12 stepped-cavity RMDO works near the critical magnetic field at the boundary between two modes, these two factors would lead to the operation modes changing.

  7. Vitalistic causality in young children's naive biology.

    PubMed

    Inagaki, Kayoko; Hatano, Giyoo

    2004-08-01

    One of the key issues in conceptual development research concerns what kinds of causal devices young children use to understand the biological world. We review evidence that children predict and interpret biological phenomena, especially human bodily processes, on the basis of 'vitalistic causality'. That is, they assume that vital power or life force taken from food and water makes humans active, prevents them from being taken ill, and enables them to grow. These relationships are also extended readily to other animals and even to plants. Recent experimental results show that a majority of preschoolers tend to choose vitalistic explanations as most plausible. Vitalism, together with other forms of intermediate causality, constitute unique causal devices for naive biology as a core domain of thought.

  8. Naive optics: acting on mirror reflections.

    PubMed

    Hecht, Heiko; Bertamini, Marco; Gamer, Matthias

    2005-10-01

    It is known that naive observers have striking misconceptions about mirror reflections. In 5 experiments, this article systematically extends the findings to graphic stimuli, to interactive visual tasks, and finally to tasks involving real mirrors. The results show that the perceptual knowledge of nonexpert adults is far superior to their conceptual knowledge. Whereas conceptual errors include the assumption of left-right reversals in mirror images and often blatant extensions of the boundary of mirror space, the perceptual context prevents most such errors. However, a consistent bias to misjudge objects in mirrors too far to the outside is demonstrable in all cases including tasks with real mirrors. The authors present a 2-stage hypothesis consisting of an implicit bias of judging the mirror surface to be turned toward the observer's line of sight followed by a normalization that becomes explicit.

  9. Naive Probability: A Mental Model Theory of Extensional Reasoning.

    ERIC Educational Resources Information Center

    Johnson-Laird, P. N.; Legrenzi, Paolo; Girotto, Vittorio; Legrenzi, Maria Sonino; Caverni, Jean-Paul

    1999-01-01

    Outlines a theory of naive probability in which individuals who are unfamiliar with the probability calculus can infer the probabilities of events in an "extensional" way. The theory accommodates reasoning based on numerical premises, and explains how naive reasoners can infer posterior probabilities without relying on Bayes's theorem.…

  10. How Do Females With PTSD and Substance Abuse View 12-Step Groups? An Empirical Study of Attitudes and Attendance Patterns.

    PubMed

    Najavits, Lisa M; de Haan, Hein; Kok, Tim

    2015-01-01

    Self-help groups are beneficial for many people with addiction, predominantly through 12-step models. Yet obstacles to attendance also occur. We explored attendance patterns and attitudes toward self-help groups by 165 outpatient females with co-occurring posttraumatic stress disorder (PTSD) and substance use disorder (SUD), the first study of its kind. Cross-sectional self-report data compared adults versus adolescents, and those currently attending self-help versus not attending. We also explored attendance in relation to perceptions of the PTSD/SUD relationship and symptom severity. Adults reported higher attendance at self-help than adolescents, both lifetime and currently. Among current attendees, adults also attended more weekly groups than adolescents. Yet only a minority of both age cohorts attended any self-help in the past week. Adults perceived a stronger relationship between PTSD and SUD than adolescents, but both age groups gave low ratings to the fact that self-help groups do not address PTSD. That item also had low ratings by both those currently attending and not attending self-help. Analysis of those not currently attending identified additional negative attitudes toward self-help (spirituality, addiction as a life-long illness, sayings, and the fellowship). Symptom severity was not associated with attendance, but may reflect a floor effect. Finally, a surprising finding was that all-female groups were not preferred by any subsample. Conclusions/Importance. Creative solutions are needed to address obstacles to self-help among this population. Addressing trauma and PTSD, not just SUD, was valued by females we surveyed, and may be more helpful than all-female groups per se.

  11. Fuzzy Naive Bayesian for constructing regulated network with weights.

    PubMed

    Zhou, Xi Y; Tian, Xue W; Lim, Joon S

    2015-01-01

    In the data mining field, classification is a very crucial technology, and the Bayesian classifier has been one of the hotspots in classification research area. However, assumptions of Naive Bayesian and Tree Augmented Naive Bayesian (TAN) are unfair to attribute relations. Therefore, this paper proposes a new algorithm named Fuzzy Naive Bayesian (FNB) using neural network with weighted membership function (NEWFM) to extract regulated relations and weights. Then, we can use regulated relations and weights to construct a regulated network. Finally, we will classify the heart and Haberman datasets by the FNB network to compare with experiments of Naive Bayesian and TAN. The experiment results show that the FNB has a higher classification rate than Naive Bayesian and TAN.

  12. Molecular Criteria for Defining the Naive Human Pluripotent State.

    PubMed

    Theunissen, Thorold W; Friedli, Marc; He, Yupeng; Planet, Evarist; O'Neil, Ryan C; Markoulaki, Styliani; Pontis, Julien; Wang, Haoyi; Iouranova, Alexandra; Imbeault, Michaël; Duc, Julien; Cohen, Malkiel A; Wert, Katherine J; Castanon, Rosa; Zhang, Zhuzhu; Huang, Yanmei; Nery, Joseph R; Drotar, Jesse; Lungjangwa, Tenzin; Trono, Didier; Ecker, Joseph R; Jaenisch, Rudolf

    2016-10-06

    Recent studies have aimed to convert cultured human pluripotent cells to a naive state, but it remains unclear to what extent the resulting cells recapitulate in vivo naive pluripotency. Here we propose a set of molecular criteria for evaluating the naive human pluripotent state by comparing it to the human embryo. We show that transcription of transposable elements provides a sensitive measure of the concordance between pluripotent stem cells and early human development. We also show that induction of the naive state is accompanied by genome-wide DNA hypomethylation, which is reversible except at imprinted genes, and that the X chromosome status resembles that of the human preimplantation embryo. However, we did not see efficient incorporation of naive human cells into mouse embryos. Overall, the different naive conditions we tested showed varied relationships to human embryonic states based on molecular criteria, providing a backdrop for future analysis of naive human pluripotency. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1

    PubMed Central

    Mease, Philip J; Ritchlin, Christopher T; Okada, Masato; Cuchacovich, Raquel S; Shuler, Catherine L; Lin, Chen-Yen; Braun, Daniel K; Lee, Chin H; Gladman, Dafna D

    2017-01-01

    Objective To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA). Methods Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24. Results Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7–66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05). Conclusions In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo. Trial registration number NCT01695239; EudraCT2011-002326-49; Results. PMID:27553214

  14. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1.

    PubMed

    Mease, Philip J; van der Heijde, Désirée; Ritchlin, Christopher T; Okada, Masato; Cuchacovich, Raquel S; Shuler, Catherine L; Lin, Chen-Yen; Braun, Daniel K; Lee, Chin H; Gladman, Dafna D

    2017-01-01

    To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA). Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24. Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05). In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo. NCT01695239; EudraCT2011-002326-49; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Comparison of Pain Tolerance between Opioid Dependent Patients on Methadone Maintenance Therapy (MMT) and Opioid Naive Individuals.

    PubMed

    Zahari, Zalina; Lee, Chee Siong; Ibrahim, Muslih Abdulkarim; Musa, Nurfadhlina; Mohd Yasin, Mohd Azhar; Lee, Yeong Yeh; Tan, Soo Choon; Mohamad, Nasir; Ismail, Rusli

    2016-01-01

    This study compared pain sensitivity among opioid dependent patients on methadone maintenance therapy (MMT) and opioid naive subjects. The three hundred participants comprised 152 opioid naive subjects and 148 opioid dependent patients. Opioid naive subjects had not taken any opioids including morphine and methadone to their best knowledge and were presumed so after two consecutive negative urine screenings for drugs. All opioid dependent patients were stabilized in treatment, defined as having been enrolled in the program for more than one month with no change of methadone dosage over the past one month. Excluded from the study were individuals with chronic or ongoing acute pain and individuals with a history of analgesics ingestion within 3 d before the cold pressor test (CPT). Pain tolerance to CPT was evaluated at 0 h, and at 2, 4, 8, 12, and 24 h post-methadone dose. Patients exhibited a significantly shorter mean pain tolerance time of 34.17 s (95% CI 24.86, 43.49) versus 61.36 (52.23, 70.48) [p < 0.001] compared with opioid naive subjects. Time-dependent mean pain tolerance was also significantly different when naive subjects were compared to patients (p = 0.016). This study revealed hyperalgesia amongst patients on MMT, as manifested by their quicker hand withdrawal. The complaints of pain in this population should not be underestimated and the pain should be evaluated seriously and managed aggressively.

  16. Mapping the route from naive pluripotency to lineage specification

    PubMed Central

    Kalkan, Tüzer; Smith, Austin

    2014-01-01

    In the mouse blastocyst, epiblast cells are newly formed shortly before implantation. They possess a unique developmental plasticity, termed naive pluripotency. For development to proceed, this naive state must be subsumed by multi-lineage differentiation within 72 h following implantation. In vitro differentiation of naive embryonic stem cells (ESCs) cultured in controlled conditions provides a tractable system to dissect and understand the process of exit from naive pluripotency and entry into lineage specification. Exploitation of this system in recent large-scale RNAi and mutagenesis screens has uncovered multiple new factors and modules that drive or facilitate progression out of the naive state. Notably, these studies show that the transcription factor network that governs the naive state is rapidly dismantled prior to upregulation of lineage specification markers, creating an intermediate state that we term formative pluripotency. Here, we summarize these findings and propose a road map for state transitions in ESC differentiation that reflects the orderly dynamics of epiblast progression in the embryo. PMID:25349449

  17. Extracellular adenosine regulates naive T cell development and peripheral maintenance

    PubMed Central

    Cekic, Caglar; Sag, Duygu; Day, Yuan-Ji

    2013-01-01

    Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A2A receptor (A2AR) gene, Adora2a, and show that either global A2AR deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A2AR signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K)–AKT pathway, thereby reducing IL-7Rα down-regulation and naive T cell apoptosis. Patterns of IL-7Rα expression on T cells in chimeric mice reconstituted with Adora2a+/+ and Adora2a−/− bone marrow cells suggest that decreased IL-7Rα in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A2AR expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7Rα expression. Therefore, A2AR signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery. PMID:24145516

  18. Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice.

    PubMed

    Mika, Joanna; Wawrzczak-Bargiela, Agnieszka; Osikowicz, Maria; Makuch, Wioletta; Przewlocka, Barbara

    2009-01-01

    We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.

  19. Automated detection of circulating tumor cells with naive Bayesian classifiers.

    PubMed

    Svensson, Carl-Magnus; Krusekopf, Solveigh; Lücke, Jörg; Thilo Figge, Marc

    2014-06-01

    Personalized medicine is a modern healthcare approach where information on each person's unique clinical constitution is exploited to realize early disease intervention based on more informed medical decisions. The application of diagnostic tools in combination with measurement evaluation that can be performed in a reliable and automated fashion plays a key role in this context. As the progression of various cancer diseases and the effectiveness of their treatments are related to a varying number of tumor cells that circulate in blood, the determination of their extremely low numbers by liquid biopsy is a decisive prognostic marker. To detect and enumerate circulating tumor cells (CTCs) in a reliable and automated fashion, we apply methods from machine learning using a naive Bayesian classifier (NBC) based on a probabilistic generative mixture model. Cells are collected with a functionalized medical wire and are stained for fluorescence microscopy so that their color signature can be used for classification through the construction of Red-Green-Blue (RGB) color histograms. Exploiting the information on the fluorescence signature of CTCs by the NBC does not only allow going beyond previous approaches but also provides a method of unsupervised learning that is required for unlabeled training data. A quantitative comparison with a state-of-the-art support vector machine, which requires labeled data, demonstrates the competitiveness of the NBC method.

  20. Risk of Erectile Dysfunction in Transfusion-naive Thalassemia Men

    PubMed Central

    Chen, Yu-Guang; Lin, Te-Yu; Lin, Cheng-Li; Dai, Ming-Shen; Ho, Ching-Liang; Kao, Chia-Hung

    2015-01-01

    Abstract Based on the mechanism of pathophysiology, thalassemia major or transfusion-dependent thalassemia patients may have an increased risk of developing organic erectile dysfunction resulting from hypogonadism. However, there have been few studies investigating the association between erectile dysfunction and transfusion-naive thalassemia populations. We constructed a population-based cohort study to elucidate the association between transfusion-naive thalassemia populations and organic erectile dysfunction This nationwide population-based cohort study involved analyzing data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending to the end of 2011. We identified men with transfusion-naive thalassemia and selected a comparison cohort that was frequency-matched with these according to age, and year of diagnosis thalassemia at a ratio of 1 thalassemia man to 4 control men. We analyzed the risks for transfusion-naive thalassemia men and organic erectile dysfunction by using Cox proportional hazards regression models. In this study, 588 transfusion-naive thalassemia men and 2337 controls were included. Total 12 patients were identified within the thalassaemia group and 10 within the control group. The overall risks for developing organic erectile dysfunction were 4.56-fold in patients with transfusion-naive thalassemia men compared with the comparison cohort after we adjusted for age and comorbidities. Our long-term cohort study results showed that in transfusion-naive thalassemia men, there was a higher risk for the development of organic erectile dysfunction, particularly in those patients with comorbidities. PMID:25837766

  1. Severe liver disease related to chronic hepatitis C virus infection in treatment-naive patients: epidemiological characteristics and associated factors at first expert centre visit, France, 2000 to 2007 and 2010 to 2014

    PubMed Central

    Sanna, Alice; Le Strat, Yann; Roudot-Thoraval, Françoise; Deuffic Burban, Sylvie; Carrieri, Patrizia; Delarocque-Astagneau, Elisabeth; Larsen, Christine

    2017-01-01

    Given recent profound improvements in the effectiveness of antiviral treatment for chronic Hepatitis C virus (HCV) infection, we aimed to describe the characteristics of patients referred to hepatology expert centres in France from 2000 to 2007 and from 2010 to 2014, and to identify factors associated with severe liver disease at their first visit for evaluation. We analysed data from two sources covering all of France: the former hepatitis C surveillance network, which included patients between 2000 and 2007, and the ANRS CO22 HEPATHER multi-centre cohort, which included patients between 2012 and 2014. Severe liver disease (SLD) was defined as the presence of either cirrhosis (histological, biochemical or clinical) or hepatocellular carcinoma. Multivariable Poisson regression models were used to identify the factors associated with SLD in complete-case analysis and after multiple imputation. Overall, 16,851 patients were included in the analysis and SLD was diagnosed in 11.6%. SLD at first visit was significantly associated with known risk factors (male sex, history of excessive alcohol intake, HCV genotype 3), late referral to hepatologists after diagnosis and HCV diagnosis at an older age. Providing earlier specialised care and treatment may be an important target for public health action. PMID:28797326

  2. Derivation of novel human ground state naive pluripotent stem cells.

    PubMed

    Gafni, Ohad; Weinberger, Leehee; Mansour, Abed AlFatah; Manor, Yair S; Chomsky, Elad; Ben-Yosef, Dalit; Kalma, Yael; Viukov, Sergey; Maza, Itay; Zviran, Asaf; Rais, Yoach; Shipony, Zohar; Mukamel, Zohar; Krupalnik, Vladislav; Zerbib, Mirie; Geula, Shay; Caspi, Inbal; Schneir, Dan; Shwartz, Tamar; Gilad, Shlomit; Amann-Zalcenstein, Daniela; Benjamin, Sima; Amit, Ido; Tanay, Amos; Massarwa, Rada; Novershtern, Noa; Hanna, Jacob H

    2013-12-12

    Mouse embryonic stem (ES) cells are isolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naive inner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor (LIF) and small molecule inhibition of ERK1/ERK2 and GSK3β signalling (termed 2i/LIF conditions). Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distal enhancer, retaining a pre-inactivation X chromosome state, and global reduction in DNA methylation and in H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters. Upon withdrawal of 2i/LIF, naive mouse ES cells can drift towards a primed pluripotent state resembling that of the post-implantation epiblast. Although human ES cells share several molecular features with naive mouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells (EpiSCs). These include predominant use of the proximal enhancer element to maintain OCT4 expression, pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNA methylation and prominent deposition of H3K27me3 and bivalent domain acquisition on lineage regulatory genes. The feasibility of establishing human ground state naive pluripotency in vitro with equivalent molecular and functional features to those characterized in mouse ES cells remains to be defined. Here we establish defined conditions that facilitate the derivation of genetically unmodified human naive pluripotent stem cells from already established primed human ES cells, from somatic cells through induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naive pluripotent cells validated herein retain molecular characteristics and functional properties that are highly similar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. This includes competence in the generation

  3. Strongyloides ratti: transplantation of adults recovered from the small intestine at different days after infection into the colon of naive and infection-primed Wistar rats, and the effect of antioxidant treatment on large intestinal parasitism.

    PubMed

    Shintoku, Y; Takagi, H; Kadosaka, T; Nagaoka, F; Kondo, S; Itoh, M; Honda, S; Kimura, E

    2011-07-01

    Strongyloides ratti (Nagoya strain) is unique in that a portion of adults parasitizing the small intestine withstands 'worm expulsion', which starts at around day 8 post-infection (p.i.) by host immunity, and establishes in the large intestine after day 19 p.i. To investigate the mechanism, adults obtained from the small intestine at day 7 or 19 p.i. were transplanted into the colon of infection-primed immune rats. Adults obtained at day 7 p.i. were rejected quickly, whereas those obtained at day 19 p.i. could establish infection. Moreover, the body length and the number of intrauterine eggs increased in the large intestine. In a separate experiment, large intestinal parasitism was abolished by the treatment of host rats with an anti-oxidant, butylated hydroxyanisole. These results indicate that small intestinal adults between days 7 and 19 p.i. acquired the ability to parasitize the large intestine of immune rats, and that free radicals produced by the host may have played a significant role in the process.

  4. Relationship between the catechol-O-methyl transferase Val108/158Met genotype and brain volume in treatment-naive major depressive disorder: Voxel-based morphometry analysis.

    PubMed

    Watanabe, Keita; Kakeda, Shingo; Yoshimura, Reiji; Abe, Osamu; Ide, Satoru; Hayashi, Kenji; Katsuki, Asuka; Umene-Nakano, Wakako; Watanabe, Rieko; Nakamura, Jun; Korogi, Yukunori

    2015-09-30

    Catechol-O-methyltransferase (COMT) is a methylation enzyme engaged in the degradation of dopamine and noradrenaline by catalyzing the transfer of a methyl group from S-adenosylmethionine. An association was found between the Valine (Val) 108/158Methionine (Met) COMT polymorphism (rs4680) and major depressive disorder (MDD). The authors prospectively investigated the relationship between the Val108/158Met COMT genotype and voxel-based morphometry (VBM) findings for patients with first-episode and treatment-naïve MDD and healthy subjects (HS). Participants comprised 30 MDD patients and 48 age- and sex-matched HS who were divided according to the COMT genotype. Effects of diagnosis, COMT genotype, and the genotype-diagnosis interaction in relation to brain morphology in the Val/Met and Val/Val individuals were evaluated using a VBM analysis of high-resolution magnetic resonance imaging findings. Among the Val/Met individuals, the volume of the bilateral caudate was significantly smaller for MDD patients than for HS. In the Val/Val individuals, the caudate volume was comparable between MDD patients and HS. Significant genotype-diagnosis interaction effects on brain morphology were noted in the right caudate.

  5. Prescription of Opioids for Opioid-Naive Medical Inpatients

    PubMed Central

    Lail, Sharan; Sequeira, Kelly; Lieu, Jenny; Dhalla, Irfan A

    2014-01-01

    Background: Harms associated with prescription opioids are a major and increasing public health concern. Prescribing of opioids for inpatients may contribute to the problem, especially if primary care practitioners continue opioid therapy that is initiated in hospital. Objectives: To describe the extent and nature of opioid prescribing for opioid-naive patients (i.e., no use of opioids within 2 weeks before admission) on an internal medicine unit. Methods: This single-centre study involved chart review for opioid-naive patients admitted to the internal medicine unit of a large academic health sciences centre in Toronto, Ontario. Over 12 weeks, patients were prospectively identified for the study, and charts were later reviewed to characterize opioid use during the hospital stay and upon discharge. The primary outcomes were the proportions of opioid-naive patients for whom opioids were prescribed in hospital and upon discharge. Data on serious adverse events related to opioid use (e.g., need for naloxone or occurrence of falls) were also collected through chart review. Results: From July 4 to September 22, 2011, a total of 721 patients were admitted to the study unit, of whom 381 (53%) were classified as opioid-naive. Opioids were prescribed for 82 (22%) of these opioid-naive patients while they were in hospital. Among the opioid-naive patients, there were a total of 247 opioid prescriptions, with hydromorphone (110 prescriptions) and morphine (92 prescriptions) being the drugs most commonly prescribed. For 23 (28%) of the patients with a prescription for opioids in hospital (6% of all opioid-naive patients), an opioid was also prescribed upon discharge. The indication for opioids was documented in 16 (70%) of the 23 discharge prescriptions. No adverse events or deaths related to opioid use were identified during the hospital stays. Conclusions: Among opioid-naive patients admitted to the internal medicine unit, opioids were prescribed for about 1 in 5 patients, and

  6. A Workshop for High School Students on Naive Set Theory

    ERIC Educational Resources Information Center

    Wegner, Sven-Ake

    2014-01-01

    In this article we present the prototype of a workshop on naive set theory designed for high school students in or around the seventh year of primary education. Our concept is based on two events which the author organized in 2006 and 2010 for students of elementary school and high school, respectively. The article also includes a practice report…

  7. Naive vs. Sophisticated Methods of Forecasting Public Library Circulations.

    ERIC Educational Resources Information Center

    Brooks, Terrence A.

    1984-01-01

    Two sophisticated--autoregressive integrated moving average (ARIMA), straight-line regression--and two naive--simple average, monthly average--forecasting techniques were used to forecast monthly circulation totals of 34 public libraries. Comparisons of forecasts and actual totals revealed that ARIMA and monthly average methods had smallest mean…

  8. Children's Conceptions of Mental Illness: A Naive Theory Approach

    ERIC Educational Resources Information Center

    Fox, Claudine; Buchanan-Barrow, Eithne; Barrett, Martyn

    2010-01-01

    This paper reports two studies that investigated children's conceptions of mental illness using a naive theory approach, drawing upon a conceptual framework for analysing illness representations which distinguishes between the identity, causes, consequences, curability, and timeline of an illness. The studies utilized semi-structured interviewing…

  9. Children's Conceptions of Mental Illness: A Naive Theory Approach

    ERIC Educational Resources Information Center

    Fox, Claudine; Buchanan-Barrow, Eithne; Barrett, Martyn

    2010-01-01

    This paper reports two studies that investigated children's conceptions of mental illness using a naive theory approach, drawing upon a conceptual framework for analysing illness representations which distinguishes between the identity, causes, consequences, curability, and timeline of an illness. The studies utilized semi-structured interviewing…

  10. Thinking Process of Naive Problem Solvers to Solve Mathematical Problems

    ERIC Educational Resources Information Center

    Mairing, Jackson Pasini

    2017-01-01

    Solving problems is not only a goal of mathematical learning. Students acquire ways of thinking, habits of persistence and curiosity, and confidence in unfamiliar situations by learning to solve problems. In fact, there were students who had difficulty in solving problems. The students were naive problem solvers. This research aimed to describe…

  11. The Profession of Psychology Scale: Sophisticated and Naive Students' Responses

    ERIC Educational Resources Information Center

    Rosenthal, Gary T.; Soper, Barlow; Rachal, Chris; McKnight, Richard R.; Price, A. W.

    2004-01-01

    The Profession of Psychology Scale (Rosenthal, McKnight & Price, 2001) was used to investigate whether taking more psychology courses results in a more accurate understanding of what is required to become a psychologist. Data indicate that though misconceptions exist in both Naive students (those who had not completed any psychology courses) and…

  12. Three Naive Questions: Addressed to the Modern Educational Optimism

    ERIC Educational Resources Information Center

    Krstic, Predrag

    2016-01-01

    This paper aims to question anew the popular and supposedly self-evident affirmation of education, in its modern incarnation as in its historical notion. The "naive" questions suggest that we have recently taken for granted that education ought to be for the masses, that it ought to be upbringing, and that it is better than ignorance.…

  13. Theory-Driven Science and Naive Empiricism in Counseling Psychology.

    ERIC Educational Resources Information Center

    Strong, Stanley R.

    1991-01-01

    Asserts that counseling psychologists' aversion to theory-driven science and their enthusiasm for naive empiricism impede scientific progress. Identifies "received view" of science as theory-driven science, points out symptoms and consequences of the failure to apply this view, and argues that greater scientific progress will result from moving…

  14. Three Naive Questions: Addressed to the Modern Educational Optimism

    ERIC Educational Resources Information Center

    Krstic, Predrag

    2016-01-01

    This paper aims to question anew the popular and supposedly self-evident affirmation of education, in its modern incarnation as in its historical notion. The "naive" questions suggest that we have recently taken for granted that education ought to be for the masses, that it ought to be upbringing, and that it is better than ignorance.…

  15. Multimethod Longitudinal HIV Drug Resistance Analysis in Antiretroviral-Therapy-Naive Patients.

    PubMed

    Nanfack, Aubin J; Redd, Andrew D; Bimela, Jude S; Ncham, Genesis; Achem, Emmanuel; Banin, Andrew N; Kirkpatrick, Allison R; Porcella, Stephen F; Agyingi, Lucy A; Meli, Josephine; Colizzi, Vittorio; Nádas, Arthur; Gorny, Miroslaw K; Nyambi, Phillipe N; Quinn, Thomas C; Duerr, Ralf

    2017-09-01

    The global intensification of antiretroviral therapy (ART) can lead to increased rates of HIV drug resistance (HIVDR) mutations in treated and also in ART-naive patients. ART-naive HIV-1-infected patients from Cameroon were subjected to a multimethod HIVDR analysis using amplification-refractory mutation system (ARMS)-PCR, Sanger sequencing, and longitudinal next-generation sequencing (NGS) to determine their profiles for the mutations K103N, Y181C, K65R, M184V, and T215F/Y. We processed 66 ART-naive HIV-1-positive patients with highly diverse subtypes that underlined the predominance of CRF02_AG and the increasing rate of F2 and other recombinant forms in Cameroon. We compared three resistance testing methods for 5 major mutation sites. Using Sanger sequencing, the overall prevalence of HIVDR mutations was 7.6% (5/66) and included all studied mutations except K65R. Comparing ARMS-PCR with Sanger sequencing as a reference, we obtained a sensitivity of 100% (5/5) and a specificity of 95% (58/61), caused by three false-positive calls with ARMS-PCR. For 32/66 samples, we obtained NGS data and we observed two additional mismatches made up of minority variants (7% and 18%) that might not be clinically relevant. Longitudinal NGS analyses revealed changes in HIVDR mutations in all five positive subjects that could not be attributed to treatment. In one of these cases, superinfection led to the temporary masking of a resistant virus. HIVDR mutations can be sensitively detected by ARMS-PCR and sequencing methods with comparable performances. Longitudinal changes in HIVDR mutations have to be considered even in the absence of treatment. Copyright © 2017 American Society for Microbiology.

  16. Efficacy and Tolerability of Integrase Inhibitors in Antiretroviral-Naive Patients.

    PubMed

    D'Abbraccio, Maurizio; Busto, Annunziata; De Marco, Mario; Figoni, Mario; Maddaloni, Adelaide; Abrescia, Nicola

    2015-01-01

    Integrase strand transfer inhibitors are a new class of antiretroviral agents recently licensed for the treatment of both naive and experienced HIV-infected patients. They inhibit the catalytic activity of the HIV-encoded enzyme integrase and prevent the integration of the HIV genome into the host cell genome, so slowing the propagation of the infection. Integrase strand transfer inhibitors cause a rapid drop in viral load, exhibit very low drug interactions (except elvitegravir/cobicistat), and have low pill burden and convenient dosing frequency. Drugs in this class have been compared to others in antiretroviral-naive patients with efavirenz and with protease inhibitors. Final results of the STARTMRK trial highlighted the better virologic and immunologic performance of raltegravir over efavirenz/emtricitabine/tenofovir disoproxil co-formulation. Raltegravir was also superior to atazanavir/ritonavir and darunavir/ritonavir in the ACTG 5257 study for the combined virologic/tolerability endpoint. Elvitegravir/cobicistat/emtricitabine/tenofovir was non-inferior to efavirenz/emtricitabine/tenofovir and to atazanavir/ritonavir plus emtricitabine/tenofovir in terms of confirmed virologic response in the GS-US-236-0102 and GS-US-236-0103 studies, respectively. Finally, dolutegravir showed non-inferiority compared to raltegravir in the SPRING-2 study and was superior to efavirenz and darunavir/ritonavir in the SINGLE and FLAMINGO trials, respectively. The aim of this review is to analyze the data on efficacy and safety of integrase strand transfer inhibitors in antiretroviral-naive HIV patients and discuss the strengths and weaknesses of drugs within this class.

  17. Children's naive theories of intelligence influence their metacognitive judgments.

    PubMed

    Miele, David B; Son, Lisa K; Metcalfe, Janet

    2013-01-01

    Recent studies have shown that the metacognitive judgments adults infer from their experiences of encoding effort vary in accordance with their naive theories of intelligence. To determine whether this finding extends to elementary schoolchildren, a study was conducted in which 27 third graders (M(age) = 8.27) and 24 fifth graders (M(age) = 10.39) read texts presented in easy- or difficult-to-encode fonts. The more children in both grades viewed intelligence as fixed, the less likely they were to interpret effortful or difficult encoding as a sign of increasing mastery and the more likely they were to report lower levels of comprehension as their perceived effort increased. This suggests that children may use naive theories of intelligence to make motivationally relevant inferences earlier than previously thought.

  18. Acquiring a naive theory of kinship through inference.

    PubMed

    Springer, K

    1995-04-01

    The present study focused on how children acquire a naive theory of kinship. Young children appear to have theoretical beliefs about the biological meaning of kinship relations. It was argued here that these beliefs reflect inductive inferences from simple facts about prenatal growth (e.g, where babies grow). An informal model of the inferences linking facts to theory was proposed and tested. In Experiment 1, 4-7-year-olds who knew the basic facts of prenatal growth were most likely to also express the naive theory of kinship. Virtually none of the children who expressed the theory were unaware of the basic facts. In Experiment 2, teaching the facts to a sample of preschoolers led to some increase in their acceptance of the kinship theory. Overall, the results implicate a type of theory building that involves inferences from preexisting knowledge rather than structural change, use of analogy, or acquisition of new knowledge.

  19. Naive Physics, Event Perception, Lexical Semantics, and Language Acquisition

    DTIC Science & Technology

    1993-04-01

    AD-A276 799 Technical Report 1456 P Naive Physics, Event Perception, Lexical Semantics, and Language Acquisition DTICS ELFCTE MAR 0 91094D v F...Event Perception, Lexical Semantics, and Language Acquisition by .Jeffrev Mark Siskiiid Accesion For B.A. Computer Science (1979) NTIS CRAM Technion...hypotheses about child language acquisition , these systems use only positive examples to drive their acquisition of a language model. MAIMRA. the

  20. Autoantibodies in biological agent naive patients with psoriatic arthritis

    PubMed Central

    Johnson, S; Schentag, C; Gladman, D

    2005-01-01

    Objective: To investigate the prevalence of autoantibodies in biological agent naive patients with psoriatic arthritis (PsA). Methods: 94 consecutive, prospectively collected, biological agent naive patients with PsA at the University of Toronto PsA clinic underwent clinical and laboratory assessment. Disease activity was assessed by the number of actively inflamed joints, and the Psoriasis Activity and Severity Index (PASI) score. Antinuclear antibodies (ANA), rheumatoid factor (RF), double stranded DNA (dsDNA), Ro, La, Smith, and RNP were tested. Descriptive statistics and non-parametric tests were used to analyse the data. Results: 44/94 (47%) patients with PsA were ANA positive (⩾1/40); 13/94 (14%) had a clinically significant titre of ⩾1/80. Three per cent had dsDNA antibodies, 2% had RF and anti-Ro antibodies, 1% had anti-RNP antibodies, and none had anti-La or anti-Smith antibodies. Conclusions: The background prevalence of ANA ⩾1/80 in patients with PsA was 14%, with very few patients having specific lupus antibodies. This should serve as a baseline figure for the frequency of autoantibodies in biological agent naive patients with PsA for studies of the use of anti-TNFα agents. PMID:15834057

  1. Neuropsychological functioning in stimulant-naive boys with hyperkinetic disorder.

    PubMed

    Rhodes, Sinead M; Coghill, David R; Matthews, Keith

    2005-08-01

    Although children with hyperkinetic disorder and/or attention deficit hyperactivity disorder (ADHD) show disordered executive neuropsychological functioning, the nature of these changes remains controversial. Additionally, impairments in non-executive neuropsychological functioning have been relatively unexplored. Here, the authors describe the neuropsychological functioning of a sample of stimulant drug-naive boys with hyperkinetic disorder on a battery of neuropsychological tasks sensitive to impairments of both executive and non-executive functions. Seventy-five stimulant drug-naive boys meeting diagnostic criteria for ICD-10 hyperkinetic disorder were compared with 70 healthy developing controls matched for age but not IQ on computerized tests of neuropsychological functioning from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and a Go/No-Go inhibition task. Boys with hyperkinetic disorder exhibited impairments on tasks with a prominent executive component--working memory, planning, strategy formation, attentional set-shifting and on a reaction time task. However, they were also impaired on tasks without prominent executive components--pattern and spatial recognition, spatial span, delayed matching to sample and paired associates learning. Contrary to predictions, no impairment was observed on the Go/No-Go inhibition task. Medication-naive boys with hyperkinetic disorder displayed a broad range of neuropsychological impairments. Deficits were demonstrated on tasks with and without prominent executive components. Impairments were not confined to tasks dependent upon frontostriatal functioning, cannot wholly be explained by deficits in inhibitory control, nor can they be attributed to intelligence or previous exposure to stimulant medication.

  2. Interleukin-7 induces HIV replication in primary naive T cells through a nuclear factor of activated T cell (NFAT)-dependent pathway

    SciTech Connect

    Managlia, Elizabeth Z. . E-mail: lalharth@rush.edu

    2006-07-05

    Interleukin (IL)-7 plays several roles critical to T cell maturation, survival, and homeostasis. Because of these functions, IL-7 is under investigation as an immune-modulator for therapeutic use in lymphopenic clinical conditions, including HIV. We reported that naive T cells, typically not permissive to HIV, can be productively infected when pre-treated with IL-7. We evaluated the mechanism by which IL-7-mediates this effect. IL-7 potently up-regulated the transcriptional factor NFAT, but had no effect on NF{kappa}B. Blocking NFAT activity using a number of reagents, such as Cyclosporin A, FK-506, or the NFAT-specific inhibitor known as VIVIT peptide, all markedly reduced IL-7-mediated induction of HIV replication in naive T cells. Additional neutralization of cytokines present in IL-7-treated cultures and/or those that have NFAT-binding sequences within their promotors indicated that IL-10, IL-4, and most significantly IFN{gamma}, all contribute to IL-7-induction of HIV productive replication in naive T cells. These data clarify the mechanism by which IL-7 can overcome the block to HIV productive infection in naive T cells, despite their quiescent cell status. These findings are relevant to the treatment of HIV disease and understanding HIV pathogenesis in the naive CD4+ T cell compartment, especially in light of the vigorous pursuit of IL-7 as an in vivo immune modulator.

  3. Neonatal thymectomy reveals differentiation and plasticity within human naive T cells

    PubMed Central

    van den Broek, Theo; Delemarre, Eveline M.; Janssen, Willemijn J.M.; Nievelstein, Rutger A.J.; Broen, Jasper C.; Tesselaar, Kiki; Borghans, Jose A.M.; Nieuwenhuis, Edward E.S.; Prakken, Berent J.; Mokry, Michal; Jansen, Nicolaas J.G.

    2016-01-01

    The generation of naive T cells is dependent on thymic output, but in adults, the naive T cell pool is primarily maintained by peripheral proliferation. Naive T cells have long been regarded as relatively quiescent cells; however, it was recently shown that IL-8 production is a signatory effector function of naive T cells, at least in newborns. How this functional signature relates to naive T cell dynamics and aging is unknown. Using a cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4+ T cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic tissue regeneration later in life resulted in functional restoration of the naive T cell compartment, implicating the thymus as having functional regenerative capacity. Together, these data shed further light on functional differentiation within the naive T cell compartment and the importance of the thymus in human naive T cell homeostasis and premature aging. In addition, these results affect and alter our current understanding on the identification of truly naive T cells and recent thymic emigrants. PMID:26901814

  4. Rheumatoid Arthritis Naive T Cells Share Hypermethylation Sites With Synoviocytes

    PubMed Central

    Rhead, Brooke; Holingue, Calliope; Cole, Michael; Shao, Xiaorong; Quach, Hong L.; Quach, Diana; Shah, Khooshbu; Sinclair, Elizabeth; Graf, John; Link, Thomas; Harrison, Ruby; Rahmani, Elior; Halperin, Eran; Wang, Wei; Firestein, Gary S.; Barcellos, Lisa F.

    2017-01-01

    Objective To determine whether differentially methylated CpGs in synovium‐derived fibroblast‐like synoviocytes (FLS) of patients with rheumatoid arthritis (RA) were also differentially methylated in RA peripheral blood (PB) samples. Methods For this study, 371 genome‐wide DNA methylation profiles were measured using Illumina HumanMethylation450 BeadChips in PB samples from 63 patients with RA and 31 unaffected control subjects, specifically in the cell subsets of CD14+ monocytes, CD19+ B cells, CD4+ memory T cells, and CD4+ naive T cells. Results Of 5,532 hypermethylated FLS candidate CpGs, 1,056 were hypermethylated in CD4+ naive T cells from RA PB compared to control PB. In analyses of a second set of CpG candidates based on single‐nucleotide polymorphisms from a genome‐wide association study of RA, 1 significantly hypermethylated CpG in CD4+ memory T cells and 18 significant CpGs (6 hypomethylated, 12 hypermethylated) in CD4+ naive T cells were found. A prediction score based on the hypermethylated FLS candidates had an area under the curve of 0.73 for association with RA case status, which compared favorably to the association of RA with the HLA–DRB1 shared epitope risk allele and with a validated RA genetic risk score. Conclusion FLS‐representative DNA methylation signatures derived from the PB may prove to be valuable biomarkers for the risk of RA or for disease status. PMID:27723282

  5. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients.

    PubMed

    Azad, Arun A; Eigl, Bernhard J; Murray, R Nevin; Kollmannsberger, Christian; Chi, Kim N

    2015-01-01

    The activity of enzalutamide after prior treatment with both abiraterone acetate (abiraterone) and docetaxel has been examined in several retrospective studies. However, limited data are available on the efficacy of enzalutamide following abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). To compare the activity of enzalutamide after abiraterone in docetaxel-experienced and docetaxel-naive mCRPC patients. The British Columbia Cancer Agency Cancer Registry was searched for mCRPC patients who received enzalutamide after prior abiraterone. Clinicopathologic characteristics, confirmed prostate-specific antigen (PSA) response rates (PSA decline ≥ 50% confirmed ≥ 3 wk later), and survival data were collected. Outcomes on enzalutamide were compared between docetaxel-experienced and docetaxel-naive patients using chi-square for PSA response and log-rank test for time to PSA progression and overall survival (OS). Univariate analysis was performed to identify variables associated with confirmed PSA response on enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables. A total of 115 patients received enzalutamide after abiraterone: 68 had received prior docetaxel and 47 were docetaxel naive. Median time on enzalutamide was 4.1 mo. Confirmed PSA response rates (22% vs 26%; p=0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p=0.6), and median OS (10.6 mo vs 8.6 mo; p=0.2) did not differ significantly between docetaxel-experienced and docetaxel-naive patients. No clinical variables (including prior response to abiraterone) were found to associate significantly with confirmed PSA response to enzalutamide. Antitumour activity of enzalutamide following abiraterone was limited in mCRPC patients irrespective of prior docetaxel use. Identifying clinical and molecular factors predictive of response to enzalutamide remains a high priority for future

  6. A Combined Omics Approach to Generate the Surface Atlas of Human Naive CD4+ T Cells during Early T-Cell Receptor Activation.

    PubMed

    Graessel, Anke; Hauck, Stefanie M; von Toerne, Christine; Kloppmann, Edda; Goldberg, Tatyana; Koppensteiner, Herwig; Schindler, Michael; Knapp, Bettina; Krause, Linda; Dietz, Katharina; Schmidt-Weber, Carsten B; Suttner, Kathrin

    2015-08-01

    Naive CD4(+) T cells are the common precursors of multiple effector and memory T-cell subsets and possess a high plasticity in terms of differentiation potential. This stem-cell-like character is important for cell therapies aiming at regeneration of specific immunity. Cell surface proteins are crucial for recognition and response to signals mediated by other cells or environmental changes. Knowledge of cell surface proteins of human naive CD4(+) T cells and their changes during the early phase of T-cell activation is urgently needed for a guided differentiation of naive T cells and may support the selection of pluripotent cells for cell therapy. Periodate oxidation and aniline-catalyzed oxime ligation technology was applied with subsequent quantitative liquid chromatography-tandem MS to generate a data set describing the surface proteome of primary human naive CD4(+) T cells and to monitor dynamic changes during the early phase of activation. This led to the identification of 173 N-glycosylated surface proteins. To independently confirm the proteomic data set and to analyze the cell surface by an alternative technique a systematic phenotypic expression analysis of surface antigens via flow cytometry was performed. This screening expanded the previous data set, resulting in 229 surface proteins, which were expressed on naive unstimulated and activated CD4(+) T cells. Furthermore, we generated a surface expression atlas based on transcriptome data, experimental annotation, and predicted subcellular localization, and correlated the proteomics result with this transcriptional data set. This extensive surface atlas provides an overall naive CD4(+) T cell surface resource and will enable future studies aiming at a deeper understanding of mechanisms of T-cell biology allowing the identification of novel immune targets usable for the development of therapeutic treatments. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. A Combined Omics Approach to Generate the Surface Atlas of Human Naive CD4+ T Cells during Early T-Cell Receptor Activation*

    PubMed Central

    Graessel, Anke; Hauck, Stefanie M.; von Toerne, Christine; Kloppmann, Edda; Goldberg, Tatyana; Koppensteiner, Herwig; Schindler, Michael; Knapp, Bettina; Krause, Linda; Dietz, Katharina; Schmidt-Weber, Carsten B.; Suttner, Kathrin

    2015-01-01

    Naive CD4+ T cells are the common precursors of multiple effector and memory T-cell subsets and possess a high plasticity in terms of differentiation potential. This stem-cell-like character is important for cell therapies aiming at regeneration of specific immunity. Cell surface proteins are crucial for recognition and response to signals mediated by other cells or environmental changes. Knowledge of cell surface proteins of human naive CD4+ T cells and their changes during the early phase of T-cell activation is urgently needed for a guided differentiation of naive T cells and may support the selection of pluripotent cells for cell therapy. Periodate oxidation and aniline-catalyzed oxime ligation technology was applied with subsequent quantitative liquid chromatography-tandem MS to generate a data set describing the surface proteome of primary human naive CD4+ T cells and to monitor dynamic changes during the early phase of activation. This led to the identification of 173 N-glycosylated surface proteins. To independently confirm the proteomic data set and to analyze the cell surface by an alternative technique a systematic phenotypic expression analysis of surface antigens via flow cytometry was performed. This screening expanded the previous data set, resulting in 229 surface proteins, which were expressed on naive unstimulated and activated CD4+ T cells. Furthermore, we generated a surface expression atlas based on transcriptome data, experimental annotation, and predicted subcellular localization, and correlated the proteomics result with this transcriptional data set. This extensive surface atlas provides an overall naive CD4+ T cell surface resource and will enable future studies aiming at a deeper understanding of mechanisms of T-cell biology allowing the identification of novel immune targets usable for the development of therapeutic treatments. PMID:25991687

  8. MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages*

    PubMed Central

    Saha, Banishree; Momen-Heravi, Fatemeh; Kodys, Karen; Szabo, Gyongyi

    2016-01-01

    Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals. Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration- and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGFβ and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol-treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR-27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcohol-exposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte-derived EVs can program naive monocytes to polarize into M2 macrophages. PMID:26527689

  9. Fuzzy Naive Bayesian model for medical diagnostic decision support.

    PubMed

    Wagholikar, Kavishwar B; Vijayraghavan, Sundararajan; Deshpande, Ashok W

    2009-01-01

    This work relates to the development of computational algorithms to provide decision support to physicians. The authors propose a Fuzzy Naive Bayesian (FNB) model for medical diagnosis, which extends the Fuzzy Bayesian approach proposed by Okuda. A physician's interview based method is described to define a orthogonal fuzzy symptom information system, required to apply the model. For the purpose of elaboration and elicitation of characteristics, the algorithm is applied to a simple simulated dataset, and compared with conventional Naive Bayes (NB) approach. As a preliminary evaluation of FNB in real world scenario, the comparison is repeated on a real fuzzy dataset of 81 patients diagnosed with infectious diseases. The case study on simulated dataset elucidates that FNB can be optimal over NB for diagnosing patients with imprecise-fuzzy information, on account of the following characteristics - 1) it can model the information that, values of some attributes are semantically closer than values of other attributes, and 2) it offers a mechanism to temper exaggerations in patient information. Although the algorithm requires precise training data, its utility for fuzzy training data is argued for. This is supported by the case study on infectious disease dataset, which indicates optimality of FNB over NB for the infectious disease domain. Further case studies on large datasets are required to establish utility of FNB.

  10. Naive theory impairment in schizophrenia: is it domain-specific?

    PubMed

    Bonshtein, Udi; Leiser, David; Levine, Joseph

    2006-10-01

    The ability to represent mental states of self and others to account for behavior is called theory of mind (ToM). This study examined whether ToM deficit in schizophrenia patients is a specific deficit in the cognitive component of interpersonal skills or a more global deficit, involving impaired information processing skills. Schizophrenia inpatients (N = 41) were compared with a control group of healthy subjects (N = 22) and to nonschizophrenia psychiatric patients (24 with affective disorders, seven with other psychosis) over a range of ToM tasks and another naive theory (theory of biology; ToB). Psychiatric inpatients as a whole showed significant deficit compared with the control group of healthy subjects in ToM tasks. The schizophrenia patients showed significantly larger deficits compared with patients suffering from affective disorder, while the performance of patients with nonschizophrenia psychosis was intermediate. In contrast, no difference was observed in the performance of the different groups on the ToB tasks. The fact that a deficit was found in ToM but not in ToB suggests a specific deficit in a cognitive component of interpersonal skills in schizophrenia rather than a general deficit in information processing skills. Naive theories deficits in schizophrenia seem to be domain-dependent.

  11. [Naive objectivism in the assessment of behavioral disorders].

    PubMed

    Schmid, P

    1977-01-01

    Naive objectivism is a widespread attitude in human and social science research, although it disregards important principles of the theory of cognition. In the history of philosophy two naive approaches to the understanding of the world were continually disputed; 1. rationalism which purports unlimited cognitive power of the human mind, 2. a kind of empiricism which denies subjective elements in the process of cognition. Today the overestimation of human understanding is reflected in a dogmatic adherence to specific professional or idealogically biased doctrines and in the dubious ideal of a purely empirical science with its limited applicability to mankind. The exaggerated expectations regarding the inherent lawfulness of the empirical research field is demonstrated by excessive data collection and by the useless attempt to define behavioral disorders as deviation from the statistical norm. However, behavior disorders can only be understood, if the totality of being human is considered. They are to be seen as failing attempts to give and to maintain a meaning to life.

  12. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis

    PubMed Central

    Fleischmann, Roy M; Huizinga, Tom W J; Kavanaugh, Arthur F; Wilkinson, Bethanie; Kwok, Kenneth; DeMasi, Ryan; van Vollenhoven, Ronald F

    2016-01-01

    Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA. Methods MTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial. Results Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. Conclusions Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. Trial registration number NCT01039688; Results. PMID:27493790

  13. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis.

    PubMed

    Fleischmann, Roy M; Huizinga, Tom W J; Kavanaugh, Arthur F; Wilkinson, Bethanie; Kwok, Kenneth; DeMasi, Ryan; van Vollenhoven, Ronald F

    2016-01-01

    Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA. MTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial. Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. NCT01039688; Results.

  14. Fatal attraction: sexually cannibalistic invaders attract naive native mantids

    PubMed Central

    Fea, Murray P.; Stanley, Margaret C.; Holwell, Gregory I.

    2013-01-01

    Overlap in the form of sexual signals such as pheromones raises the possibility of reproductive interference by invasive species on similar, yet naive native species. Here, we test the potential for reproductive interference through heterospecific mate attraction and subsequent predation of males by females of a sexually cannibalistic invasive praying mantis. Miomantis caffra is invasive in New Zealand, where it is widely considered to be displacing the only native mantis species, Orthodera novaezealandiae, and yet mechanisms behind this displacement are unknown. We demonstrate that native males are more attracted to the chemical cues of introduced females than those of conspecific females. Heterospecific pairings also resulted in a high degree of mortality for native males. This provides evidence for a mechanism behind displacement that has until now been undetected and highlights the potential for reproductive interference to greatly influence the impact of an invasive species. PMID:24284560

  15. A NAIVE BAYES SOURCE CLASSIFIER FOR X-RAY SOURCES

    SciTech Connect

    Broos, Patrick S.; Getman, Konstantin V.; Townsley, Leisa K.; Feigelson, Eric D.; Garmire, Gordon P.; Povich, Matthew S.

    2011-05-01

    The Chandra Carina Complex Project (CCCP) provides a sensitive X-ray survey of a nearby starburst region over >1 deg{sup 2} in extent. Thousands of faint X-ray sources are found, many concentrated into rich young stellar clusters. However, significant contamination from unrelated Galactic and extragalactic sources is present in the X-ray catalog. We describe the use of a naive Bayes classifier to assign membership probabilities to individual sources, based on source location, X-ray properties, and visual/infrared properties. For the particular membership decision rule adopted, 75% of CCCP sources are classified as members, 11% are classified as contaminants, and 14% remain unclassified. The resulting sample of stars likely to be Carina members is used in several other studies, which appear in this special issue devoted to the CCCP.

  16. Naive optics: understanding the geometry of mirror reflections.

    PubMed

    Croucher, Camilla J; Bertamini, Marco; Hecht, Heiko

    2002-06-01

    Paper-and-pencil tasks showed that many university students believed that when laterally approaching a mirror, they would see a reflection in the mirror before it was geometrically possible. Participants failed to adequately factor in the observer's location in the room. However, when asked about the behavior of a ray of light, participants knew about the law of reflection. No differences between psychology and physics students were detected, suggesting that the phenomenon is widespread and refractory to training. The findings were replicated with observers making judgments about image locations in a real room using a pretend mirror. Possible heuristics about mirror reflection that might explain the data are discussed. Naive optics is a promising venue to further knowledge of how observers understand basic laws of physics.

  17. HIV type 1 drug resistance among naive patients from Venezuela.

    PubMed

    Bouchard, Morella; Masquelier, Bernard; Moreno, Melcenia; Deibis, Leopoldo; De Pérez, Gloria Echeverría; Fleury, Herve; Castro, Erika

    2007-03-01

    In this study, we characterize proviral DNA of 20 HIV-1 asymptomatic antiretroviral-naive patients from Venezuela in env, gag, and pol genes regions. Results from both env/gag HMA subtyping and phylogenetic analysis of pol partial sequences led to the description of clade B in all cases. Nevertheless, the high prevalence of polymorphisms was particularly evident among the protease sequences. A 10% prevalence of major resistance mutations to RTIs was found. Our data also suggested that the protease polymorphisms I62T and V77T could be considered as molecular markers of the subtype B local epidemic. In addition, we show how proviral DNA can be used as a reliable tool to follow trends of resistance mutation transmission.

  18. Naive Bayes-guided bat algorithm for feature selection.

    PubMed

    Taha, Ahmed Majid; Mustapha, Aida; Chen, Soong-Der

    2013-01-01

    When the amount of data and information is said to double in every 20 months or so, feature selection has become highly important and beneficial. Further improvements in feature selection will positively affect a wide array of applications in fields such as pattern recognition, machine learning, or signal processing. Bio-inspired method called Bat Algorithm hybridized with a Naive Bayes classifier has been presented in this work. The performance of the proposed feature selection algorithm was investigated using twelve benchmark datasets from different domains and was compared to three other well-known feature selection algorithms. Discussion focused on four perspectives: number of features, classification accuracy, stability, and feature generalization. The results showed that BANB significantly outperformed other algorithms in selecting lower number of features, hence removing irrelevant, redundant, or noisy features while maintaining the classification accuracy. BANB is also proven to be more stable than other methods and is capable of producing more general feature subsets.

  19. Professional Stereotypes of Interprofessional Education Naive Pharmacy and Nursing Students

    PubMed Central

    Thurston, Maria Miller; Harris, Elaine C.; Ryan, Gina J.

    2017-01-01

    Objective. To assess and compare interprofessional education (IPE) naive pharmacy and nursing student stereotypes prior to completion of an IPE activity. Methods. Three hundred and twenty-three pharmacy students and 275 nursing students at Mercer University completed the Student Stereotypes Rating Questionnaire. Responses from pharmacy and nursing students were compared, and responses from different level learners within the same profession also were compared. Results. Three hundred and fifty-six (59.5%) students completed the survey. Pharmacy students viewed pharmacists more favorably than nursing students viewed pharmacists for all attributes except the ability to work independently. Additionally, nursing students viewed nurses less favorably than pharmacy students viewed nurses for academic ability and practical skills. There was some variability in stereotypes between professional years. Conclusion. This study confirms the existence of professional stereotypes, although overall student perceptions of their own profession and the other were generally positive. PMID:28720912

  20. The Persistence of "Solid" and "Liquid" Naive Conceptions: A Reaction Time Study

    ERIC Educational Resources Information Center

    Babai, Reuven; Amsterdamer, Anat

    2008-01-01

    The study explores whether the naive concepts of "solid" and "liquid" persist in adolescence. Accuracy of responses and reaction times where measured while 41 ninth graders classified different solids (rigid, non-rigid and powders) and different liquids (runny, dense) into solid or liquid. The results show that these naive conceptions affect…

  1. Children and Adolescents' Understandings of Family Resemblance: A Study of Naive Inheritance Concepts

    ERIC Educational Resources Information Center

    Williams, Joanne M.

    2012-01-01

    This paper aims to provide developmental data on two connected naive inheritance concepts and to explore the coherence of children's naive biology knowledge. Two tasks examined children and adolescents' (4, 7, 10, and 14 years) conceptions of phenotypic resemblance across kin (in physical characteristics, disabilities, and personality traits). The…

  2. What Fits into a Mirror: Naive Beliefs about the Field of View

    ERIC Educational Resources Information Center

    Bianchi, Ivana; Savardi, Ugo

    2012-01-01

    Research on naive physics and naive optics have shown that people hold surprising beliefs about everyday phenomena that are in contrast with what they see. In this article, we investigated what adults expect to be the field of view of a mirror from various viewpoints. The studies presented here confirm that humans have difficulty dealing with the…

  3. Naive Theory of Biology: The Pre-School Child's Explanation of Death

    ERIC Educational Resources Information Center

    Vlok, Milandre; de Witt, Marike W.

    2012-01-01

    This article explains the naive theory of biology that the pre-school child uses to explain the cause of death. The empirical investigation showed that the young participants do use a naive theory of biology to explain function and do make reference to "vitalistic causality" in explaining organ function. Furthermore, most of these…

  4. What Fits into a Mirror: Naive Beliefs about the Field of View

    ERIC Educational Resources Information Center

    Bianchi, Ivana; Savardi, Ugo

    2012-01-01

    Research on naive physics and naive optics have shown that people hold surprising beliefs about everyday phenomena that are in contrast with what they see. In this article, we investigated what adults expect to be the field of view of a mirror from various viewpoints. The studies presented here confirm that humans have difficulty dealing with the…

  5. Children and Adolescents' Understandings of Family Resemblance: A Study of Naive Inheritance Concepts

    ERIC Educational Resources Information Center

    Williams, Joanne M.

    2012-01-01

    This paper aims to provide developmental data on two connected naive inheritance concepts and to explore the coherence of children's naive biology knowledge. Two tasks examined children and adolescents' (4, 7, 10, and 14 years) conceptions of phenotypic resemblance across kin (in physical characteristics, disabilities, and personality traits). The…

  6. The Persistence of "Solid" and "Liquid" Naive Conceptions: A Reaction Time Study

    ERIC Educational Resources Information Center

    Babai, Reuven; Amsterdamer, Anat

    2008-01-01

    The study explores whether the naive concepts of "solid" and "liquid" persist in adolescence. Accuracy of responses and reaction times where measured while 41 ninth graders classified different solids (rigid, non-rigid and powders) and different liquids (runny, dense) into solid or liquid. The results show that these naive conceptions affect…

  7. Naive Theory of Biology: The Pre-School Child's Explanation of Death

    ERIC Educational Resources Information Center

    Vlok, Milandre; de Witt, Marike W.

    2012-01-01

    This article explains the naive theory of biology that the pre-school child uses to explain the cause of death. The empirical investigation showed that the young participants do use a naive theory of biology to explain function and do make reference to "vitalistic causality" in explaining organ function. Furthermore, most of these…

  8. Dynamic analysis of naive adaptive brain-machine interfaces.

    PubMed

    Kowalski, Kevin C; He, Bryan D; Srinivasan, Lakshminarayan

    2013-09-01

    The closed-loop operation of brain-machine interfaces (BMI) provides a context to discover foundational principles behind human-computer interaction, with emerging clinical applications to stroke, neuromuscular diseases, and trauma. In the canonical BMI, a user controls a prosthetic limb through neural signals that are recorded by electrodes and processed by a decoder into limb movements. In laboratory demonstrations with able-bodied test subjects, parameters of the decoder are commonly tuned using training data that include neural signals and corresponding overt arm movements. In the application of BMI to paralysis or amputation, arm movements are not feasible, and imagined movements create weaker, partially unrelated patterns of neural activity. BMI training must begin naive, without access to these prototypical methods for parameter initialization used in most laboratory BMI demonstrations. Naive adaptive BMI refer to a class of methods recently introduced to address this problem. We first identify the basic elements of existing approaches based on adaptive filtering and define a decoder, ReFIT-PPF to represent these existing approaches. We then present Joint RSE, a novel approach that logically extends prior approaches. Using recently developed human- and synthetic-subjects closed-loop BMI simulation platforms, we show that Joint RSE significantly outperforms ReFIT-PPF and nonadaptive (static) decoders. Control experiments demonstrate the critical role of jointly estimating neural parameters and user intent. In addition, we show that nonzero sensorimotor delay in the user significantly degrades ReFIT-PPF but not Joint RSE, owing to differences in the prior on intended velocity. Paradoxically, substantial differences in the nature of sensory feedback between these methods do not contribute to differences in performance between Joint RSE and ReFIT-PPF. Instead, BMI performance improvement is driven by machine learning, which outpaces rates of human learning in

  9. Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification.

    PubMed

    Respuela, Patricia; Nikolić, Miloš; Tan, Minjia; Frommolt, Peter; Zhao, Yingming; Wysocka, Joanna; Rada-Iglesias, Alvaro

    2016-01-07

    Following implantation, mouse epiblast cells transit from a naive to a primed state in which they are competent for both somatic and primordial germ cell (PGC) specification. Using mouse embryonic stem cells as an in vitro model to study the transcriptional regulatory principles orchestrating peri-implantation development, here we show that the transcription factor Foxd3 is necessary for exit from naive pluripotency and progression to a primed pluripotent state. During this transition, Foxd3 acts as a repressor that dismantles a significant fraction of the naive pluripotency expression program through decommissioning of active enhancers associated with key naive pluripotency and early germline genes. Subsequently, Foxd3 needs to be silenced in primed pluripotent cells to allow re-activation of relevant genes required for proper PGC specification. Our findings therefore uncover a cycle of activation and deactivation of Foxd3 required for exit from naive pluripotency and subsequent PGC specification. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Naive Pluripotent Stem Cells Derived Directly from Isolated Cells of the Human Inner Cell Mass

    PubMed Central

    Guo, Ge; von Meyenn, Ferdinand; Santos, Fatima; Chen, Yaoyao; Reik, Wolf; Bertone, Paul; Smith, Austin; Nichols, Jennifer

    2016-01-01

    Summary Conventional generation of stem cells from human blastocysts produces a developmentally advanced, or primed, stage of pluripotency. In vitro resetting to a more naive phenotype has been reported. However, whether the reset culture conditions of selective kinase inhibition can enable capture of naive epiblast cells directly from the embryo has not been determined. Here, we show that in these specific conditions individual inner cell mass cells grow into colonies that may then be expanded over multiple passages while retaining a diploid karyotype and naive properties. The cells express hallmark naive pluripotency factors and additionally display features of mitochondrial respiration, global gene expression, and genome-wide hypomethylation distinct from primed cells. They transition through primed pluripotency into somatic lineage differentiation. Collectively these attributes suggest classification as human naive embryonic stem cells. Human counterparts of canonical mouse embryonic stem cells would argue for conservation in the phased progression of pluripotency in mammals. PMID:26947977

  11. Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation.

    PubMed

    Kreisberg, Jason F; Yonemoto, Wes; Greene, Warner C

    2006-04-17

    Human immunodeficiency virus (HIV) can infect resting CD4 T cells residing in lymphoid tissues but not those circulating in peripheral blood. The molecular mechanisms producing this difference remain unknown. We explored the potential role of the tissue microenvironment and its influence on the action of the antiviral factor APOBEC3G (A3G) in regulating permissivity to HIV infection. We found that endogenous IL-2 and -15 play a key role in rendering resident naive CD4 T cells susceptible to HIV infection. Infection of memory CD4 T cells also requires endogenous soluble factors, but not IL-2 or -15. A3G is found in a high molecular mass complex in HIV infection-permissive, tissue-resident naive CD4 T cells but resides in a low molecular mass form in nonpermissive, blood-derived naive CD4 T cells. Upon treatment with endogenous soluble factors, these cells become permissive for HIV infection, as low molecular mass A3G is induced to assemble into high molecular mass complexes. These findings suggest that in lymphoid tissues, endogenous soluble factors, likely including IL-2 and -15 and others, stimulate the formation of high molecular mass A3G complexes in tissue-resident naive CD4 T cells, thereby relieving the potent postentry restriction block for HIV infection conferred by low molecular mass A3G.

  12. Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients.

    PubMed

    Cheng, Pin-Nan; Chang, Ting-Tsung

    2008-10-01

    Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement -- with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.

  13. CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART.

    PubMed

    Sauter, Rafael; Huang, Ruizhu; Ledergerber, Bruno; Battegay, Manuel; Bernasconi, Enos; Cavassini, Matthias; Furrer, Hansjakob; Hoffmann, Matthias; Rougemont, Mathieu; Günthard, Huldrych F; Held, Leonhard

    2016-10-01

    Plasma HIV viral load is related to declining CD4 lymphocytes. The extent to which CD8 cells, in addition to RNA viral load, predict the depletion of CD4 cells is not well characterized so far. We examine if CD8 cell count is a prognostic factor for CD4 cell counts during an HIV infection.A longitudinal analysis is conducted using data from the Swiss HIV cohort study collected between January 2000 and October 2014. Linear mixed regression models were applied to observations from HIV-1-infected treatment naive patients (NAIVE) and cART-treated patients to predict the short-term evolution of CD4 cell counts. For each subgroup, it was quantified to which extent CD8 cell counts or CD4/CD8 ratios are prognostic factors for disease progression.In both subgroups, 2500 NAIVE and 8902 cART patients, past CD4 cells are positively (P < 0.0001) and past viral load is negatively (P < 0.0001) associated with the outcome. Including additionally past CD8 cell counts improves the fit significantly (P < 0.0001) and increases the marginal explained variation 31.7% to 40.7% for the NAIVE and from 44.1% to 50.7% for the cART group. The past CD4/CD8 ratio (instead of the past CD8 level) is positively associated with the outcome, increasing the explained variation further to 41.8% for NAIVE and 51.9% for cART.

  14. CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART

    PubMed Central

    Sauter, Rafael; Huang, Ruizhu; Ledergerber, Bruno; Battegay, Manuel; Bernasconi, Enos; Cavassini, Matthias; Furrer, Hansjakob; Hoffmann, Matthias; Rougemont, Mathieu; Günthard, Huldrych F; Held, Leonhard

    2016-01-01

    Abstract Plasma HIV viral load is related to declining CD4 lymphocytes. The extent to which CD8 cells, in addition to RNA viral load, predict the depletion of CD4 cells is not well characterized so far. We examine if CD8 cell count is a prognostic factor for CD4 cell counts during an HIV infection. A longitudinal analysis is conducted using data from the Swiss HIV cohort study collected between January 2000 and October 2014. Linear mixed regression models were applied to observations from HIV-1-infected treatment naive patients (NAIVE) and cART-treated patients to predict the short-term evolution of CD4 cell counts. For each subgroup, it was quantified to which extent CD8 cell counts or CD4/CD8 ratios are prognostic factors for disease progression. In both subgroups, 2500 NAIVE and 8902 cART patients, past CD4 cells are positively (P < 0.0001) and past viral load is negatively (P < 0.0001) associated with the outcome. Including additionally past CD8 cell counts improves the fit significantly (P < 0.0001) and increases the marginal explained variation 31.7% to 40.7% for the NAIVE and from 44.1% to 50.7% for the cART group. The past CD4/CD8 ratio (instead of the past CD8 level) is positively associated with the outcome, increasing the explained variation further to 41.8% for NAIVE and 51.9% for cART. PMID:27759638

  15. Telomere Length and Pulse Pressure in Newly Diagnosed, Antipsychotic-Naive Patients With Nonaffective Psychosis

    PubMed Central

    Fernandez-Egea, Emilio; Bernardo, Miguel; Heaphy, Christopher M.; Griffith, Jeffrey K.; Parellada, Eduard; Esmatjes, Enric; Conget, Ignacio; Nguyen, Linh; George, Varghese; Stöppler, Hubert; Kirkpatrick, Brian

    2009-01-01

    Introduction: Recent studies suggest that in addition to factors such as treatment side effects, suicide, and poor health habits, people with schizophrenia may have an increased risk of diabetes prior to antipsychotic treatment. Diabetes is associated with an increased pulse pressure (PP) and a shortened telomere. We tested the hypothesis that prior to antipsychotic treatment, schizophrenia and related disorders are associated with a shortened telomere, as well as an increased PP. Methods: Telomere content (which is highly correlated with telomere length) and PP were measured in newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders on first clinical contact and in matched control subjects. Both groups were also administered an oral glucose tolerance test. Results: Compared with control subjects, the patients with psychosis had decreased telomere content and an increased PP. As previously reported, they also had increased glucose concentrations at 2 hours. These differences could not be attributed to differences in age, ethnicity, smoking, gender, body mass index, neighborhood of residence, socioeconomic status, aerobic conditioning, or an increased cortisol concentration in the psychotic subjects. Discussion: These results suggest that prior to antipsychotic use, nonaffective psychosis is associated with reduced telomere content and increased PP, indices that have been linked to an increased risk of diabetes and hypertension. PMID:19279086

  16. Applying Naive Bayesian Networks to Disease Prediction: a Systematic Review.

    PubMed

    Langarizadeh, Mostafa; Moghbeli, Fateme

    2016-10-01

    Naive Bayesian networks (NBNs) are one of the most effective and simplest Bayesian networks for prediction. This paper aims to review published evidence about the application of NBNs in predicting disease and it tries to show NBNs as the fundamental algorithm for the best performance in comparison with other algorithms. PubMed was electronically checked for articles published between 2005 and 2015. For characterizing eligible articles, a comprehensive electronic searching method was conducted. Inclusion criteria were determined based on NBN and its effects on disease prediction. A total of 99 articles were found. After excluding the duplicates (n= 5), the titles and abstracts of 94 articles were skimmed according to the inclusion criteria. Finally, 38 articles remained. They were reviewed in full text and 15 articles were excluded. Eventually, 23 articles were selected which met our eligibility criteria and were included in this study. In this article, the use of NBN in predicting diseases was described. Finally, the results were reported in terms of Accuracy, Sensitivity, Specificity and Area under ROC curve (AUC). The last column in Table 2 shows the differences between NBNs and other algorithms. This systematic review (23 studies, 53,725 patients) indicates that predicting diseases based on a NBN had the best performance in most diseases in comparison with the other algorithms. Finally in most cases NBN works better than other algorithms based on the reported accuracy. The method, termed NBNs is proposed and can efficiently construct a prediction model for disease.

  17. Light controls cerebral blood flow in naive animals

    PubMed Central

    Rungta, Ravi L; Osmanski, Bruno-Félix; Boido, Davide; Tanter, Mickael; Charpak, Serge

    2017-01-01

    Optogenetics is increasingly used to map brain activation using techniques that rely on functional hyperaemia, such as opto-fMRI. Here we test whether light stimulation protocols similar to those commonly used in opto-fMRI or to study neurovascular coupling modulate blood flow in mice that do not express light sensitive proteins. Combining two-photon laser scanning microscopy and ultrafast functional ultrasound imaging, we report that in the naive mouse brain, light per se causes a calcium decrease in arteriolar smooth muscle cells, leading to pronounced vasodilation, without excitation of neurons and astrocytes. This photodilation is reversible, reproducible and energy-dependent, appearing at about 0.5 mJ. These results impose careful consideration on the use of photo-activation in studies involving blood flow regulation, as well as in studies requiring prolonged and repetitive stimulations to correct cellular defects in pathological models. They also suggest that light could be used to locally increase blood flow in a controlled fashion. PMID:28139643

  18. Applying Naive Bayesian Networks to Disease Prediction: a Systematic Review

    PubMed Central

    Langarizadeh, Mostafa; Moghbeli, Fateme

    2016-01-01

    Introduction: Naive Bayesian networks (NBNs) are one of the most effective and simplest Bayesian networks for prediction. Objective: This paper aims to review published evidence about the application of NBNs in predicting disease and it tries to show NBNs as the fundamental algorithm for the best performance in comparison with other algorithms. Methods: PubMed was electronically checked for articles published between 2005 and 2015. For characterizing eligible articles, a comprehensive electronic searching method was conducted. Inclusion criteria were determined based on NBN and its effects on disease prediction. A total of 99 articles were found. After excluding the duplicates (n= 5), the titles and abstracts of 94 articles were skimmed according to the inclusion criteria. Finally, 38 articles remained. They were reviewed in full text and 15 articles were excluded. Eventually, 23 articles were selected which met our eligibility criteria and were included in this study. Result: In this article, the use of NBN in predicting diseases was described. Finally, the results were reported in terms of Accuracy, Sensitivity, Specificity and Area under ROC curve (AUC). The last column in Table 2 shows the differences between NBNs and other algorithms. Discussion: This systematic review (23 studies, 53,725 patients) indicates that predicting diseases based on a NBN had the best performance in most diseases in comparison with the other algorithms. Finally in most cases NBN works better than other algorithms based on the reported accuracy. Conclusion: The method, termed NBNs is proposed and can efficiently construct a prediction model for disease. PMID:28077895

  19. Early Remission Is a Realistic Target in a Majority of Patients with DMARD-naive Rheumatoid Arthritis.

    PubMed

    Rannio, Tuomas; Asikainen, Juha; Kokko, Arto; Hannonen, Pekka; Sokka, Tuulikki

    2016-04-01

    We analyzed remission rates at 3 and 12 months in patients with rheumatoid arthritis (RA) who were naive for disease-modifying antirheumatic drugs (DMARD) and who were treated in a Finnish rheumatology clinic from 2008 to 2011. We compared remission rates and drug treatments between patients with RA and patients with undifferentiated arthritis (UA). Data from all DMARD-naive RA and UA patients from the healthcare district were collected using software that includes demographic and clinical characteristics, disease activity, medications, and patient-reported outcomes. Our rheumatology clinic applies the treat-to-target principle, electronic monitoring of patients, and multidisciplinary care. Out of 409 patients, 406 had data for classification by the 2010 RA criteria of the American College of Rheumatology/European League Against Rheumatism. A total of 68% were female, and mean age (SD) was 58 (16) years. Respectively, 56%, 60%, and 68% were positive for anticyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF), and RF/anti-CCP, and 19% had erosive disease. The median (interquartile range) duration of symptoms was 6 (4-12) months. A total of 310 were classified as RA and 96 as UA. The patients with UA were younger, had better functional status and lower disease activity, and were more often seronegative than the patients with RA. The 28-joint Disease Activity Score (3 variables) remission rates of RA and UA patients at 3 months were 67% and 58% (p = 0.13), and at 12 months, 71% and 79%, respectively (p = 0.16). Sustained remission was observed in 57%/56% of RA/UA patients. Patients with RA used more conventional synthetic DMARD combinations than did patients with UA. None used biological DMARD at 3 months, and only 2.7%/1.1% of the patients (RA/UA) used them at 12 months (p = 0.36). Remarkably high remission rates are achievable in real-world DMARD-naive patients with RA or UA.

  20. Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats.

    PubMed

    Levant, Beth; Pazdernik, Thomas L

    2004-04-02

    Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2-deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing doses of morphine (5-25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg (b.i.d.) for 4-7 days. For the 2-DG procedure, rats were injected with saline or ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46 brain regions. In drug-naive animals, ibogaine produced significant increases in LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared to controls consistent with its activity as a hallucinogen and a tremorogen. Morphine-dependent rats had only minor alterations in LCGU at the time assessed in this experiment. However, in morphine-dependent animals, ibogaine produced a global decrease in LCGU that was greatest in brain regions such as the lateral and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell, inferior colliculus, locus coeruleus, and flocculus compared to morphine-dependent animals treated with saline. These findings indicate that ibogaine produces distinctly different effects on LCGU in drug-naive and morphine-dependent rats. This suggests that different mechanisms may underlie ibogaine's hallucinogenic and anti-addictive effects.

  1. Respiratory effects of buprenorphine/naloxone alone and in combination with diazepam in naive and tolerant rats.

    PubMed

    Cohier, Camille; Chevillard, Lucie; Risède, Patricia; Roussel, Olivier; Mégarbane, Bruno

    2014-07-15

    Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP-tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P<0.05) without altering minute volume (VE). In combination to DZP, BUP/NLX significantly increased expiratory time (P<0.01) and decreased f (P<0.01), tidal volume (VT, P<0.001), and VE (P<0.001) while BUP only decreased VT (P<0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P<0.001) and decreased f (P<0.01) and VE (P<0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  2. Neisseria lactamica selectively induces mitogenic proliferation of the naive B cell pool via cell surface Ig.

    PubMed

    Vaughan, Andrew T; Brackenbury, Louise S; Massari, Paola; Davenport, Victoria; Gorringe, Andrew; Heyderman, Robert S; Williams, Neil A

    2010-09-15

    Neisseria lactamica is a commensal bacteria that colonizes the human upper respiratory tract mucosa during early childhood. In contrast to the closely related opportunistic pathogen Neisseria meningitidis, there is an absence of adaptive cell-mediated immunity to N. lactamica during the peak age of carriage. Instead, outer membrane vesicles derived from N. lactamica mediate a B cell-dependent proliferative response in mucosal mononuclear cells that is associated with the production of polyclonal IgM. We demonstrate in this study that this is a mitogenic human B cell response that occurs independently of T cell help and any other accessory cell population. The ability to drive B cell proliferation is a highly conserved property and is present in N. lactamica strains derived from diverse clonal complexes. CFSE staining of purified human tonsillar B cells demonstrated that naive IgD(+) and CD27(-) B cells are selectively induced to proliferate by outer membrane vesicles, including the innate CD5(+) subset. Neither purified lipooligosaccharide nor PorB from N. lactamica is likely to be responsible for this activity. Prior treatment of B cells with pronase to remove cell-surface Ig or treatment with BCR-specific Abs abrogated the proliferative response to N. lactamica outer membrane vesicles, suggesting that this mitogenic response is dependent upon the BCR.

  3. Improving Naive Bayes with Online Feature Selection for Quick Adaptation to Evolving Feature Usefulness

    SciTech Connect

    Pon, R K; Cardenas, A F; Buttler, D J

    2007-09-19

    The definition of what makes an article interesting varies from user to user and continually evolves even for a single user. As a result, for news recommendation systems, useless document features can not be determined a priori and all features are usually considered for interestingness classification. Consequently, the presence of currently useless features degrades classification performance [1], particularly over the initial set of news articles being classified. The initial set of document is critical for a user when considering which particular news recommendation system to adopt. To address these problems, we introduce an improved version of the naive Bayes classifier with online feature selection. We use correlation to determine the utility of each feature and take advantage of the conditional independence assumption used by naive Bayes for online feature selection and classification. The augmented naive Bayes classifier performs 28% better than the traditional naive Bayes classifier in recommending news articles from the Yahoo! RSS feeds.

  4. Do naive juvenile seabirds forage differently from adults?

    PubMed Central

    Riotte-Lambert, Louise; Weimerskirch, Henri

    2013-01-01

    Foraging skills of young individuals are assumed to be inferior to those of adults. The reduced efficiency of naive individuals may be the primary cause of the high juvenile mortality and explain the deferment of maturity in long-lived species. However, the study of juvenile and immature foraging behaviour has been limited so far. We used satellite telemetry to compare the foraging movements of juveniles, immatures and breeding adult wandering albatrosses Diomedea exulans, a species where foraging success is positively influenced by the distance covered daily. We showed that juveniles are able to use favourable winds as soon as the first month of independence, but cover shorter distances daily and spend more time sitting on water than adults during the first two months after fledging. These reduced movement capacities do not seem to be the cause of higher juvenile mortality. Moreover, juveniles almost never restrict their movement to specific areas, as adults and immatures frequently do over shelf edges or oceanic zones, which suggest that the location of appropriate areas is learned through experience. Immatures and adults have equivalent movement capacities, but when they are central place foragers, i.e. when adults breed or immatures come to the colony to display and pair, immatures make shorter trips than adults. The long duration of immaturity in this species seems to be related to a long period of learning to integrate the foraging constraints associated with reproduction and central place foraging. Our results indicate that foraging behaviour of young albatrosses is partly innate and partly learned progressively over immaturity. The first months of learning appear critical in terms of survival, whereas the long period of immaturity is necessary for young birds to attain the skills necessary for efficient breeding without fitness costs. PMID:23926153

  5. Do naive juvenile seabirds forage differently from adults?

    PubMed

    Riotte-Lambert, Louise; Weimerskirch, Henri

    2013-10-07

    Foraging skills of young individuals are assumed to be inferior to those of adults. The reduced efficiency of naive individuals may be the primary cause of the high juvenile mortality and explain the deferment of maturity in long-lived species. However, the study of juvenile and immature foraging behaviour has been limited so far. We used satellite telemetry to compare the foraging movements of juveniles, immatures and breeding adult wandering albatrosses Diomedea exulans, a species where foraging success is positively influenced by the distance covered daily. We showed that juveniles are able to use favourable winds as soon as the first month of independence, but cover shorter distances daily and spend more time sitting on water than adults during the first two months after fledging. These reduced movement capacities do not seem to be the cause of higher juvenile mortality. Moreover, juveniles almost never restrict their movement to specific areas, as adults and immatures frequently do over shelf edges or oceanic zones, which suggest that the location of appropriate areas is learned through experience. Immatures and adults have equivalent movement capacities, but when they are central place foragers, i.e. when adults breed or immatures come to the colony to display and pair, immatures make shorter trips than adults. The long duration of immaturity in this species seems to be related to a long period of learning to integrate the foraging constraints associated with reproduction and central place foraging. Our results indicate that foraging behaviour of young albatrosses is partly innate and partly learned progressively over immaturity. The first months of learning appear critical in terms of survival, whereas the long period of immaturity is necessary for young birds to attain the skills necessary for efficient breeding without fitness costs.

  6. Naive Juveniles Are More Likely to Become Breeders after Witnessing Predator Mobbing.

    PubMed

    Griesser, Michael; Suzuki, Toshitaka N

    2017-01-01

    Responding appropriately during the first predatory attack in life is often critical for survival. In many social species, naive juveniles acquire this skill from conspecifics, but its fitness consequences remain virtually unknown. Here we experimentally demonstrate how naive juvenile Siberian jays (Perisoreus infaustus) derive a long-term fitness benefit from witnessing knowledgeable adults mobbing their principal predator, the goshawk (Accipiter gentilis). Siberian jays live in family groups of two to six individuals that also can include unrelated nonbreeders. Field observations showed that Siberian jays encounter predators only rarely, and, indeed, naive juveniles do not respond to predator models when on their own but do when observing other individuals mobbing them. Predator exposure experiments demonstrated that naive juveniles had a substantially higher first-winter survival after observing knowledgeable group members mobbing a goshawk model, increasing their likelihood of acquiring a breeding position later in life. Previous research showed that naive individuals may learn from others how to respond to predators, care for offspring, or choose mates, generally assuming that social learning has long-term fitness consequences without empirical evidence. Our results demonstrate a long-term fitness benefit of vertical social learning for naive individuals in the wild, emphasizing its evolutionary importance in animals, including humans.

  7. Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.

    PubMed

    Sahakyan, Anna; Kim, Rachel; Chronis, Constantinos; Sabri, Shan; Bonora, Giancarlo; Theunissen, Thorold W; Kuoy, Edward; Langerman, Justin; Clark, Amander T; Jaenisch, Rudolf; Plath, Kathrin

    2017-01-05

    Naive human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X chromosome state has remained unresolved. Here, we show that the inactive X chromosome (Xi) of primed hESCs was reactivated in naive culture conditions. Like cells of the blastocyst, the resulting naive cells contained two active X chromosomes with XIST expression and chromosome-wide transcriptional dampening and initiated XIST-mediated X inactivation upon differentiation. Both establishment of and exit from the naive state (differentiation) happened via an XIST-negative XaXa intermediate. Together, these findings identify a cell culture system for functionally exploring the two X chromosome dosage compensation processes in early human development: X dampening and X inactivation. However, remaining differences between naive hESCs and embryonic cells related to mono-allelic XIST expression and non-random X inactivation highlight the need for further culture improvement. As the naive state resets Xi abnormalities seen in primed hESCs, it may provide cells better suited for downstream applications.

  8. Immunovirological Efficacy of Once-Daily Maraviroc Plus Ritonavir-Boosted Atazanavir After 48 Weeks in Naive HIV-Infected Patients.

    PubMed

    Pulido, Ildefonso; Genebat, Miguel; Alvarez-Rios, Ana I; De Pablo-Bernal, Rebeca S; Rafii-El-Idrissi Benhnia, Mohammed; Pacheco, Yolanda M; Ruiz-Mateos, Ezequiel; Leal, Manuel

    2016-10-01

    Toxicities related to the use of nucleoside analogues have increased the interest in developing nucleoside-sparing regimens, mainly combining protease inhibitors with raltegravir. However, data regarding the use of CCR5-antagonists in this setting and in the naive scenario are scarce. The main objective was to analyze the immunovirological efficacy and tolerability of a low-dose, once-daily, maraviroc (MVC)-containing, nucleoside reverse transcriptase inhibitor-sparing dual therapy compared with standard triple therapy after 48 weeks for naive HIV-infected patients in the routine clinical practice setting. All naive HIV-infected patients with stable clinical condition that started antiretroviral treatment since February 1, 2008 to May 30,h 2012 were included. MVC clinical test was used to select candidate subjects to MVC therapy. Thirty-two subjects with MVC + atazanavir/ritonavir (ATV/r) and 66 with standard triple therapy were analyzed. A comparable virological efficacy between groups was found after 48 weeks (87.5% vs. 80.3% of HIV undetectability, p = 0.37, MVC + ATV/r and triple therapy groups, respectively). The CD4 recovery after 48 weeks was similar and more than 200 cells/mm(3) in both groups. No need of therapy changes or treatment discontinuations was observed in the MVC + ATV/r group. Effect on lipid profile, high-sensitivity C reactive protein, and β2-microglobulin was similar for both groups. Noteworthy, a significant increase of erythrocyte mean corpuscular volume was observed only in the triple therapy group. A nucleoside-sparing MVC-containing dual therapy showed similar immunovirological efficacy and tolerability than standard triple therapy in naive HIV-infected patients.

  9. In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin

    PubMed Central

    Singh, Madhuri; Sasaki, Takashi; Morimoto, Yuh; Hishinuma, Tomomi; Hiramatsu, Keiichi

    2016-01-01

    ABSTRACT The mechanisms underlying bacterial tolerance to antibiotics are unclear. A possible adaptation strategy was explored by exposure of drug-naive methicillin-susceptible Staphylococcus aureus strain FDA209P to vancomycin in vitro. Strains surviving vancomycin treatment (vancomycin survivor strains), which appeared after 96 h of exposure, were slow-growing derivatives of the parent strain. Although the vancomycin MICs for the survivor strains were within the susceptible range, the cytokilling effects of vancomycin at 20-fold the MIC were significantly lower for the survivor strains than for the parent strain. Whole-genome sequencing demonstrated that ileS, encoding isoleucyl-tRNA synthetase (IleRS), was mutated in two of the three vancomycin survivor strains. The IleRS Y723H mutation is located close to the isoleucyl-tRNA contact site and potentially affects the affinity of IleRS binding to isoleucyl-tRNA, thereby inhibiting protein synthesis and leading to vancomycin tolerance. Introduction of the mutation encoding IleRS Y723H into FDA209P by allelic replacement successfully transferred the vancomycin tolerance phenotype. We have identified mutation of ileS to be one of the bona fide genetic events leading to the acquisition of vancomycin tolerance in S. aureus, potentially acting via inhibition of the function of IleRS. PMID:27855063

  10. Prolactin variations during risperidone therapy in a sample of drug-naive children and adolescents

    PubMed Central

    Matera, Emilia; Petruzzelli, Maria G.; Simone, Marta; Lamanna, Anna L.; Pastore, Adriana; Palmieri, Vincenzo O.; Margari, Francesco

    2015-01-01

    The aim of this prospective observational study was to investigate the variations of serum prolactin hormone (PRL) in a sample of 34 drug-naive patients (mean age 13 years) who started risperidone therapy assuming that several factors may favor the increase in serum PRL. Serum PRL and hyperprolactinemia clinical signs were examined at baseline (T0) and after almost 3 months of treatment (T1). We considered sex, pubertal status, risperidone dosage, psychiatric diagnosis, and any personal/family history of autoimmune diseases. The mean serum PRL value increased between T0 and T1 (P=0.004). The mean serum PRL was higher in females in the pubertal/postpubertal stage and for risperidone dosage up 1 mg/day. Hyperprolactinemia was found in 20% of patients at T0 and in 38% of patients at T1 (P=0.03). The mean serum PRL increase was greater in early-onset schizophrenia spectrum psychosis patients compared with no-early-onset schizophrenia spectrum psychosis patients (P=0.04). The increase in PRL was higher in patients with a personal and a family history of autoimmune diseases. This study suggests that the increase in serum PRL in patients treated with risperidone may be linked not only to the drug and its dosage but also to several risk factors such as sex, pubertal stage, psychiatric disease, and autoimmune disorders. PMID:25514607

  11. Differential T cell receptor-mediated signaling in naive and memory CD4 T cells.

    PubMed

    Farber, D L; Acuto, O; Bottomly, K

    1997-08-01

    Naive and memory CD4 T cells differ in cell surface phenotype, function, activation requirements, and modes of regulation. To investigate the molecular bases for the dichotomies between naive and memory CD4 T cells and to understand how the T cell receptor (TCR) directs diverse functional outcomes, we investigated proximal signaling events triggered through the TCR/CD3 complex in naive and memory CD4 T cell subsets isolated on the basis of CD45 isoform expression. Naive CD4 T cells signal through TCR/CD3 similar to unseparated CD4 T cells, producing multiple tyrosine-phosphorylated protein species overall and phosphorylating the T cell-specific ZAP-70 tyrosine kinase which is recruited to the CD3zeta subunit of the TCR. Memory CD4 T cells, however, exhibit a unique pattern of signaling through TCR/CD3. Following stimulation through TCR/CD3, memory CD4 T cells produce fewer species of tyrosine-phosphorylated substrates and fail to phosphorylate ZAP-70, yet unphosphorylated ZAP-70 can associate with the TCR/CD3 complex. Moreover, a 26/28-kDa phosphorylated doublet is associated with CD3zeta in resting and activated memory but not in naive CD4 T cells. Despite these differences in the phosphorylation of ZAP-70 and CD3-associated proteins, the ZAP-70-related kinase, p72syk, exhibits similar phosphorylation in naive and memory T cell subsets, suggesting that this kinase could function in place of ZAP-70 in memory CD4 T cells. These results indicate that proximal signals are differentially coupled to the TCR in naive versus memory CD4 T cells, potentially leading to distinct downstream signaling events and ultimately to the diverse functions elicited by these two CD4 T cell subsets.

  12. Effect of serostatus for hepatitis C virus on mortality among antiretrovirally naive HIV-positive patients

    PubMed Central

    Braitstein, Paula; Yip, Benita; Montessori, Valentina; Moore, David; Montaner, Julio S.G.; Hogg, Robert S.

    2005-01-01

    Background We examined the effect of hepatitis C virus (HCV) seropositivity on risk of death among people receiving their first antiretroviral treatment (ART) for HIV infection. Methods In British Columbia, the HIV/ AIDS Drug Treatment Program is the only source of free ART. Patients who initiated a triple-drug ART regimen between July 31, 1996, and July 31, 2000, were included if they were ART-naive and had baseline HCV serological data. Outcomes of interest for survival analysis were deaths from natural and HIV-related causes, with a data cutoff of June 30, 2003. Results Of 1186 eligible subjects, 606 (51%) were HCV positive and 580, negative. Fewer HCV-positive people were male (78% v. 93%, p < 0.001) and had an AIDS diagnosis at baseline (11% v. 15%, p = 0.028). Their CD4 fraction was significantly higher at baseline (19% v. 16% of T lymphocytes, p < 0.001) but their absolute CD4 counts, log HIV viral load and the type of ART initiated were similar to those of HCV negative people. Of 163 deaths (from natural causes only) during the study period, 118 (19%) were in HCV positive and 45 (8%) in HCV negative patients (p < 0.001); of the 114 deaths attributed to HIV infection, these proportions were 79 (13%) versus 35 (6%; p < 0.001). After adjustment for potential confounders, HCV seropositivity remained predictive of death (adjusted hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.50– 3.21, p < 0.001), especially HIV-related death (adjusted HR 1.75, 95% CI 1.13– 2.72, p = 0.012). Interpretation In this population-based HIV treatment program, we found HCV seropositivity to be an independent predictor of mortality, especially death related to HIV infection. PMID:16027432

  13. Effect of serostatus for hepatitis C virus on mortality among antiretrovirally naive HIV-positive patients.

    PubMed

    Braitstein, Paula; Yip, Benita; Montessori, Valentina; Moore, David; Montaner, Julio S G; Hogg, Robert S

    2005-07-19

    We examined the effect of hepatitis C virus (HCV) seropositivity on risk of death among people receiving their first antiretroviral treatment (ART) for HIV infection. In British Columbia, the HIV/ AIDS Drug Treatment Program is the only source of free ART. Patients who initiated a triple-drug ART regimen between July 31, 1996, and July 31, 2000, were included if they were ART-naive and had baseline HCV serological data. Outcomes of interest for survival analysis were deaths from natural and HIV-related causes, with a data cutoff of June 30, 2003. Of 1186 eligible subjects, 606 (51%) were HCV positive and 580, negative. Fewer HCV-positive people were male (78% v. 93%, p < 0.001) and had an AIDS diagnosis at baseline (11% v. 15%, p = 0.028). Their CD4 fraction was significantly higher at baseline (19% v. 16% of T lymphocytes, p < 0.001) but their absolute CD4 counts, log HIV viral load and the type of ART initiated were similar to those of HCV negative people. Of 163 deaths (from natural causes only) during the study period, 118 (19%) were in HCV positive and 45 (8%) in HCV negative patients (p < 0.001); of the 114 deaths attributed to HIV infection, these proportions were 79 (13%) versus 35 (6%; p < 0.001). After adjustment for potential confounders, HCV seropositivity remained predictive of death (adjusted hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.50- 3.21, p < 0.001), especially HIV-related death (adjusted HR 1.75, 95% CI 1.13- 2.72, p = 0.012). In this population-based HIV treatment program, we found HCV seropositivity to be an independent predictor of mortality, especially death related to HIV infection.

  14. Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the "COPA" pilot randomized trial.

    PubMed

    Gori, A; Rizzardini, G; Van't Land, B; Amor, K B; van Schaik, J; Torti, C; Quirino, T; Tincati, C; Bandera, A; Knol, J; Benlhassan-Chahour, K; Trabattoni, D; Bray, D; Vriesema, A; Welling, G; Garssen, J; Clerici, M

    2011-09-01

    Intestinal mucosal immune system is an early target for human immunodeficiency virus type 1 (HIV-1) infection, resulting in CD4(+) T-cell depletion, deterioration of gut lining, and fecal microbiota composition. We evaluated the effects of a prebiotic oligosaccharide mixture in highly active antiretroviral therapy (HAART)-naive HIV-1-infected adults. In a pilot double-blind, randomized, placebo-controlled study, 57 HAART-naive HIV-1-infected patients received a unique oligosaccharide mixture (15 or 30 g short chain galactooligosaccharides/long chain fructooligosaccharides/pectin hydrolysate-derived acidic oligosaccharides (scGOS/lcFOS/pAOS) daily) or a placebo for 12 weeks. Microbiota composition improved significantly with increased bifidobacteria, decreased Clostridium coccoides/Eubacterium rectale cluster, and decreased pathogenic Clostridium lituseburense/Clostridium histolyticum group levels upon prebiotic supplementation. In addition, a reduction of soluble CD14 (sCD14), activated CD4(+)/CD25(+) T cells, and significantly increased natural killer (NK) cell activity when compared with control group were seen in the treatment group. The results of this pilot trial highly significantly show that dietary supplementation with a prebiotic oligosaccharide mixture results in improvement of the gut microbiota composition, reduction of sCD14, CD4(+) T-cell activation (CD25), and improved NK cell activity in HAART-naive HIV-infected individuals.

  15. Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the “COPA” pilot randomized trial

    PubMed Central

    Gori, A; Rizzardini, G; van't Land, B; Amor, K B; van Schaik, J; Torti, C; Quirino, T; Tincati, C; Bandera, A; Knol, J; Benlhassan-Chahour, K; Trabattoni, D; Bray, D; Vriesema, A; Welling, G; Garssen, J; Clerici, M

    2011-01-01

    Intestinal mucosal immune system is an early target for human immunodeficiency virus type 1 (HIV-1) infection, resulting in CD4+ T-cell depletion, deterioration of gut lining, and fecal microbiota composition. We evaluated the effects of a prebiotic oligosaccharide mixture in highly active antiretroviral therapy (HAART)-naive HIV-1-infected adults. In a pilot double-blind, randomized, placebo-controlled study, 57 HAART-naive HIV-1-infected patients received a unique oligosaccharide mixture (15 or 30 g short chain galactooligosaccharides/long chain fructooligosaccharides/pectin hydrolysate-derived acidic oligosaccharides (scGOS/lcFOS/pAOS) daily) or a placebo for 12 weeks. Microbiota composition improved significantly with increased bifidobacteria, decreased Clostridium coccoides/Eubacterium rectale cluster, and decreased pathogenic Clostridium lituseburense/Clostridium histolyticum group levels upon prebiotic supplementation. In addition, a reduction of soluble CD14 (sCD14), activated CD4+/CD25+ T cells, and significantly increased natural killer (NK) cell activity when compared with control group were seen in the treatment group. The results of this pilot trial highly significantly show that dietary supplementation with a prebiotic oligosaccharide mixture results in improvement of the gut microbiota composition, reduction of sCD14, CD4+ T-cell activation (CD25), and improved NK cell activity in HAART-naive HIV-infected individuals. PMID:21525866

  16. Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson’s Disease

    PubMed Central

    Kustrimovic, Natasa; Rasini, Emanuela; Legnaro, Massimiliano; Bombelli, Raffaella; Aleksic, Iva; Blandini, Fabio; Comi, Cristoforo; Mauri, Marco; Minafra, Brigida; Riboldazzi, Giulio; Sanchez-Guajardo, Vanesa; Marino, Franca; Cosentino, Marco

    2016-01-01

    Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D1-like DR decrease, while in T memory cells D2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs. PMID:27652978

  17. White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa.

    PubMed

    Hoare, Jacqueline; Fouche, Jean-Paul; Phillips, Nicole; Joska, John A; Paul, Robert; Donald, Kirsten A; Thomas, Kevin G F; Stein, Dan J

    2015-09-10

    To describe the effect of HIV on white matter integrity and neurocognitive function in children vertically infected with HIV, compared to a HIV-negative healthy control group. Cross-sectional. We compared 75 HIV-infected children aged 6-16 years, including children on antiretroviral therapy (ART) and those who were ART-naive, with 30 controls on diffusion tensor imaging and a neuropsychological battery sensitive to fronto-striatal pathology. In a secondary analysis, we compared 'slow progressor' ART-naive children, children on ART without a diagnosis of encephalopathy and children on ART with HIV encephalopathy. Compared to controls (n = 30), HIV-infected children (n = 75) displayed decreased fractional anisotropy and axial diffusion, and increased mean diffusivity and radial diffusion, indicating damaged neuronal microstructure. HIV-infected children performed poorly on the neuropsychological battery (P = <0.001). Within the HIV-infected group, children with HIV encephalopathy (n = 14) had poor white matter integrity when compared to ART-treated children without encephalopathy (n = 41), and there was significant myelin loss in ART-naive children (n = 20), compared with ART-treated children. ART-treated children had significant axonal damage in the corpus callosum (P = 0.009). Children infected with HIV, irrespective of treatment status, displayed significantly poorer white matter integrity and impaired cognition compared to HIV-negative controls. Our findings suggest that despite immune recovery in children on ART, they remain at risk for developing central nervous system disease, and that initiation of ART as early as possible may reduce the risk of developing white matter damage in ART-naive slow progressors.

  18. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

    PubMed Central

    Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan; Acero, Luis; Grimes, H. Leighton; Katz, Jonathan D.; Finkelman, Fred D.; Hildeman, David A.

    2007-01-01

    We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells. PMID:17591857

  19. Pertussis toxin activates adult and neonatal naive human CD4+ T lymphocytes.

    PubMed

    Tonon, Sandrine; Badran, Bassam; Benghiat, Fleur Samantha; Goriely, Stanislas; Flamand, Véronique; Willard-Gallo, Karen; Willems, Fabienne; Goldman, Michel; De Wit, Dominique

    2006-07-01

    Pertussis toxin (PTX) is known to be mitogenic for T lymphocytes, but its direct action on naive human T cells has not been specified. Herein, we show that PTX induces the proliferation of purified adult CD45RA(+)CD4(+) T cells independently of its ADP-ribosyltransferase activity. PTX directly induces TNF-alpha and IL-2 mRNA expression, modulates the level of several cell surface receptors and induces Forkhead box p3 (Foxp3) protein accumulation in naive CD4(+) T cells. Addition of autologous dendritic cells was found to be required for the production of high levels of IFN-gamma by PTX-stimulated naive T cells. These effects of PTX occurred in conjunction with activation of NF-kappaB and NFAT transcription factors. Overall, responses of neonatal CD4(+) T cells to PTX were similar to those of adult CD45RA(+)CD4(+) naive T cells except for their blunted CD40 ligand up-regulation. We suggest that the adjuvant properties of PTX during primary cell-mediated immune responses involve a direct action on naive T lymphocytes in addition to activation of antigen-presenting cells.

  20. Steroid naive eosinophilic asthma: anti-inflammatory effects of fluticasone and montelukast

    PubMed Central

    Jayaram, L; Pizzichini, E; Lemiere, C; Man, S; Cartier, A; Hargreave, F; Pizzichini, M

    2005-01-01

    Background: Inhaled corticosteroids and leukotriene receptor antagonists reduce airway eosinophilia and have been used as first line anti-inflammatory therapy for mild persistent asthma. Methods: A multicentre, randomised, placebo controlled, parallel group study was performed to compare the anti-inflammatory effects of fluticasone propionate and montelukast as measured by sputum eosinophils in 50 adults with symptomatic steroid naive asthma and sputum eosinophilia of ⩾3.5%. Results: Eighteen patients received low dose fluticasone (250 µg/day), 19 received montelukast (10 mg/day), and 13 were given placebo for 8 weeks. Fluticasone treatment resulted in a greater reduction in sputum eosinophils (geometric mean (SD) 11.9 (2.3)% to 1.7 (5.1)%) than montelukast (10.7 (2.3)% to 6.9 (3.8)%; p = 0.04) or placebo (15.4 (2.4)% to 7.8 (4.2)%; p = 0.002), and improvement in FEV1 (mean (SD) 2.6 (0.9) l to 3.0 (0.9) l) than montelukast (2.8 (0.7) l to 2.8 (0.9) l; p = 0.02) or placebo (2.4 (0.8) l to 2.4 (0.9) l; p = 0.01). Treatment with fluticasone suppressed sputum eosinophilia within a week while montelukast only attenuated it. The effect of montelukast was maximal at 1 week and was maintained over 4 weeks. The effect of fluticasone was maintained over 8 weeks while that of montelukast was not. Conclusions: Montelukast is not as effective as low dose fluticasone in reducing or maintaining an anti-inflammatory effect in steroid naïve eosinophilic asthma. PMID:15681495

  1. Consistent Safety and Infectivity in Sporozoite Challenge Model of Plasmodium vivax in Malaria-Naive Human Volunteers

    PubMed Central

    Herrera, Sócrates; Solarte, Yezid; Jordán-Villegas, Alejandro; Echavarría, Juan Fernando; Rocha, Leonardo; Palacios, Ricardo; Ramírez, Óscar; Vélez, Juan D.; Epstein, Judith E.; Richie, Thomas L.; Arévalo-Herrera, Myriam

    2011-01-01

    A safe and reproducible Plasmodium vivax infectious challenge method is required to evaluate the efficacy of malaria vaccine candidates. Seventeen healthy Duffy (+) and five Duffy (−) subjects were randomly allocated into three (A–C) groups and were exposed to the bites of 2–4 Anopheles albimanus mosquitoes infected with Plasmodium vivax derived from three donors. Duffy (−) subjects were included as controls for each group. Clinical manifestations of malaria and parasitemia were monitored beginning 7 days post-challenge. All Duffy (+) volunteers developed patent malaria infection within 16 days after challenge. Prepatent period determined by thick smear, was longer for Group A (median 14.5 d) than for Groups B and C (median 10 d/each). Infected volunteers recovered rapidly after treatment with no serious adverse events. The bite of as low as two P. vivax-infected mosquitoes provides safe and reliable infections in malaria-naive volunteers, suitable for assessing antimalarial and vaccine efficacy trials. PMID:21292872

  2. The Persistence of Solid and Liquid Naive Conceptions: A Reaction Time Study

    NASA Astrophysics Data System (ADS)

    Babai, Reuven; Amsterdamer, Anat

    2008-12-01

    The study explores whether the naive concepts of solid and liquid persist in adolescence. Accuracy of responses and reaction times where measured while 41 ninth graders classified different solids (rigid, non-rigid and powders) and different liquids (runny, dense) into solid or liquid. The results show that these naive conceptions affect adolescences' classifications in terms of both accuracy and reaction time. The rate of correct classifications of non-rigid solids and powders was significantly lower than of rigid solids. Lower rate of success was also found for classification of dense liquids compared with runny liquids. In addition, the reaction time results of correct classifications for non-rigid solids and powders were longer than those for rigid solids and, likewise, reaction times for dense liquids were longer than for runny ones. These results suggest that reasoning processes associated with correct classification of objects that are not consistent with the naive conceptions are more demanding.

  3. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition.

    PubMed

    Sperber, Henrik; Mathieu, Julie; Wang, Yuliang; Ferreccio, Amy; Hesson, Jennifer; Xu, Zhuojin; Fischer, Karin A; Devi, Arikketh; Detraux, Damien; Gu, Haiwei; Battle, Stephanie L; Showalter, Megan; Valensisi, Cristina; Bielas, Jason H; Ericson, Nolan G; Margaretha, Lilyana; Robitaille, Aaron M; Margineantu, Daciana; Fiehn, Oliver; Hockenbery, David; Blau, C Anthony; Raftery, Daniel; Margolin, Adam A; Hawkins, R David; Moon, Randall T; Ware, Carol B; Ruohola-Baker, Hannele

    2015-12-01

    For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs).  Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development.

  4. A Chinese minority script recognition method based on wavelet feature and multinomial naive Bayes

    NASA Astrophysics Data System (ADS)

    Guo, Hai; Zhao, Jing-ying

    2009-07-01

    The existing Chinese Minorities OCR system is mainly oriented in the "literacy" level, the script recognition has not attracted the attention it deserves, and the area of recognizing the kinds of Chinese minority scripts is still in a blank. This paper presents a method of recognizing the kinds of Chinese minority scripts based on wavelet analysis and Multinomial Naive Bayes. The method of recognizing the kinds of Chinese minority scripts based on wavelet analysis and Multinomial Naive Bayes is presented which adopts wavelet decomposition that obtains feature descriptor of wavelet energy and wavelet energy distribution proportion. Combined with the texture feature of Chinese minority scripts, radially classification in Multinomial Naive Bayes. Among Chinese, English and Chinese minority scripts such as Tibetan, Tai Lue, Naxi Pictographs, Uighur, Tai Le, Yi, the experimental results show the recognition rate is up to 90%.

  5. Virtual reality phacoemulsification: a comparison between skilled surgeons and students naive to cataract surgery

    NASA Astrophysics Data System (ADS)

    Soderberg, Per; Laurell, Carl-Gustaf; Simawi, Wamidh; Nordqvist, Per; Skarman, Eva; Nordh, Leif

    2005-04-01

    We have developed a simulator for virtual phacoemulsification surgery. In the current study, the performance of one experienced cataract surgeon was compared to the performance of four subjects naive to cataract surgery. They all operated on the same virtual patient and a number of different response variables were measured. It was found that the experienced subject performed better than the naive subjects on almost all response variables. This indicates that the simulator developed by us is authentic for phaco emulsification surgery. The lack of negative effects in case of complications during virtual phacoemulsification surgery makes the phaco simulator that we developed a very attractive tool for learning phacoemulsification surgery.

  6. Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4+ T Cells In Vitro

    PubMed Central

    Zerbato, Jennifer M.; Serrao, Erik; Lenzi, Gina; Kim, Baek; Ambrose, Zandrea; Watkins, Simon C.; Engelman, Alan N.

    2016-01-01

    into the contribution of CD4+ naive T (TN) cells to the latent reservoir. In this study, we show that although TN cells harbor significantly lower levels of HIV-1 DNA, following latency reversal, they produced as many virions as did the TCM cells (if not more virions). This suggests that latently infected TN cells may be a major source of virus following treatment interruption or failure. These findings highlight the need for a better understanding of the establishment and reversal of HIV-1 latency in TN cells in evaluating therapeutic approaches to eliminate the latent reservoir. PMID:27356901

  7. Longitudinal study of tuberculosis outcomes among immunologically naive Aché natives of Paraguay.

    PubMed

    Hurtado, A Magdalena; Hill, Kim R; Rosenblatt, Wilhelm; Bender, Jacquelyn; Scharmen, Tom

    2003-06-01

    This study documents the course of a tuberculosis epidemic in an immunologically naive group of South American Indians within fewer than 20 years after first sustained contact with outsiders. Groups of Northern Aché (ah-CHAY) of eastern Paraguay were contacted and settled on reservations between 1971-1979. Not surprisingly, the Aché are very susceptible to tuberculosis, and the epidemiological characteristics of the disease are quite different from those of populations that have had tuberculosis for centuries. Within 6 years of the first detected case of tuberculosis among the Aché, the prevalence rate of active tuberculosis cases reached 18.2%, and of infected cases among adults, 64.6%, some of the highest rates ever reported for any human group. Remarkably, males and females are equally likely to have been diagnosed with active tuberculosis, Aché children between birth and 5 years of age are least vulnerable to tuberculosis, high nutritional and socioeconomic status do not decrease the risk of disease or infection, and children immunized with BCG are less responsive to tuberculin challenge than are other children. Moreover, similar to the Yanomamö, but unlike populations of European or African descent, a high percentage of Aché with active disease test negative on tuberculin challenge tests (purified protein derivative; PPD). These differences may be due to a high prevalence of diminished cell-mediated immunity, and T-helper 2 dominance. We also hypothesize that these immunological characteristics, low genetic diversity, hostile intergroup interactions, and behavioral noncompliance to treatment protocols together contribute to the high rates of active disease observed. Existing tuberculosis control programs are poorly equipped to handle the impact of these causal complexities on the course of recent tuberculosis epidemics that have quickly spread throughout native communities of Latin America during the last decade.

  8. Thymosin-alpha 1 plus interferon-alpha for naive patients with chronic hepatitis C: results of a randomized controlled pilot trial.

    PubMed

    Andreone, P; Gramenzi, A; Cursaro, C; Felline, F; Loggi, E; D'Errico, A; Spinosa, M; Lorenzini, S; Biselli, M; Bernardi, M

    2004-01-01

    In this pilot study, we evaluated the efficacy of interferon-alpha (IFN) plus Thymosin-alpha 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon-alpha 2b (3 million units three times a week) plus thymosin-alpha l (900 microg/m2 body surface area) and 19 received interferon-alpha 2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus-RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end-of-treatment response (P = 0.03). At 6-month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end-of-treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment.

  9. 12 Steps to Provide Accessible Programs.

    ERIC Educational Resources Information Center

    Hasbrouck, JoAnn

    1993-01-01

    College compliance with the Americans with Disabilities of Act of 1990 means including a statement about disabilities in publications, providing transportation for off-campus trips, eliminating physical barriers, providing nonvoice terminal telephones, using captioned films, having assistive listening devices, reserving designated seating,…

  10. Providing probability distributions for the causal pathogen of clinical mastitis using naive Bayesian networks.

    PubMed

    Steeneveld, W; van der Gaag, L C; Barkema, H W; Hogeveen, H

    2009-06-01

    Clinical mastitis (CM) can be caused by a wide variety of pathogens and farmers must start treatment before the actual causal pathogen is known. By providing a probability distribution for the causal pathogen, naive Bayesian networks (NBN) can serve as a management tool for farmers to decide which treatment to use. The advantage of providing a probability distribution for the causal pathogen, rather than only providing the most likely causal pathogen, is that the uncertainty involved is visible and a more informed treatment decision can be made. The objective of this study was to illustrate provision of probability distributions for the gram status and for the causal pathogen for CM cases. For constructing the NBN, data were used from 274 Dutch dairy herds in which the occurrence of CM was recorded over an 18-mo period. The data set contained information on 3,833 CM cases. Two-thirds of the data set was used for the construction process and one-third was retained for validation. One NBN was constructed with the CM cases classified according to their gram status, and another was built with the CM cases classified into streptococci, Staphylococcus aureus, or Escherichia coli. Information usually available at a dairy farm was included in both NBN (parity, month in lactation, season of the year, quarter position, SCC and CM history, being sick or not, and color and texture of the milk). Accuracy was calculated to obtain insight in the quality of the constructed NBN. The accuracy of classifying CM cases into gram-positive or gram-negative pathogens was 73%, while the accuracy of classifying CM cases into streptococci, Staph. aureus, or E. coli was 52%. Because only CM cases with a high probability for a single causal pathogen will be considered for pathogen-specific treatment, accuracies based on only classifying CM cases above a particular probability threshold were determined. For instance, for CM cases in which either gram-negative or gram-positive had a probability

  11. Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naive T cells.

    PubMed

    Kamimura, Daisuke; Arima, Yasunobu; Tsuruoka, Mineko; Jiang, Jing-Jing; Bando, Hidenori; Meng, Jie; Sabharwal, Lavannya; Stofkova, Andrea; Nishikawa, Naoki; Higuchi, Kotaro; Ogura, Hideki; Atsumi, Toru; Murakami, Masaaki

    2016-03-01

    KDEL receptor 1 (KDELR1) regulates integrated stress responses (ISR) to promote naive T-cell survival in vivo. In a mouse line having nonfunctional KDELR1, T-Red (naive T-cell reduced) mice, polyclonal naive T cells show excessive ISR and eventually undergo apoptosis. However, breeding T-Red mice with TCR-transgenic mice bearing relatively high TCR affinity rescued the T-Red phenotype, implying a link between ISR-induced apoptosis and TCR-mediated signaling. Here, we showed that strong TCR stimulation reduces ISR in naive T cells. In mice lacking functional KDELR1, surviving naive T cells expressed significantly higher levels of CD5, a surrogate marker of TCR self-reactivity. In addition, higher TCR affinity/avidity was confirmed using a tetramer dissociation assay on the surviving naive T cells, suggesting that among the naive T-cell repertoire, those that receive relatively stronger TCR-mediated signals via self-antigens survive enhanced ISR. Consistent with this observation, weak TCR stimulation with altered peptide ligands decreased the survival and proliferation of naive T cells, whereas stimulation with ligands having higher affinity had no such effect. These results suggest a novel role of TCR-mediated signals in the attenuation of ISR in vivo.

  12. Exposure of Creosote-Naive and Creosote-Conditioned Limnoria tripunctata (Menzies) of Untreated and Creosote-Treated Wood.

    DTIC Science & Technology

    1983-06-13

    20 AGSTRACT (Conflnuod) -5 A creosote-naive (never exposed to creosote) population of L . tripunciata exhibited 95% sur- vival and produced numerous...ENTA L D ESIG N .................................................................................................. 4 Exposure of Creosote-Naive...and ammoniacal -copper-arsenate) are effective, but wood treated with these preservatives tends to lose its mechanical strength 15,61, and treated

  13. Decreased glutathione levels and impaired antioxidant enzyme activities in drug-naive first-episode schizophrenic patients

    PubMed Central

    2011-01-01

    Background The aim of this study was to determine glutathione levels and antioxidant enzyme activities in the drug-naive first-episode patients with schizophrenia in comparison with healthy control subjects. Methods It was a case-controlled study carried on twenty-three patients (20 men and 3 women, mean age = 29.3 ± 7.5 years) recruited in their first-episode of schizophrenia and 40 healthy control subjects (36 men and 9 women, mean age = 29.6 ± 6.2 years). In patients, the blood samples were obtained prior to the initiation of neuroleptic treatments. Glutathione levels: total glutathione (GSHt), reduced glutathione (GSHr) and oxidized glutathione (GSSG) and antioxidant enzyme activities: superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) were determined by spectrophotometry. Results GSHt and reduced GSHr were significantly lower in patients than in controls, whereas GSSG was significantly higher in patients. GPx activity was significantly higher in patients compared to control subjects. CAT activity was significantly lower in patients, whereas the SOD activity was comparable to that of controls. Conclusion This is a report of decreased plasma levels of GSHt and GSHr, and impaired antioxidant enzyme activities in drug-naive first-episode patients with schizophrenia. The GSH deficit seems to be implicated in psychosis, and may be an important indirect biomarker of oxidative stress in schizophrenia early in the course of illness. Finally, our results provide support for further studies of the possible role of antioxidants as neuroprotective therapeutic strategies for schizophrenia from early stages. PMID:21810251

  14. MRI study of caudate nucleus volume and its cognitive correlates in neuroleptic-naive patients with schizotypal personality disorder.

    PubMed

    Levitt, James J; McCarley, Robert W; Dickey, Chandlee C; Voglmaier, Martina M; Niznikiewicz, Margaret A; Seidman, Larry J; Hirayasu, Yoshio; Ciszewski, Aleksandra A; Kikinis, Ron; Jolesz, Ferenc A; Shenton, Martha E

    2002-07-01

    "Cognitive" circuits anatomically link the frontal lobe to subcortical structures; therefore, pathology in any of the core components of these circuits, such as in the caudate nucleus, may result in neurobehavioral syndromes similar to those of the frontal lobe. Neuroleptic medication, however, affects the size of the caudate nucleus. For this reason, individuals diagnosed with schizotypal personality disorder offer an ideal group for the measurement of the caudate nucleus because they may be genetically related to individuals with schizophrenia but do not require neuroleptic treatment because of their less severe symptoms. Magnetic resonance imagining (MRI) scans obtained on a 1.5-T magnet with 1.5-mm contiguous slices were used to measure the caudate nucleus and lateral ventricles in 15 right-handed male subjects with schizotypal personality disorder who had no previous neuroleptic exposure and in 14 normal comparison subjects. Subjects were group matched for parental socioeconomic status, handedness, and gender. First, the authors found significantly lower left and right absolute (13.1%, 13.2%) and relative (9.1%, 9.2%) caudate nucleus volumes in never-medicated subjects with schizotypal personality disorder than in normal subjects. Second, they found significant, inverse correlations between caudate nucleus volume and the severity of perseveration in two distinct working memory tasks in these neuroleptic-naive subjects with schizotypal personality disorder. These data are consistent with the findings of reduced caudate nucleus volume reported in studies of neuroleptic-naive patients experiencing their first episode of schizophrenia and support the association of intrinsic pathology in the caudate nucleus with abnormalities in working memory in the schizophrenia spectrum.

  15. Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection.

    PubMed

    Tubo, Noah J; Pagán, Antonio J; Taylor, Justin J; Nelson, Ryan W; Linehan, Jonathan L; Ertelt, James M; Huseby, Eric S; Way, Sing Sing; Jenkins, Marc K

    2013-05-09

    A naive CD4(+) T cell population specific for a microbial peptide:major histocompatibility complex II ligand (p:MHCII) typically consists of about 100 cells, each with a different T cell receptor (TCR). Following infection, this population produces a consistent ratio of effector cells that activate microbicidal functions of macrophages or help B cells make antibodies. We studied the mechanism that underlies this division of labor by tracking the progeny of single naive T cells. Different naive cells produced distinct ratios of macrophage and B cell helpers but yielded the characteristic ratio when averaged together. The effector cell pattern produced by a given naive cell correlated with the TCR-p:MHCII dwell time or the amount of p:MHCII. Thus, the consistent production of effector cell subsets by a polyclonal population of naive cells results from averaging the diverse behaviors of individual clones, which are instructed in part by the strength of TCR signaling.

  16. Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates.

    PubMed

    Cicin-Sain, Luka; Smyk-Pearson, Susan; Smyk-Paerson, Sue; Currier, Noreen; Byrd, Laura; Koudelka, Caroline; Robinson, Tammie; Swarbrick, Gwendolyn; Tackitt, Shane; Legasse, Alfred; Fischer, Miranda; Nikolich-Zugich, Dragana; Park, Byung; Hobbs, Theodore; Doane, Cynthia J; Mori, Motomi; Axthelm, Michael K; Axthelm, Michael T; Lewinsohn, Deborah A; Nikolich-Zugich, Janko

    2010-06-15

    Aging is usually accompanied by diminished immune protection upon infection or vaccination. Although aging results in well-characterized changes in the T cell compartment of long-lived, outbred, and pathogen-exposed organisms, their relevance for primary Ag responses remain unclear. Therefore, it remains unclear whether and to what extent the loss of naive T cells, their partial replacement by oligoclonal memory populations, and the consequent constriction of TCR repertoire limit the Ag responses in aging primates. We show in this study that aging rhesus monkeys (Macaca mulatta) exhibit poor CD8 T cell and B cell responses in the blood and poor CD8 responses in the lungs upon vaccination with the modified vaccinia strain Ankara. The function of APCs appeared to be maintained in aging monkeys, suggesting that the poor response was likely intrinsic to lymphocytes. We found that the loss of naive CD4 and CD8 T cells, and the appearance of persisting T cell clonal expansions predicted poor CD8 responses in individual monkeys. There was strong correlation between early CD8 responses in the transitory CD28+ CD62L- CD8+ T cell compartment and the peak Ab titers upon boost in individual animals, as well as a correlation of both parameters of immune response to the frequency of naive CD8+ T cells in old but not in adult monkeys. Therefore, our results argue that T cell repertoire constriction and naive cell loss have prognostic value for global immune function in aging primates.

  17. Effects of Noise Suppression on Intelligibility: Experts' Opinions and Naive Normal-Hearing Listeners' Performance

    ERIC Educational Resources Information Center

    Hilkhuysen, Gaston L. M.; Gaubitch, Nikolay; Huckvale, Mark

    2013-01-01

    Purpose: In this study, the authors investigated how well experts can adjust the settings of a commercial noise-reduction system to optimize the intelligibility for naive normal-hearing listeners. Method: In Experiment 1, 5 experts adjusted parameters for a noise-reduction system while aiming to optimize intelligibility. The stimuli consisted of…

  18. Characterization of the finch embryo supports evolutionary conservation of the naive stage of development in amniotes

    PubMed Central

    Mak, Siu-Shan; Alev, Cantas; Nagai, Hiroki; Wrabel, Anna; Matsuoka, Yoko; Honda, Akira; Sheng, Guojun; Ladher, Raj K

    2015-01-01

    Innate pluripotency of mouse embryos transits from naive to primed state as the inner cell mass differentiates into epiblast. In vitro, their counterparts are embryonic (ESCs) and epiblast stem cells (EpiSCs), respectively. Activation of the FGF signaling cascade results in mouse ESCs differentiating into mEpiSCs, indicative of its requirement in the shift between these states. However, only mouse ESCs correspond to the naive state; ESCs from other mammals and from chick show primed state characteristics. Thus, the significance of the naive state is unclear. In this study, we use zebra finch as a model for comparative ESC studies. The finch blastoderm has mESC-like properties, while chick blastoderm exhibits EpiSC features. In the absence of FGF signaling, finch cells retained expression of pluripotent markers, which were lost in cells from chick or aged finch epiblasts. Our data suggest that the naive state of pluripotency is evolutionarily conserved among amniotes. DOI: http://dx.doi.org/10.7554/eLife.07178.001 PMID:26359635

  19. Is Children's Naive Knowledge Consistent?: A Comparison of the Concepts of Sound and Heat

    ERIC Educational Resources Information Center

    Lautrey, Jacques; Mazens, Karine

    2004-01-01

    The aim of this study was to shed some light on the organization of naive knowledge, and on the process of conceptual change in everyday physics, more specifically regarding the concepts of sound and heat. Eighty-three 8-year-old children were interviewed individually in order to see if they attributed the properties of objects (such as…

  20. Naive Versus Sophisticated Item-Writers for the Assessment of Anxiety.

    ERIC Educational Resources Information Center

    Sharpley, Christopher F.; Rogers, H. Jane

    1985-01-01

    Compared items from psychologically naive vs. psychologically sophisticated item-writers vs. a standardized test (N=552). Results showed that nonpsychologists with no formal definition of the construct they were to measure were able to write items that were as valid as those elicited from psychologists. (BH)

  1. An Investigation of Factors Affecting the Degree of Naive Impetus Theory Application

    ERIC Educational Resources Information Center

    Liu, Xiufeng; MacIsaac, Dan

    2005-01-01

    This study investigates factors affecting the degree of novice physics students application of the naive impetus theory. Six hundred and fourteen first-year university engineering physics students answered the Force Concept Inventory as a pre-test for their calculus-based course. We examined the degree to which students consistently applied the…

  2. Effects of Noise Suppression on Intelligibility: Experts' Opinions and Naive Normal-Hearing Listeners' Performance

    ERIC Educational Resources Information Center

    Hilkhuysen, Gaston L. M.; Gaubitch, Nikolay; Huckvale, Mark

    2013-01-01

    Purpose: In this study, the authors investigated how well experts can adjust the settings of a commercial noise-reduction system to optimize the intelligibility for naive normal-hearing listeners. Method: In Experiment 1, 5 experts adjusted parameters for a noise-reduction system while aiming to optimize intelligibility. The stimuli consisted of…

  3. The Effect of Naive Ideas on Students' Reasoning about Electricity and Magnetism

    ERIC Educational Resources Information Center

    Leppavirta, Johanna

    2012-01-01

    Traditional multiple-choice concept inventories measure students' critical conceptual understanding and are designed to reveal students' naive or alternate ideas. The overall scores, however, give little information about the state of students' knowledge and the consistency of reasoning. This study investigates whether students have consistent…

  4. Is Children's Naive Knowledge Consistent?: A Comparison of the Concepts of Sound and Heat

    ERIC Educational Resources Information Center

    Lautrey, Jacques; Mazens, Karine

    2004-01-01

    The aim of this study was to shed some light on the organization of naive knowledge, and on the process of conceptual change in everyday physics, more specifically regarding the concepts of sound and heat. Eighty-three 8-year-old children were interviewed individually in order to see if they attributed the properties of objects (such as…

  5. Testing the Development of Linguistic Knowledge in Adult Naive Learners of American Sign Language

    ERIC Educational Resources Information Center

    Von Pein, Margreta; Altarriba, Jeanette

    2011-01-01

    The present study was designed to investigate the ways in which notions of semantics and phonology are acquired by adult naive learners of American Sign Language (ASL) when they are first exposed to a set of simple signs. First, a set of ASL signs was tested for nontransparency and a set of signs was selected for subsequent use. Next, a set of…

  6. The Effect of Naive Ideas on Students' Reasoning about Electricity and Magnetism

    ERIC Educational Resources Information Center

    Leppavirta, Johanna

    2012-01-01

    Traditional multiple-choice concept inventories measure students' critical conceptual understanding and are designed to reveal students' naive or alternate ideas. The overall scores, however, give little information about the state of students' knowledge and the consistency of reasoning. This study investigates whether students have consistent…

  7. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

    PubMed Central

    Klebanoff, Christopher A.; Scott, Christopher D.; Leonardi, Anthony J.; Yamamoto, Tori N.; Cruz, Anthony C.; Ouyang, Claudia; Ramaswamy, Madhu; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L.; Sukumar, Madhusudhanan; Crompton, Joseph G.; Palmer, Douglas C.; Borman, Zachary A.; Clever, David; Thomas, Stacy K.; Patel, Shashankkumar; Yu, Zhiya; Muranski, Pawel; Liu, Hui; Wang, Ena; Marincola, Francesco M.; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A.; Siegel, Richard M.; Restifo, Nicholas P.

    2015-01-01

    Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell–T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory–induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell–based immunotherapies. PMID:26657860

  8. Children's Naive Theories of Intelligence Influence Their Metacognitive Judgments

    ERIC Educational Resources Information Center

    Miele, David B.; Son, Lisa K.; Metcalfe, Janet

    2013-01-01

    Recent studies have shown that the metacognitive judgments adults infer from their experiences of encoding effort vary in accordance with their naive theories of intelligence. To determine whether this finding extends to elementary schoolchildren, a study was conducted in which 27 third graders (M[subscript age] = 8.27) and 24 fifth graders…

  9. Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts.

    PubMed

    Emery, Vincent C; Hassan-Walker, Aycan F; Burroughs, Andrew K; Griffiths, Paul D

    2002-06-15

    Human cytomegalovirus (HCMV) can infect both HCMV-naive and -experienced transplant patients. In this study, the growth rate of HCMV in HCMV-naive hosts (1.82 units/day; 95% confidence interval [CI], 1.44-2.56 units/day) was shown to be significantly faster than the growth rate of virus in HCMV-experienced hosts undergoing recurrent infection (0.61 units/day; 95% CI, 0.55-0.7 units/day; P<.0001). The basic reproductive number (R(0)) for HCMV-naive liver transplant patients was 15.1 (95% CI, 8.9-44) but was only 2.4 (95% CI, 2.35-2.8) for HCMV-experienced transplant recipients, corresponding to an anti-HCMV immune efficacy of approximately 84%, despite immunosuppressive therapy. The R(0) values suggest that an anti-HCMV drug or vaccine with an efficacy of >93% (95% CI, 89%-98%) is required to eliminate viral growth during infection of HCMV-naive liver transplant recipients, whereas lower efficacy levels are sufficient to reduce the R(0) value to <1 in hosts with prior HCMV immunity.

  10. Generalised insulin oedema after intensification of treatment with insulin analogues.

    PubMed

    Adamo, Luigi; Thoelke, Mark

    2013-02-20

    We report a case of generalised insulin oedema after intensification of treatment with genetically modified insulin. This is the first case of generalised oedema in response to treatment with insulin analogues in a patient not insulin naive.

  11. Postthymic expansion in human CD4 naive T cells defined by expression of functional high-affinity IL-2 receptors.

    PubMed

    Pekalski, Marcin L; Ferreira, Ricardo C; Coulson, Richard M R; Cutler, Antony J; Guo, Hui; Smyth, Deborah J; Downes, Kate; Dendrou, Calliope A; Castro Dopico, Xaquin; Esposito, Laura; Coleman, Gillian; Stevens, Helen E; Nutland, Sarah; Walker, Neil M; Guy, Catherine; Dunger, David B; Wallace, Chris; Tree, Timothy I M; Todd, John A; Wicker, Linda S

    2013-03-15

    As the thymus involutes with age, the maintenance of peripheral naive T cells in humans becomes strongly dependent on peripheral cell division. However, mechanisms that orchestrate homeostatic division remain unclear. In this study we present evidence that the frequency of naive CD4 T cells that express CD25 (IL-2 receptor α-chain) increases with age on subsets of both CD31(+) and CD31(-) naive CD4 T cells. Analyses of TCR excision circles from sorted subsets indicate that CD25(+) naive CD4 T cells have undergone more rounds of homeostatic proliferation than their CD25(-) counterparts in both the CD31(+) and CD31(-) subsets, indicating that CD25 is a marker of naive CD4 T cells that have preferentially responded to survival signals from self-Ags or cytokines. CD25 expression on CD25(-) naive CD4 T cells can be induced by IL-7 in vitro in the absence of TCR activation. Although CD25(+) naive T cells respond to lower concentrations of IL-2 as compared with their CD25(-) counterparts, IL-2 responsiveness is further increased in CD31(-) naive T cells by their expression of the signaling IL-2 receptor β-chain CD122, forming with common γ-chain functional high-affinity IL-2 receptors. CD25 plays a role during activation: CD25(+) naive T cells stimulated in an APC-dependent manner were shown to produce increased levels of IL-2 as compared with their CD25(-) counterparts. This study establishes CD25(+) naive CD4 T cells, which are further delineated by CD31 expression, as a major functionally distinct immune cell subset in humans that warrants further characterization in health and disease.

  12. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells.

    PubMed

    Mendoza, Alejandra; Fang, Victoria; Chen, Cynthia; Serasinghe, Madhavika; Verma, Akanksha; Muller, James; Chaluvadi, V Sai; Dustin, Michael L; Hla, Timothy; Elemento, Olivier; Chipuk, Jerry E; Schwab, Susan R

    2017-06-01

    Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer's patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P1 receptor (S1P1R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer's patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P1R on T cells, and that the requirement for S1P1R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.

  13. Corpus Callosum Anatomy in Chronically Treated and Stimulant Naive ADHD

    ERIC Educational Resources Information Center

    Schnoebelen, Sarah; Semrud-Clikeman, Margaret; Pliszka, Steven R.

    2010-01-01

    Objective: To determine the effect of chronic stimulant treatment on corpus callosum (CC) size in children with ADHD using volumetric and area measurements. Previously published research indicated possible medication effects on specific areas of the CC. Method: Measurements of the CC from anatomical MRIs were obtained from children aged 9-16 in…

  14. Corpus Callosum Anatomy in Chronically Treated and Stimulant Naive ADHD

    ERIC Educational Resources Information Center

    Schnoebelen, Sarah; Semrud-Clikeman, Margaret; Pliszka, Steven R.

    2010-01-01

    Objective: To determine the effect of chronic stimulant treatment on corpus callosum (CC) size in children with ADHD using volumetric and area measurements. Previously published research indicated possible medication effects on specific areas of the CC. Method: Measurements of the CC from anatomical MRIs were obtained from children aged 9-16 in…

  15. Effects of Dopamine D2/D3 Blockade on Human Sensory and Sensorimotor Gating in Initially Antipsychotic-Naive, First-Episode Schizophrenia Patients

    PubMed Central

    Düring, Signe; Glenthøj, Birte Y; Andersen, Gitte Saltoft; Oranje, Bob

    2014-01-01

    It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits. PMID:24954063

  16. The feature of Metabolic Syndrome in HIV naive patients is not the same of those treated: results from a prospective study.

    PubMed

    Bonfanti, Paolo; De Socio, Giuseppe Vittorio; Ricci, Elena; Antinori, Andrea; Martinelli, Canio; Vichi, Francesca; Penco, Giovanni; Madeddu, Giordano; Orofino, Giancarlo; Valsecchi, Laura; Rusconi, Stefano; Menzaghi, Barbara; Pocaterra, Daria; Quirino, Tiziana

    2012-07-01

    Metabolic Syndrome (MS) is a common disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. Its prevalence among HIV-infected people is still debated. Besides, how antiretroviral therapy and HIV infection per se are related to MS is still unclear. All treatment-naïve patients attending scheduled visits at CISAI group hospitals between January and December 2007 were eligible for the study. Patients without MS at enrolment were followed-up for 3 years or until they developed MS, diagnosed according to the National Cholesterol Education Program (NCEP) definition. The main objective was to assess the 3-years incidence of MS. MS was evaluated for 188 subjects. Out of them, 62 (33.0%) had started HAART at enrolment, whereas 67 (35.6%) more started during the observation. 59 (31.4%) were still treatment-naive at the study end. MS was newly diagnosed in 14 patients. The incidence was 2.60 cases/100 person-years (95% CI 1.47-4.51), 2.75 (1.11-5.72) among HAART-naïve patients and 2.65 (1.23-5.03) in subjects on HAART. Blood pressure did not change in the study period, whereas in naive patients the HDL level significantly lowered (median -6.0 vs. 4.0, P<0.0001) compared to HAART-treated patients. Triglicerides increased significantly in HAART subjects (median 12.0 vs. 1.0, P=0.02), as well as blood glucose (median 6.0 vs. 1.0, P=0.01). In our population, the overall MS incidence was low and largely similar in patients who started HAART or remained naive. However, the feature of MS was different in the two groups, suggesting that in untreated and treated patients MS developed through different metabolic pathways. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  17. The European medicines agency review of abiraterone for the treatment of metastatic castration-resistant prostate cancer in adult men after docetaxel chemotherapy and in chemotherapy-naive disease: summary of the scientific assessment of the committee for medicinal products for human use.

    PubMed

    Gravanis, Iordanis; Lopez, Arantxa Sancho; Hemmings, Robert James; Jiménez, Jorge Camarero; Garcia-Carbonero, Rocio; Gallego, Isabel García; Giménez, Elena Valencia; O'Connor, Daniel; Giuliani, Rosa; Salmonson, Tomas; Pignatti, Francesco

    2013-01-01

    On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54-0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45-0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema.

  18. Increased serum prolactin levels in drug-naive first-episode male patients with schizophrenia.

    PubMed

    Albayrak, Yakup; Beyazyüz, Murat; Beyazyüz, Elmas; Kuloğlu, Murat

    2014-07-01

    Prolactin is a hormone receiving considerable attention in psychiatry. Increased serum prolactin level is frequently associated with dopamine blocking antipsychotics. Furthermore, decreased prolactin level was considered a reflector of the effect of antipsychotics. However, there is restricted numbers of investigations that researched baseline prolactin levels in first-episode patients with schizophrenia. We purpose to investigate serum baseline prolactin levels in drug-naive first-episode patients with schizophrenia (FES) and to explore the differences in serum prolactin levels between FES, drug-free schizophrenic patients (DFS) and healthy controls (HC). The study was conducted in the Departments of Psychiatry, Gölbaşı Hasvak and Kırklareli State Hospitals, Turkey. Thirty male FES, 41 male DFS and 32 male HC were included in study. All participants were clinically examined and individually interviewed. Before initiating any pharmacological treatment, 5 ml of venous blood was collected to measure serum prolactin levels between 08:00 and 10:00 h, which was determined by radioimmunoassay (RIA). Prolactin levels were also collected from the consenting HC using the same assay. The mean age was higher in the DFS group. The mean score of Brief Psychiatric Rating Scale was higher in the FES group and mean score of Scale for the Assessment of Negative Symptoms was higher in the DFS group. The mean value of prolactin was higher in the FES group (34.1 ± 19.9 ng/dl) compared with DFS (17.9 ± 6.5 ng/dl) and HC (9.7 ± 2.3 ng/dl) (F = 35.5, P < 0.001). Additionally, the mean value of serum prolactin is higher in the DFS group compared with HC (P < 0.001). To our knowledge, this study is the first to demonstrate higher serum prolactin levels in male FES compared with male DFS and male HC. Prolactin might act as a protective factor while first episode of schizophrenia is experienced. Future studies are needed to provide the role of prolactin in schizophrenia.

  19. Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but not in antipsychotic-naive first-episode schizophrenia patients.

    PubMed

    Arranz, Belén; Rosel, Pilar; Ramírez, Nicolas; Dueñas, Rosa; Fernández, Paloma; Sanchez, Jose María; Navarro, Miguel Angel; San, Luis

    2004-10-01

    The onset of diabetes and impaired glucose metabolism among schizophrenic patients has been the topic of numerous recently published articles, with research implicating weight gain, the use of antipsychotic medication, history of diabetes mellitus in family members, and the diagnosis of schizophrenia itself as risk factors. Therefore, it was the aim of this study to determine the glucose metabolism parameters in noncompliant unmedicated schizophrenic patients (antipsychotic-free) and first-episode antipsychotic-naive schizophrenic patients to investigate whether there is a preexisting impairment of glucose metabolism in never-medicated schizophrenic patients. Plasma glucose, insulin, C-peptide, and leptin concentrations were determined in 50 antipsychotic-free and 50 antipsychotic-naive DSM-IV schizophrenia patients and 50 healthy control subjects. Insulin resistance was calculated through the homeostatic model assessment (HOMA). The General Linear Model (univariate) procedure was used to perform analysis of covariance. Patients were recruited from July 2001 to December 2002. Antipsychotic-free patients showed significantly increased insulin (p = .001) and C-peptide (p = .02) concentrations and a significantly higher degree of insulin resistance (p = .003), as measured with the HOMA index, in comparison with the antipsychotic-naive patients and the control group. Significantly increased leptin concentrations (p = .000) were also noted in the antipsychotic-free patients and were attributed to the effects of body mass index (p = .000) and sex (p = .000). The results reported in this study suggest the effect of previous antipsychotic treatment on glucose metabolism parameters and weight-related hormones such as leptin, while ruling out a preexisting impairment of glucose metabolism in never-medicated first-episode schizophrenic patients.

  20. Ultradeep sequencing of B and non-B HIV-1 subtypes: Viral diversity and drug resistance mutations before and after one month of antiretroviral therapy in naive patients.

    PubMed

    Epaulard, Olivier; Signori-Schmuck, Anne; Larrat, Sylvie; Kulkarni, Om; Blum, Michael G; Fusillier, Katia; Blanc, Myriam; Leclercq, Pascale; François, Olivier; Morand, Patrice

    2017-10-01

    Ultradeep pyrosequencing technologies permit an assessment of the genetic diversity and the presence and frequency of minority variants in a viral population. The effect of these parameters on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected patients is poorly understood. The present study used the pyrosequencing Roche 454 prototype assay to determine whether antiretroviral efficacy is correlated with viral diversity and minority drug resistance mutations in HIV-infected treatment-naive patients and to compare assay performance in B and non-B subtypes. The study included 30 HIV-1 infected naive patients (20 with subtype non-B and 10 with subtype B). Ultradeep pyrosequencing of protease and reverse transcriptase genes was performed at baseline and 1 month after HAART initiation. Plasma HIV VL was measured at 0 and after 1, 3, and 6 months of HAART. Pre-HAART minority drug resistance mutations were observed to NRTI in 4 patients, to NNRTI in 6 patients, and to PI in 1 patient; there was no difference in HAART-induced VL decay between patients. Pre-HAART diversity was significantly correlated with the time elapsed since HIV-1 infection diagnosis, but not with the subtype, VL, or CD4 count. Patients with an undetectable VL after 3 months of HAART had a higher pre-HAART diversity. Pre- and post-HAART diversities were not statistically different. There was no difference in assay performance between subtype B and non-B. A high pre-HAART viral diversity might have a positive effect on the outcome of HAART. Pre-therapeutic minority drug resistance mutations are uncommon in naive patients. Copyright © 2017. Published by Elsevier B.V.

  1. Role of the tongue and senses in feeding of naive and experienced garter snakes.

    PubMed

    Burghardt, G M; Pruitt, C H

    1975-02-01

    Prey attack behavior was studied in two species of garter snakes (Thamnophis sirtalis and T. radix). Newborn, ingestively naive, and experienced snakes had their tongues severed surgically, while control groups retained their tongues. Attack latency, tongue flick frequency and an orientation-interest measure were recorded for each subject on responses to extracts prepared from species-characteristic prey. Feeding, as well as responses to prey extracts, were found to be suppressed almost totally in the tongueless naive snakes. A detongued adult, however, readily ate although its behavior was abnormal. Temporary blind and anosmic conditions did not have a significant effect on response rates of the tongueless or control groups. While importance of the tongue-Jacobson's organ system is demonstrated, the length of tongue removed and presurgery experience are important factors.

  2. The effect of phencyclidine on [3H]GABA and [3H]flunitrazepam binding in the brain of naive and handling-habituated rats.

    PubMed

    Lillrank, S M; Oja, S S; Saransaari, P

    1995-01-01

    The effects of handling and handling combined with phencyclidine (PCP) treatment on GABAergic neurotransmission were studied in Sprague-Dawley rats. The animal material consisted of handling-habituated (HH, for 11 d), acutely handled (naive, N), handling-habituated and PCP-treated (10 mg kg-1 i.p., HH + PCP) and acutely handled (naive) PCP-treated (N + PCP) and unhandled 'control' rats. The binding of [3H]GABA and [3H]flunitrazepam (FLU) was studied with membranes and the release of [3H]GABA with slices prepared from the striatum and frontal cortex. In the striatum the maximal binding capacity (Bmax) and the binding constant (KD) of [3H]GABA were the same in N and HH rats, but in the frontal cortex KD was lower in N rats. KD constants of [3H]FLU were significantly lower in both brain areas in N rats than in HH rats. After PCP treatment both Bmax and KD for [3H]FLU increased in these two brain areas in handling-habituated rats, whereas Bmax of [3H]GABA diminished. Neither handling nor PCP had any effect on [3H]GABA release from striatal and frontal cortical slices. Handling prior to killing thus affects differently the GABAergic parameters studied and modulates the PCP-induced effects.

  3. Divine intervention and the treatment of chemical dependency.

    PubMed

    Ellis, A; Schoenfeld, E

    1990-01-01

    Alcoholics Anonymous and related 12-step programs are the predominant influence on chemical dependency treatment programs in the United States today. 12-step programs have a strong religious orientation, despite rationalizations that Higher Power need not mean the traditional definition of God. The teaching of religious beliefs is not a proper function of therapists treating addictions in a general population. Moreover, teaching patients they can only recover through the intervention of a Higher Power locks them into a pattern of dependence on something outside themselves in order to function. 12-step programs have helped millions of people. Even more could be helped were they to eliminate the concept of needing a Higher Power.

  4. Safety, Efficacy, and Biomarkers of Nivolumab With Vaccine in Ipilimumab-Refractory or -Naive Melanoma

    PubMed Central

    Weber, Jeffrey S.; Kudchadkar, Ragini Reiney; Yu, Bin; Gallenstein, Donna; Horak, Christine E.; Inzunza, H. David; Zhao, Xiuhua; Martinez, Alberto J.; Wang, Wenshi; Gibney, Geoffrey; Kroeger, Jodi; Eysmans, Cabell; Sarnaik, Amod A.; Chen, Y. Ann

    2013-01-01

    Purpose Nivolumab, a human immunoglobulin G4–blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma. Patients and Methods In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Results Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1–specific CD8+ T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab. Conclusion In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab. PMID:24145345

  5. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma.

    PubMed

    Weber, Jeffrey S; Kudchadkar, Ragini Reiney; Yu, Bin; Gallenstein, Donna; Horak, Christine E; Inzunza, H David; Zhao, Xiuhua; Martinez, Alberto J; Wang, Wenshi; Gibney, Geoffrey; Kroeger, Jodi; Eysmans, Cabell; Sarnaik, Amod A; Chen, Y Ann

    2013-12-01

    Nivolumab, a human immunoglobulin G4-blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma. In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1-specific CD8(+) T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab. In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab.

  6. Antibiotic Activity against Naive and Induced Streptococcus pneumoniae Biofilms in an In Vitro Pharmacodynamic Model

    PubMed Central

    Vandevelde, Nathalie M.; Tulkens, Paul M.

    2014-01-01

    Biofilms play a role in the pathogenicity of pneumococcal infections. A pharmacodynamic in vitro model of biofilm was developed that allows characterization of the activity of antibiotics against viability and biomass by using in parallel capsulated (ATCC 49619) and noncapsulated (R6) reference strains. Naive biofilms were obtained by incubating fresh planktonic cultures for 2 to 11 days in 96-well polystyrene plates. Induced biofilms were obtained using planktonic bacteria collected from the supernatant of 6-day-old naive biofilms. Biomass production was more rapid and intense in the induced model, but the levels were similar for both strains. Full concentration responses fitting sigmoidal regressions allowed calculation of maximal efficacies and relative potencies of drugs. All antibiotics tested (amoxicillin, clarithromycin, solithromycin, levofloxacin, and moxifloxacin) were more effective against young naive biofilms than against old or induced biofilms, except macrolides/ketolides, which were as effective at reducing viability in 2-day-old naive biofilms and in 11-day-old induced biofilms of R6. Macrolides/ketolides, however, were less potent than fluoroquinolones against R6 (approximately 5- to 20-fold-higher concentrations needed to reduction viability of 20%). However, at concentrations obtainable in epithelial lining fluid, the viabilities of mature or induced biofilms were reduced 15 to 45% (amoxicillin), 17 to 44% (macrolides/ketolides), and 12 to 64% (fluoroquinolones), and biomasses were reduced 5 to 45% (amoxicillin), 5 to 60% (macrolides/ketolides), and 10 to 76% (fluoroquinolones), with solithromycin and moxifloxacin being the most effective and the most potent agents (due to lower MICs) in their respective classes. This study allowed the ranking of antibiotics with respect to their potential effectiveness in biofilm-related infections, underlining the need to search for still more effective options. PMID:24342635

  7. Diagnosis of combined faults in Rotary Machinery by Non-Naive Bayesian approach

    NASA Astrophysics Data System (ADS)

    Asr, Mahsa Yazdanian; Ettefagh, Mir Mohammad; Hassannejad, Reza; Razavi, Seyed Naser

    2017-02-01

    When combined faults happen in different parts of the rotating machines, their features are profoundly dependent. Experts are completely familiar with individuals faults characteristics and enough data are available from single faults but the problem arises, when the faults combined and the separation of characteristics becomes complex. Therefore, the experts cannot declare exact information about the symptoms of combined fault and its quality. In this paper to overcome this drawback, a novel method is proposed. The core idea of the method is about declaring combined fault without using combined fault features as training data set and just individual fault features are applied in training step. For this purpose, after data acquisition and resampling the obtained vibration signals, Empirical Mode Decomposition (EMD) is utilized to decompose multi component signals to Intrinsic Mode Functions (IMFs). With the use of correlation coefficient, proper IMFs for feature extraction are selected. In feature extraction step, Shannon energy entropy of IMFs was extracted as well as statistical features. It is obvious that most of extracted features are strongly dependent. To consider this matter, Non-Naive Bayesian Classifier (NNBC) is appointed, which release the fundamental assumption of Naive Bayesian, i.e., the independence among features. To demonstrate the superiority of NNBC, other counterpart methods, include Normal Naive Bayesian classifier, Kernel Naive Bayesian classifier and Back Propagation Neural Networks were applied and the classification results are compared. An experimental vibration signals, collected from automobile gearbox, were used to verify the effectiveness of the proposed method. During the classification process, only the features, related individually to healthy state, bearing failure and gear failures, were assigned for training the classifier. But, combined fault features (combined gear and bearing failures) were examined as test data. The achieved

  8. Naive and conditioned responses of Culex pipiens pipiens biotype molestus (Diptera: Culicidae) to flower odors.

    PubMed

    Jhumur, Umma Salma; Dötterl, Stefan; Jürgens, Andreas

    2006-11-01

    Flower odors are important signals for chemical communication between plants and flower visitors. Here, we studied the naive responses of Culex pipiens pipiens biotype molestus Forskal 1775 (Diptera: Culicidae) to typical flower odors and assessed the learning capacity of mosquitoes to floral volatiles. The odor compounds used in the bioassay, phenyl acetaldehyde, veratrole, and 2-methoxyphenol, are typically found in the floral odor of Silene otites (L.) Wibel, a plant that is pollinated by nectar-drinking mosquitoes and moths, and/or in other closely related Silene species. Wind tunnel bioassays with a mixture of these compounds revealed that attraction of mosquitoes to odors was positively correlated with time passed since the last feeding. In single component bioassays, mosquitoes showed strong innate responses to phenyl acetaldehyde and only moderate or weak responses to veratrole and 2-methoxyphenol. Furthermore, in comparison with naive mosquitoes, conditioned mosquitoes were significantly more attracted to the mixture and single volatiles. These results indicate that naive mosquitoes are effectively attracted by appropriate floral scent compounds and that learning can increase the attractiveness of these compounds.

  9. SMARCAD1 Contributes to the Regulation of Naive Pluripotency by Interacting with Histone Citrullination.

    PubMed

    Xiao, Shu; Lu, Jia; Sridhar, Bharat; Cao, Xiaoyi; Yu, Pengfei; Zhao, Tianyi; Chen, Chieh-Chun; McDee, Darina; Sloofman, Laura; Wang, Yang; Rivas-Astroza, Marcelo; Telugu, Bhanu Prakash V L; Levasseur, Dana; Zhang, Kang; Liang, Han; Zhao, Jing Crystal; Tanaka, Tetsuya S; Stormo, Gary; Zhong, Sheng

    2017-03-28

    Histone citrullination regulates diverse cellular processes. Here, we report that SMARCAD1 preferentially associates with H3 arginine 26 citrullination (H3R26Cit) peptides present on arrays composed of 384 histone peptides harboring distinct post-transcriptional modifications. Among ten histone modifications assayed by ChIP-seq, H3R26Cit exhibited the most extensive genomewide co-localization with SMARCAD1 binding. Increased Smarcad1 expression correlated with naive pluripotency in pre-implantation embryos. In the presence of LIF, Smarcad1 knockdown (KD) embryonic stem cells lost naive state phenotypes but remained pluripotent, as suggested by morphology, gene expression, histone modifications, alkaline phosphatase activity, energy metabolism, embryoid bodies, teratoma, and chimeras. The majority of H3R26Cit ChIP-seq peaks occupied by SMARCAD1 were associated with increased levels of H3K9me3 in Smarcad1 KD cells. Inhibition of H3Cit induced H3K9me3 at the overlapping regions of H3R26Cit peaks and SMARCAD1 peaks. These data suggest a model in which SMARCAD1 regulates naive pluripotency by interacting with H3R26Cit and suppressing heterochromatin formation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Naive (commonsense) geography and geobrowser usability after ten years of Google Earth

    NASA Astrophysics Data System (ADS)

    Hamerlinck, J. D.

    2016-04-01

    In 1995, the concept of ‘naive geography’ was formally introduced as an area of cognitive geographic information science representing ‘the body of knowledge that people have about the surrounding geographic world’ and reflecting ‘the way people think and reason about geographic space and time, both consciously and subconsciously’. The need to incorporate such commonsense knowledge and reasoning into design of geospatial technologies was identified but faced challenges in formalizing these relationships and processes in software implementation. Ten years later, the Google Earth geobrowser was released, marking the beginning of a new era of open access to, and application of, geographic data and information in society. Fast-forward to today, and the opportunity presents itself to take stock of twenty years of naive geography and a decade of the ubiquitous virtual globe. This paper introduces an ongoing research effort to explore the integration of naive (or commonsense) geography concepts in the Google Earth geobrowser virtual globe and their possible impact on Google Earth's usability, utility, and usefulness. A multi-phase methodology is described, combining usability reviews and usability testing with use-case scenarios involving the U.S.-Canadian Yellowstone to Yukon Initiative. Initial progress on a usability review combining cognitive walkthroughs and heuristics evaluation is presented.

  11. Ensemble of Chaotic and Naive Approaches for Performance Enhancement in Video Encryption

    PubMed Central

    Chandrasekaran, Jeyamala; Thiruvengadam, S. J.

    2015-01-01

    Owing to the growth of high performance network technologies, multimedia applications over the Internet are increasing exponentially. Applications like video conferencing, video-on-demand, and pay-per-view depend upon encryption algorithms for providing confidentiality. Video communication is characterized by distinct features such as large volume, high redundancy between adjacent frames, video codec compliance, syntax compliance, and application specific requirements. Naive approaches for video encryption encrypt the entire video stream with conventional text based cryptographic algorithms. Although naive approaches are the most secure for video encryption, the computational cost associated with them is very high. This research work aims at enhancing the speed of naive approaches through chaos based S-box design. Chaotic equations are popularly known for randomness, extreme sensitivity to initial conditions, and ergodicity. The proposed methodology employs two-dimensional discrete Henon map for (i) generation of dynamic and key-dependent S-box that could be integrated with symmetric algorithms like Blowfish and Data Encryption Standard (DES) and (ii) generation of one-time keys for simple substitution ciphers. The proposed design is tested for randomness, nonlinearity, avalanche effect, bit independence criterion, and key sensitivity. Experimental results confirm that chaos based S-box design and key generation significantly reduce the computational cost of video encryption with no compromise in security. PMID:26550603

  12. The BMP Pathway Participates in Human Naive CD4+ T Cell Activation and Homeostasis

    PubMed Central

    Martínez, Víctor G.; Sacedón, Rosa; Hidalgo, Laura; Valencia, Jaris; Fernández-Sevilla, Lidia M.; Hernández-López, Carmen

    2015-01-01

    Bone Morphogenetic Proteins (BMPs) form a group of secreted factors that belongs to the TGF-β superfamily. Among different roles in a number of immune cell types, BMPs are known to regulate T cell development within the thymus, although the role of BMP signaling in human mature T cells remains elusive. In this study, we demonstrate that canonical BMP signaling is necessary during two critical events that regulate the size and function of human naive CD4+ T cell population: activation and homeostasis. Upon stimulation via TCR, naive CD4+ T cells upregulate the expression of BMP ligands triggering canonical BMP signaling in CD25+ cells. Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling. Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis. Moreover, upregulation of two critical receptors for T cell homeostasis, CXCR4 and CCR9, triggered by IL-7 is also abrogated in the absence of BMP signaling. Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application. PMID:26110906

  13. Ensemble of Chaotic and Naive Approaches for Performance Enhancement in Video Encryption.

    PubMed

    Chandrasekaran, Jeyamala; Thiruvengadam, S J

    2015-01-01

    Owing to the growth of high performance network technologies, multimedia applications over the Internet are increasing exponentially. Applications like video conferencing, video-on-demand, and pay-per-view depend upon encryption algorithms for providing confidentiality. Video communication is characterized by distinct features such as large volume, high redundancy between adjacent frames, video codec compliance, syntax compliance, and application specific requirements. Naive approaches for video encryption encrypt the entire video stream with conventional text based cryptographic algorithms. Although naive approaches are the most secure for video encryption, the computational cost associated with them is very high. This research work aims at enhancing the speed of naive approaches through chaos based S-box design. Chaotic equations are popularly known for randomness, extreme sensitivity to initial conditions, and ergodicity. The proposed methodology employs two-dimensional discrete Henon map for (i) generation of dynamic and key-dependent S-box that could be integrated with symmetric algorithms like Blowfish and Data Encryption Standard (DES) and (ii) generation of one-time keys for simple substitution ciphers. The proposed design is tested for randomness, nonlinearity, avalanche effect, bit independence criterion, and key sensitivity. Experimental results confirm that chaos based S-box design and key generation significantly reduce the computational cost of video encryption with no compromise in security.

  14. Goodness and Accentedness Ratings of /hVt/ Tokens by Aware and Naive Listeners

    PubMed Central

    Oksanen, Kara A.; Gilfert, Kaitlyn E.

    2016-01-01

    Purpose This study compares goodness and accentedness ratings of speech tokens rated by listeners who are naive to and aware of speakers' native language backgrounds. Listener responses to open-ended questions regarding goodness and accentedness ratings are also examined. Method Twenty-eight monolingual speakers of U.S. English served as listeners. Listeners were presented with 5 blocks of /hVt/ tokens. Each block represented a different vowel target and comprised correct and incorrect productions from English, Spanish, Korean, and Japanese speakers. Listeners rated goodness and accentedness using a 9-point Likert scale and explained their decision-making criteria when judging goodness versus accentedness. Results There is a high positive correlation between goodness and accentedness. Both naive and aware listeners assigned poorer ratings when judging goodness compared with accentedness, but results varied on the basis of target accuracy. Aware listeners assigned better goodness and accentedness ratings compared with naive listeners. This difference was highly statistically significant. Both accentedness and goodness ratings are susceptible to listener bias. Conclusions Goodness and accentedness are highly correlated yet distinct measures. Goodness is more reflective of target accuracy than is accentedness. Native English tokens were affected by listener bias to a greater extent than nonnative English tokens. PMID:27893085

  15. Postural stability and skilled performance--a study on top-level and naive rifle shooters.

    PubMed

    Era, P; Konttinen, N; Mehto, P; Saarela, P; Lyytinen, H

    1996-03-01

    Posture control during aiming over a period of 7.5 s preceding the shot was studied among national top-level rifle shooters as well as among national level shooters and amateurs familiar with rifle shooting. Movement of the center of forces (COF) was analyzed in terms of the speed and amplitude of the movement. These calculations were carried out in 1.5 s windows, the first window beginning 7.5 s and ending at 6.0 s prior the shot. The last window ended at the trigger pull. Posture control data differentiated the studied groups according to their level in competitive shooting. The male top-level shooters could stabilize their posture significantly better than female top-level or male national level shooters, who were, in turn, much more stable than naive shooters. The experienced shooters were able to stabilize their posture even better during the last seconds preceding the shot, whereas in naive shooters there were no significant differences when the successive windows were compared with each other. When a comparison was made between the best and worst 20 shots of each subject, a significant difference in balance parameters was only observed among the naive shooters, who showed more pronounced movement of the COF in the less successful trials. Among the highly trained top-level shooters a miss in whole-body posture stabilization apparently seldom is a reason for a poor result.

  16. The Role of Social Supports, Spirituality, Religiousness, Life Meaning and Affiliation with 12-Step Fellowships in Quality of Life Satisfaction Among Individuals in Recovery from Alcohol and Drug Problems

    PubMed Central

    Laudet, Alexandre B.; Morgen, Keith; White, William L.

    2006-01-01

    SUMMARY Many recovering substance users report quitting drugs because they wanted a better life. The road of recovery is the path to a better life but a challenging and stressful path for most. There has been little research among recovering persons in spite of the numbers involved, and most research has focused on substance use outcomes. This study examines stress and quality of life as a function of time in recovery, and uses structural equation modeling to test the hypothesis that social supports, spirituality, religiousness, life meaning, and 12-step affiliation buffer stress toward enhanced life satisfaction. Recovering persons (N = 353) recruited in New York City were mostly inner-city ethnic minority members whose primary substance had been crack or heroin. Longer recovery time was significantly associated with lower stress and with higher quality of life. Findings supported the study hypothesis; the ‘buffer’ constructs accounted for 22% of the variance in life satisfaction. Implications for research and clinical practice are discussed. PMID:16892161

  17. Evaluation of the impact of chitosan/DNA nanoparticles on the differentiation of human naive CD4+ T cells

    NASA Astrophysics Data System (ADS)

    Liu, Lanxia; Bai, Yuanyuan; Zhu, Dunwan; Song, Liping; Wang, Hai; Dong, Xia; Zhang, Hailing; Leng, Xigang

    2011-06-01

    Chitosan (CS) is one of the most widely studied polymers in non-viral gene delivery since it is a cationic polysaccharide that forms nanoparticles with DNA and hence protects the DNA against digestion by DNase. However, the impact of CS/DNA nanoparticle on the immune system still remains poorly understood. Previous investigations did not found CS/DNA nanoparticles had any significant impact on the function of human and murine macrophages. To date, little is known about the interaction between CS/DNA nanoparticles and naive CD4+ T cells. This study was designed to investigate whether CS/DNA nanoparticles affect the initial differentiation direction of human naive CD4+ T cells. The indirect impact of CS/DNA nanoparticles on naive CD4+ T cell differentiation was investigated by incubating the nanoparticles with human macrophage THP-1 cells in one chamber of a transwell co-incubation system, with the enriched human naive CD4+ T cells being placed in the other chamber of the transwell. The nanoparticles were also co-incubated with the naive CD4+ T cells to explore their direct impact on naive CD4+ T cell differentiation by measuring the release of IL-4 and IFN-γ from the cells. It was demonstrated that CS/DNA nanoparticles induced slightly elevated production of IL-12 by THP-1 cells, possibly owing to the presence of CpG motifs in the plasmid. However, this macrophage stimulating activity was much less significant as compared with lipopolysaccharide and did not impact on the differentiation of the naive CD4+ T cells. It was also demonstrated that, when directly exposed to the naive CD4+ T cells, the nanoparticles induced neither the activation of the naive CD4+ T cells in the absence of recombinant cytokines (recombinant human IL-4 or IFN-γ) that induce naive CD4+ T cell polarization, nor any changes in the differentiation direction of naive CD4+ T cells in the presence of the corresponding cytokines.

  18. Top predators affect the composition of naive protist communities, but only in their early-successional stage.

    PubMed

    Zander, Axel; Gravel, Dominique; Bersier, Louis-Félix; Gray, Sarah M

    2016-02-01

    Introduced top predators have the potential to disrupt community dynamics when prey species are naive to predation. The impact of introduced predators may also vary depending on the stage of community development. Early-succession communities are likely to have small-bodied and fast-growing species, but are not necessarily good at defending against predators. In contrast, late-succession communities are typically composed of larger-bodied species that are more predator resistant relative to small-bodied species. Yet, these aspects are greatly neglected in invasion studies. We therefore tested the effect of top predator presence on early- and late-succession communities that were either naive or non-naive to top predators. We used the aquatic community held within the leaves of Sarracenia purpurea. In North America, communities have experienced the S. purpurea top predator and are therefore non-naive. In Europe, this predator is not present and its niche has not been filled, making these communities top-predator naive. We collected early- and late-succession communities from two non-naive and two naive sites, which are climatically similar. We then conducted a common-garden experiment, with and without the presence of the top predator, in which we recorded changes in community composition, body size spectra, bacterial density, and respiration. We found that the top predator had no statistical effect on global measures of community structure and functioning. However, it significantly altered protist composition, but only in naive, early-succession communities, highlighting that the state of community development is important for understanding the impact of invasion.

  19. IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity.

    PubMed

    Silva, Susana L; Albuquerque, Adriana S; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T; Victorino, Rui M M; Sousa, Ana E

    2017-01-01

    Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31(-) subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31(+) naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6, a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31(-) naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31(+) naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.

  20. IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity

    PubMed Central

    Silva, Susana L.; Albuquerque, Adriana S.; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T.; Victorino, Rui M. M.; Sousa, Ana E.

    2017-01-01

    Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31− subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31+ naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6, a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31− naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31+ naive CD4 T-cells, which is essential to secure T-cell diversity throughout life. PMID:28154568

  1. Gastrointestinal tolerability and quality of life in antiretroviral-naive HIV-1-infected patients: data from the CASTLE study.

    PubMed

    Malan, Niel; Su, Jun; Mancini, Marco; Yang, Rong; Wirtz, Victoria; Absalon, Judith; McGrath, Donnie

    2010-06-01

    Most ritonavir-boosted protease inhibitor (PI)-based antiretroviral regimens offer comparable levels of virological efficacy. Thus, the tolerability of the regimen becomes a distinguishing factor with implications for patient quality of life (QoL), treatment adherence, and clinical outcome. This article describes results from the CASTLE study (comparing once-daily atazanavir/ritonavir [ATV/RTV] with twice-daily lopinavir/ritonavir [LPV/RTV], both in combination with fixed-dose tenofovir/emtricitabine, in treatment-naive HIV-infected patients) and an evaluation of the impact of gastrointestinal (GI) complications of treatment on patient QoL, as measured by the irritable bowel syndrome (IBS) QoL questionnaire (IBS-QoL). Changes in IBS-QoL from baseline over time (to week 24) were classified as: "Improvement" (> or =2-point positive change from baseline), "No change" (<2-point change), or "Worsening" (> or =2-point negative change). Data were collected on GI adverse events (AEs) and use of GI medications. Of the 599 patients with IBS-QoL-evaluable data through week 24, fewer patients in the ATV/RTV group than in the LPV/RTV group experienced grade 2-4 treatment-related GI AEs including diarrhea (3% versus 10%), nausea (5% versus 7%), and vomiting (<1% on both arms). Nearly three times as many patients receiving LPV/RTV used GI medications. ATV/RTV was associated with an increase in overall IBS-QoL scores and more patients receiving ATV/RTV than LPV/RTV experienced improvement in IBS-QoL through week 24. In contrast to LPV/RTV, ATV/RTV treatment was associated with earlier and more positive improvements in QoL scores across CD4 sub-groups. Differences in the health-related QoL profile between ATV/RTV and LPV/RTV may be important when selecting PI-based antiretroviral regimens.

  2. Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer.

    PubMed

    Dong, Baijun; Fan, Liancheng; Wang, Yanqing; Chi, Chenfei; Ma, Xiaowei; Wang, Rui; Cai, Wen; Shao, Xiaoguang; Pan, Jiahua; Zhu, Yinjie; Shangguan, Xun; Xin, Zhixiang; Hu, Jianian; Xie, Shaowei; Kang, Xiaonan; Zhou, Lixin; Xue, Wei

    2017-05-01

    To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). We conducted an analysis in 115 chemotherapy-naïve mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED. Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED. We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of m

  3. Decreased interhemispheric functional connectivity in insula and angular gyrus/supramarginal gyrus: Significant findings in first-episode, drug-naive somatization disorder.

    PubMed

    Su, Qinji; Yao, Dapeng; Jiang, Muliang; Liu, Feng; Long, Liling; Dai, Yi; Yu, Miaoyu; Zhang, Zhikun; Zhang, Jian; Liu, Jianrong; Xiao, Changqing; Zhao, Jingping; Guo, Wenbin

    2016-02-28

    Neuroimaging data have demonstrated brain functional alterations in patients with somatization disorder (SD). However, there is little information on interhemispheric resting-state functional connectivity (FC) in SD. In this study, resting-state functional magnetic resonance imaging (fMRI) and voxel-mirrored homotopic connectivity (VMHC) were applied to examine the changes of interhemispheric FC of the whole brain in patients with SD. A total of 25 first-episode, medication-naive SD patients and 28 age-, sex-, education-matched healthy controls (HC) underwent resting-state fMRI, and the data were analyzed by VMHC. Compared with HC, patients had lower VMHC in the angular gyrus/supramarginal gyrus (AG/SG) and insula. The reproducibility of the results was validated using the split-half and leave-one-out validations. No significant correlation was found between the VMHC in AG/SG or insula and clinical variables. Our findings indicate that the interhemispheric FC in the AG/SG and insula is decreased in first-episode, treatment-naive patients with SD, and thus provide new insight for disruption of interhemispheric FC in the pathophysiological mechanism of SD.

  4. Baseline Naive CD4+ T-cell Level Predicting Immune Reconstitution in Treated HIV-infected Late Presenters

    PubMed Central

    Guo, Fu-Ping; Li, Yi-Jia; Qiu, Zhi-Feng; Lv, Wei; Han, Yang; Xie, Jing; Li, Yan-Ling; Song, Xiao-Jing; Du, Shan-Shan; Mehraj, Vikram; Li, Tai-Sheng; Routy, Jean-Pierre

    2016-01-01

    Background: Among HIV-infected patients initiating antiretroviral therapy (ART), early changes in CD4+ T-cell subsets are well described. However, HIV-infected late presenters initiating treatment present with a suboptimal CD4+ T-cell reconstitution and remain at a higher risk for AIDS and non-AIDS events. Therefore, factors associated with CD4+ T-cell reconstitution need to be determined in this population, which will allow designing effective immunotherapeutic strategies. Methods: Thirty-one adult patients with baseline CD4+ T-cell count <350 cells/mm3 exhibiting viral suppression after ART initiation were followed in the HIV/AIDS research center of Peking Union Medical College Hospital in Beijing, China, from October 2002 to September 2013. Changes in T-cell subsets and associated determinants were measured. Results: Median baseline CD4+ T-cell count was 70 cells/mm3. We found a biphasic reconstitution of T-cell subsets and immune activation: a rapid change during the first 6 months followed by a more gradual change over the subsequent 8 years. Baseline CD4+ T-cell count >200 cells/mm3 in comparison to CD4+ T-cell count ≤200 cells/mm3 was associated with more complete immune Reconstitution (77.8% vs. 27.3% respectively; P = 0.017) and normalized CD4/CD8 ratio. We showed that the baseline percentage of naive CD4+ T-cell was a predictive marker for complete immune reconstitution (area under receiver operating characteristic curve 0.907), and 12.4% as cutoff value had a sensitivity of 84.6% and a specificity of 88.2%. Conclusions: Baseline naive CD4+ T-cell percentage may serve as a predictive marker for optimal immune reconstitution during long-term therapy. Such study findings suggest that increasing thymic output should represent an avenue to improve patients who are diagnosed late in the course of infection. PMID:27824000

  5. D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with (11C)raclopride

    SciTech Connect

    Farde, L.; Wiesel, F.A.; Stone-Elander, S.; Halldin, C.; Nordstroem, A.L.H.; Hall, H.; Sedvall, G. )

    1990-03-01

    Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and ({sup 11}C)raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.

  6. HIV Drug Resistance in Antiretroviral-Naive Patients in Mexico After 10 Years: Is There a Difference?

    PubMed

    Escoto-Delgadillo, Martha; Torres-Mendoza, Blanca-Miriam; Flores-Soto, Mario; Vazquez-Valls, Eduardo

    2016-12-01

    The aim of this study was to compare the extent of resistance to antiretroviral (ARV) drugs among the population in Mexico before and after 2005. The mutations and drug resistance database of Stanford University were used for analyzing drug resistance tests that had been performed on HIV treatment-naive patients. The sequences obtained were divided into group 1 (isolated in 2002-2003) and group 2 (isolated in 2010-2014). Both groups showed 14% similarity in resistance mutations. In both groups, mutations in N88D protease inhibitor were identified, D67N and T69D were found for nucleoside reverse transcriptase inhibitors (NRTIs), and K103N was found for non-nucleoside reverse transcriptase inhibitors. In both groups, the resistance to ARV drugs was 7.4%. Both groups showed resistance to nelfinavir, efavirenz, and nevirapine. The prevalence of resistance to ARV therapy remained stable from 2002 to 2014. However, a marked reduction in resistance to NRTIs was observed for the same period.

  7. A Naive-Bayes model observer for detection and localization of perfusion defects in cardiac SPECT-MPI

    NASA Astrophysics Data System (ADS)

    Parages, Felipe M.; O'Connor, J. Michael; Pretorius, P. Hendrik; Brankov, Jovan G.

    2014-03-01

    Model observers (MO) are widely used in medical imaging to act as surrogates of human observers in task-based image quality evaluation, frequently towards optimization of reconstruction algorithms. In SPECT myocardial perfusion imaging (MPI), a realistic task-based approach involves detection and localization of perfusion defects, as well as a subsequent assessment of defect severity. In this paper we explore a machine-learning MO based on Naive- Bayes classification (NB-MO). NB-MO uses a set of polar-map image features to predict lesion detection, localization and severity scores given by five human readers for a set of simulated 3D SPECT-MPI patients. The simulated dataset included lesions with different sizes, perfusion-reduction ratios, and locations. Simulated projections were reconstructed using two readily used methods namely: FBP and OSEM. For validation, a multireader multi-case (MRMC) analysis of alternative free-response ROC (AFROC) curve was performed for NB-MO and human observers. For comparison, we also report performances of a statistical Hotelling Observer applied on polar-map images. Results show excellent agreement between NB-MO and humans, as well as model's good generalization between different reconstruction treatments.

  8. Altered serum levels of interleukin-3 in first-episode drug-naive and chronic medicated schizophrenia.

    PubMed

    Fu, Yin Yang; Zhang, Tong; Xiu, Mei Hong; Tang, Wei; Han, Mei; Yun, Long Tan; Chen, Da Chun; Chen, Song; Tan, Shu Ping; Soares, Jair C; Tang, Wen Jie; Zhang, Xiang Yang

    2016-10-01

    Elevated serum levels of Interleukin-3 (IL-3), a major component of the cytokines, have been observed in chronic and medicated patients with schizophrenia, but this elevation may reflect either or both medication and illness chronicity effects. Thus, we compared serum IL-3 levels in first-episode drug-naive (FEDN) to chronic medicated patients with schizophrenia and examined the association of IL-3 with their psychopathological symptoms. Serum IL-3 levels were assessed in 55 FEDN patients, 52 chronic medicated patients and 43 healthy controls. Schizophrenia symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS). Serum IL-3 levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). We found significantly lower IL-3 levels in FEDN patients than both chronic patients and healthy controls (both p<0.001), while IL-3 levels in chronic patients were markedly higher than in healthy controls. No significant association was observed between IL-3 and any clinical psychopathology in FEDN patients; however, we found a significant correlation between serum IL-3 levels and the PANSS general psychopathology subscore in chronic medicated patients (p<0.05). Decreased IL-3 levels in FEDN patients suggest that suppressed immune function may be associated with developing schizophrenia, but as the disease progresses IL-3 levels increase perhaps related to medication treatment or other factors that occur during chronic illness.

  9. Risk of erectile dysfunction in transfusion-naive thalassemia men: a nationwide population-based retrospective cohort study.

    PubMed

    Chen, Yu-Guang; Lin, Te-Yu; Lin, Cheng-Li; Dai, Ming-Shen; Ho, Ching-Liang; Kao, Chia-Hung

    2015-04-01

    Based on the mechanism of pathophysiology, thalassemia major or transfusion-dependent thalassemia patients may have an increased risk of developing organic erectile dysfunction resulting from hypogonadism. However, there have been few studies investigating the association between erectile dysfunction and transfusion-naive thalassemia populations. We constructed a population-based cohort study to elucidate the association between transfusion-naive thalassemia populations and organic erectile dysfunction. This nationwide population-based cohort study involved analyzing data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending to the end of 2011. We identified men with transfusion-naive thalassemia and selected a comparison cohort that was frequency-matched with these according to age, and year of diagnosis thalassemia at a ratio of 1 thalassemia man to 4 control men. We analyzed the risks for transfusion-naive thalassemia men and organic erectile dysfunction by using Cox proportional hazards regression models. In this study, 588 transfusion-naive thalassemia men and 2337 controls were included. Total 12 patients were identified within the thalassaemia group and 10 within the control group. The overall risks for developing organic erectile dysfunction were 4.56-fold in patients with transfusion-naive thalassemia men compared with the comparison cohort after we adjusted for age and comorbidities. Our long-term cohort study results showed that in transfusion-naive thalassemia men, there was a higher risk for the development of organic erectile dysfunction, particularly in those patients with comorbidities.

  10. The sudden emergence of pathogenicity in insect–fungus symbioses threatens naive forest ecosystems

    PubMed Central

    Hulcr, Jiri; Dunn, Robert R.

    2011-01-01

    Invasive symbioses between wood-boring insects and fungi are emerging as a new and currently uncontrollable threat to forest ecosystems, as well as fruit and timber industries throughout the world. The bark and ambrosia beetles (Curculionidae: Scolytinae and Platypodinae) constitute the large majority of these pests, and are accompanied by a diverse community of fungal symbionts. Increasingly, some invasive symbioses are shifting from non-pathogenic saprotrophy in native ranges to a prolific tree-killing in invaded ranges, and are causing significant damage. In this paper, we review the current understanding of invasive insect–fungus symbioses. We then ask why some symbioses that evolved as non-pathogenic saprotrophs, turn into major tree-killers in non-native regions. We argue that a purely pathology-centred view of the guild is not sufficient for explaining the lethal encounters between exotic symbionts and naive trees. Instead, we propose several testable hypotheses that, if correct, lead to the conclusion that the sudden emergence of pathogenicity is a new evolutionary phenomenon with global biogeographical dynamics. To date, evidence suggests that virulence of the symbioses in invaded ranges is often triggered when several factors coincide: (i) invasion into territories with naive trees, (ii) the ability of the fungus to either overcome resistance of the naive host or trigger a suicidal over-reaction, and (iii) an ‘olfactory mismatch’ in the insect whereby a subset of live trees is perceived as dead and suitable for colonization. We suggest that individual cases of tree mortality caused by invasive insect–fungus symbionts should no longer be studied separately, but in a global, biogeographically and phylogenetically explicit comparative framework. PMID:21752822

  11. The sudden emergence of pathogenicity in insect-fungus symbioses threatens naive forest ecosystems.

    PubMed

    Hulcr, Jiri; Dunn, Robert R

    2011-10-07

    Invasive symbioses between wood-boring insects and fungi are emerging as a new and currently uncontrollable threat to forest ecosystems, as well as fruit and timber industries throughout the world. The bark and ambrosia beetles (Curculionidae: Scolytinae and Platypodinae) constitute the large majority of these pests, and are accompanied by a diverse community of fungal symbionts. Increasingly, some invasive symbioses are shifting from non-pathogenic saprotrophy in native ranges to a prolific tree-killing in invaded ranges, and are causing significant damage. In this paper, we review the current understanding of invasive insect-fungus symbioses. We then ask why some symbioses that evolved as non-pathogenic saprotrophs, turn into major tree-killers in non-native regions. We argue that a purely pathology-centred view of the guild is not sufficient for explaining the lethal encounters between exotic symbionts and naive trees. Instead, we propose several testable hypotheses that, if correct, lead to the conclusion that the sudden emergence of pathogenicity is a new evolutionary phenomenon with global biogeographical dynamics. To date, evidence suggests that virulence of the symbioses in invaded ranges is often triggered when several factors coincide: (i) invasion into territories with naive trees, (ii) the ability of the fungus to either overcome resistance of the naive host or trigger a suicidal over-reaction, and (iii) an 'olfactory mismatch' in the insect whereby a subset of live trees is perceived as dead and suitable for colonization. We suggest that individual cases of tree mortality caused by invasive insect-fungus symbionts should no longer be studied separately, but in a global, biogeographically and phylogenetically explicit comparative framework.

  12. Cytokine responses to Mycobacterium leprae unique proteins differentiate between Mycobacterium leprae infected and naive armadillos.

    PubMed

    Pena, Maria; Geluk, Annemieke; Van Der Ploeg-Van Schip, Jolien J; Franken, Kees L M C; Sharma, Rahul; Truman, Richard

    2011-12-01

    New diagnostic tools for early detection of leprosy are necessary to help reduce its transmission and severity. M. leprae unique proteins have been used to assess differences in human T-cell responses in leprosy patients, household contacts and endemic controls. In this study, we examined the response of M. leprae-infected armadillos to a variety of M. leprae recombinant antigen candidates currently being examined for diagnostic efficacy in humans. Among recently M. leprae infected armadillos, IFN-gamma expression was enhanced after stimulation of PBMC with all M. leprae recombinant proteins except for ML2283 (mean: 2.65 Relative Quantification (RQ)). The group mean stimulation index for M. leprae proteins ML0009, ML1601, ML2478 and ML2531 averaged 35.2 RQ and was significantly higher (P < 0.05) than that measured among the non-infected, naive group (mean 6.2 RQ). Although ML0840 tended to enhance IFN-gamma levels, the mean IFN-gamma transcript levels of the currently experimentally inoculated group (20.1 RQ) was not significantly different statistically (P = 0.10) from the mean of the naive group (7.5 RQ). Also no statistically significant differences were observed in IFN-gamma transcript levels between the resistant and currently experimentally inoculated group (P > 0.05) or between the resistant and the naive group (P > 0.05) after stimulation of PBMCs with all M. leprae recombinant proteins. Only low levels of TNF-alpha were observed across all groups after in vitro stimulation with all the antigens examined. These data suggest that armadillos can be used effectively to help identify M. leprae specific proteins that may be applied for monitoring T-cell responses in M. leprae infected hosts as their disease progresses as well as for the early diagnosis of leprosy.

  13. The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson's disease: effects of L-DOPA and the D1 agonist SKF 82958.

    PubMed

    Andringa, G; Lubbers, L; Drukarch, B; Stoof, J C; Cools, A R

    1999-03-01

    The aim of this study was twofold: (1) to study the predictive validity of the drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD), and (2) to investigate the therapeutic and undesired effects of the D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA pretreated monkeys. A detailed ethogram was used, allowing the separation of therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased the parameters used classically to evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia. However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, induced additional undesired effects; including epileptoid behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA-unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as undesired effects. Although the effects of SKF 82958 on fore-limb movements, rotational behaviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated group from day one. It is concluded that the bilaterally MPTP-treated monkey is an animal model with predictive validity for PD: it adequately predicts the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD, because it did not induce therapeutic effects, but instead elicited several undesired effects.

  14. TLR activation excludes circulating naive CD8+ T cells from gut-associated lymphoid organs in mice.

    PubMed

    Heidegger, Simon; Kirchner, Sophie-Kathrin; Stephan, Nicolas; Bohn, Bernadette; Suhartha, Nina; Hotz, Christian; Anz, David; Sandholzer, Nadja; Stecher, Bärbel; Rüssmann, Holger; Endres, Stefan; Bourquin, Carole

    2013-05-15

    The trafficking of effector T cells is tightly regulated by the expression of site-specific sets of homing molecules. In contrast, naive T cells are generally assumed to express a uniform pattern of homing molecules and to follow a random distribution within the blood and secondary lymphoid organs. In this study, we demonstrate that systemic infection fundamentally modifies the trafficking of circulating naive CD8(+) T cells. We show that on naive CD8(+) T cells, the constitutive expression of the integrin α4β7 that effects their entry into GALT is downregulated following infection of mice with Salmonella typhimurium. We further show that this downregulation is dependent on TLR signaling, and that the TLR-activated naive CD8(+) T cells are blocked from entering GALT. This contrasts strongly with Ag-experienced effector T cells, for which TLR costimulation in the GALT potently upregulates α4β7 and enhances trafficking to intestinal tissues. Thus, TLR activation leads to opposite effects on migration of naive and effector CD8(+) T cells. Our data identify a mechanism that excludes noncognate CD8(+) T cells from selected immune compartments during TLR-induced systemic inflammation.

  15. Telomerase Is Involved in IL-7-Mediated Differential Survival of Naive and Memory CD4+ T Cells1

    PubMed Central

    Yang, Yinhua; An, Jie; Weng, Nan-ping

    2008-01-01

    IL-7 plays an essential role in T cell maintenance and survival. The survival effect of IL-7 is thought to be mediated through regulation of Bcl2 family proteins. After a comparative analysis of IL-7-induced growth and cell death of human naive and memory CD4+ T cells, we observed that more memory CD4+ T cells underwent cell division and proceeded to apoptosis than naive cells in response to IL-7. However, IL-7-induced expressions of Bcl2 family members (Bcl2, Bcl-xL, Bax, and Bad) were similar between naive and memory cells. Instead, we found that IL-7 induced higher levels of telomerase activity in naive cells than in memory cells, and the levels of IL-7-induced telomerase activity had a significant inverse correlation with cell death in CD4+ T cells. Furthermore, we showed that reducing expression of telomerase reverse transcriptase and telomerase activity significantly increased cell death of IL-7-cultured CD4+ T cells. Together, these findings demonstrate that telomerase is involved in IL-7-mediated differential survival of naive and memory CD4+ T cells. PMID:18322183

  16. Personality matters: individual variation in reactions of naive bird predators to aposematic prey

    PubMed Central

    Exnerová, Alice; Svádová, Kateřina Hotová; Fučíková, Eva; Drent, Pieter; Štys, Pavel

    2010-01-01

    Variation in reactions to aposematic prey is common among conspecific individuals of bird predators. It may result from different individual experience but it also exists among naive birds. This variation may possibly be explained by the effect of personality—a complex of correlated, heritable behavioural traits consistent across contexts. In the great tit (Parus major), two extreme personality types have been defined. ‘Fast’ explorers are bold, aggressive and routine-forming; ‘slow’ explorers are shy, non-aggressive and innovative. Influence of personality type on unlearned reaction to aposematic prey, rate of avoidance learning and memory were tested in naive, hand-reared great tits from two opposite lines selected for exploration (slow against fast). The birds were subjected to a sequence of trials in which they were offered aposematic adult firebugs (Pyrrhocoris apterus). Slow birds showed a greater degree of unlearned wariness and learned to avoid the firebugs faster than fast birds. Although birds of both personality types remembered their experience, slow birds were more cautious in the memory test. We conclude that not only different species but also populations of predators that differ in proportions of personality types may have different impacts on survival of aposematic insects under natural conditions. PMID:19889698

  17. Analysis of relationships between peptide/MHC structural features and naive T cell frequency in humans.

    PubMed

    Reiser, Jean-Baptiste; Legoux, François; Gras, Stéphanie; Trudel, Eric; Chouquet, Anne; Léger, Alexandra; Le Gorrec, Madalen; Machillot, Paul; Bonneville, Marc; Saulquin, Xavier; Housset, Dominique

    2014-12-15

    The structural rules governing peptide/MHC (pMHC) recognition by T cells remain unclear. To address this question, we performed a structural characterization of several HLA-A2/peptide complexes and assessed in parallel their antigenicity, by analyzing the frequency of the corresponding Ag-specific naive T cells in A2(+) and A2(-) individuals, as well as within CD4(+) and CD8(+) subsets. We were able to find a correlation between specific naive T cell frequency and peptide solvent accessibility and/or mobility for a subset of moderately prominent peptides. However, one single structural parameter of the pMHC complexes could not be identified to explain each peptide antigenicity. Enhanced pMHC antigenicity was associated with both highly biased TRAV usage, possibly reflecting favored interaction between particular pMHC complexes and germline TRAV loops, and peptide structural features allowing interactions with a broad range of permissive CDR3 loops. In this context of constrained TCR docking mode, an optimal peptide solvent exposed surface leading to an optimal complementarity with TCR interface may constitute one of the key features leading to high frequency of specific T cells. Altogether our results suggest that frequency of specific T cells depends on the fine-tuning of several parameters, the structural determinants governing TCR-pMHC interaction being just one of them. Copyright © 2014 by The American Association of Immunologists, Inc.

  18. DR3 regulation of apoptosis of naive T-lymphocytes in children with acute infectious mononucleosis.

    PubMed

    Filatova, Elena Nikolaevna; Anisenkova, Elena Viktorovna; Presnyakova, Nataliya Borisovna; Utkin, Oleg Vladimirovich

    2016-09-01

    Acute infectious mononucleosis (AIM) is a widespread viral disease that mostly affects children. Development of AIM is accompanied by a change in the ratio of immune cells. This is provided by means of different biological processes including the regulation of apoptosis of naive T-cells. One of the potential regulators of apoptosis of T-lymphocytes is a death receptor 3 (DR3). We have studied the role of DR3 in the regulation of apoptosis of naive CD4(+) (nTh) and CD8(+) (nCTL) T-cells in healthy children and children with AIM. In healthy children as well as in children with AIM, the activation of DR3 is accompanied by inhibition of apoptosis of nTh. In healthy children, the stimulation of DR3 resulted in the increase in apoptosis of nCTL. On the contrary, in children with AIM, the level of apoptosis of nCTL decreased after DR3 activation, which is a positive contribution to the antiviral immune response. In children with AIM, nCTL are characterized by reduced level of apoptosis as compared with healthy children. These results indicate that DR3 can be involved in the reduction of sensitivity of nCTL to apoptosis in children with AIM.

  19. Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia.

    PubMed

    Thakore, J H; Mann, J N; Vlahos, I; Martin, A; Reznek, R

    2002-01-01

    To investigate visceral fat distribution in patients with schizophrenia. Cross sectional study using CT scanning in patients with drug-naive and drug-free schizophrenia. Fifteen (13 men and two women) subjects with schizophrenia (mean age 33.7 y; mean body mass index (BMI)=26.7 kg/m(2)), and 15 age- and sex-matched controls (mean age 30.5 y; mean BMI=22.8 kg/(2)). Various fatness and fat distribution parameters (by CT scanning and anthropometry) and 16:00 h plasma cortisol. In comparison to controls, patients with schizophrenia had central obesity and had significantly higher levels of plasma cortisol. Furthermore, previous neuroleptic exposure did not appear to influence these findings as both drug-naive and drug-free patients had equally high levels of visceral fat deposition. Central obesity is a well recognized risk factor in developing certain general medical conditions. This study shows that patients with schizophrenia have increased intra-abdominal fat which may provide one explanation for why they die prematurely.

  20. Notch Signaling Regulates Antigen Sensitivity of Naive CD4+ T Cells by Tuning Co-stimulation

    PubMed Central

    Laky, Karen; Evans, Sharron; Perez-Diez, Ainhoa

    2015-01-01

    SUMMARY Adaptive immune responses begin when naive CD4+ T cells engage peptide+major histocompatibility complex class II and co-stimulatory molecules on antigen-presenting cells (APCs). Notch signaling can influence effector functions in differentiated CD4+ T helper and T regulatory cells. Whether and how ligand-induced Notch signaling influences the initial priming of CD4+ T cells has not been addressed. We have found that Delta Like Ligand 4 (DLL4)-induced Notch signaling potentiates phosphatidylinositol 3-OH kinase (PI3K)-dependent signaling downstream of the T cell receptor+CD28, allowing naive CD4+ T cells to respond to lower doses of antigen. In vitro, DLL4-deficient APCs were less efficient stimulators of CD4+ T cell activation, metabolism, proliferation, and cytokine secretion. With deletion of DLL4 from CD11c+ APCs in vivo, these deficits translated to an impaired ability to mount an effective CD4+-dependent anti-tumor response. These data implicate Notch signaling as an important regulator of adaptive immune responses. PMID:25607460

  1. Increased cerebellar-default-mode-network connectivity in drug-naive major depressive disorder at rest.

    PubMed

    Guo, Wenbin; Liu, Feng; Liu, Jianrong; Yu, Miaoyu; Zhang, Zhikun; Liu, Guiying; Xiao, Changqing; Zhao, Jingping

    2015-03-01

    The default-mode network (DMN) has been implicated in the neurobiology of major depressive disorder (MDD), and the cerebellum is suggested to be involved in high-order cognitive network such as the DMN. However, the specific contribution of the cerebellum to the DMN alterations remains equivocal. This study was conducted to examine the cerebellar-DMN connectivity in drug-naive MDD directly by using the cerebellum Crus I as seeds.Forty-four drug-naive MDD patients and 44 healthy controls participated in the resting-state scan. Functional connectivity (FC) was applied to analyze the images.Significantly increased FCs were observed between the right Crus I and the right inferior frontal cortex (orbital part)/superior temporal pole, bilateral MPFC (orbital part), and left middle temporal gyrus in the patients compared with the controls. There was a significantly positive correlation between the z values of the right Crus I-bilateral MPFC (orbital part) connectivity and the scores of Automatic Thoughts Questionnaire in the patients (r = 0.329, P = 0.029).The findings reveal that depressed patients have increased cerebellar-DMN connectivity with clinical significance, and thus highlight the contribution of the cerebellum to the DMN alterations in neurobiology of MDD.

  2. Ethanol-reinforced responding of naive rhesus monkeys: acquisition without induction procedures.

    PubMed

    Macenski, M J; Meisch, R A

    1992-01-01

    Rodents will typically consume greater amounts of low concentration ethanol (1-6%) than water. However, few primate oral self-administration studies have examined low ethanol concentrations. Additionally, there is a scarcity of data showing ethanol-maintained behavior without using induction procedures in either rats or primates. In this study, 14, free-feeding, naive, adult, male rhesus monkeys were given access to a 2% (w/v) ethanol solution and vehicle (tap water) during daily 3-hour sessions. Water was freely available between sessions. Liquids were available under a concurrent fixed-ratio four reinforcement schedule; thus, four responses (mouth-spout contacts) on either spout were immediately followed by the delivery of approximately 0.65 ml of liquid. In phase 1, tap water was available from both spouts. In phase 2, vehicle and a 2% ethanol solution were concurrently available. The 2% ethanol solution maintained considerably higher response rates than vehicle for 12 of 14 monkeys. In phase 3, food intake was limited. During this phase, the 2% ethanol solution maintained significantly higher response rates than vehicle for all monkeys. Additionally, during phase 3, ethanol intakes were greater than those in phase 2 for all monkeys. Central drug effects and taste factors are discussed. These results demonstrate that ethanol will serve as a reinforcer for naive rhesus monkeys in the absence of induction procedures.

  3. Multiple antigen-specific processing pathways for activating naive CD8+ T cells in vivo.

    PubMed

    Norbury, C C; Princiotta, M F; Bacik, I; Brutkiewicz, R R; Wood, P; Elliott, T; Bennink, J R; Yewdell, J W

    2001-04-01

    Current knowledge of the processing of viral Ags into MHC class I-associated ligands is based almost completely on in vitro studies using nonprofessional APCs (pAPCs). This is two steps removed from real immune responses to pathogens and vaccines, in which pAPCs activate naive CD8(+) T cells in vivo. Rational vaccine design requires answers to numerous questions surrounding the function of pAPCs in vivo, including their abilities to process and present peptides derived from endogenous and exogenous viral Ags. In the present study, we characterize the in vivo dependence of Ag presentation on the expression of TAP by testing the immunogenicity of model Ags synthesized by recombinant vaccinia viruses in TAP1(-/-) mice. We show that the efficiency of TAP-independent presentation in vitro correlates with TAP-independent activation of naive T cells in vivo and provide the first in vivo evidence for proteolytic processing of antigenic peptides in the secretory pathway. There was, however, a clear exception to this correlation; although the presentation of the minimal SIINFEKL determinant from chicken egg OVA in vitro was strictly TAP dependent, it was presented in a TAP-independent manner in vivo. In vivo presentation of the same peptide from a fusion protein retained its TAP dependence. These results show that determinant-specific processing pathways exist in vivo for the generation of antiviral T cell responses. We present additional findings that point to cross-priming as the likely mechanism for these protein-specific differences.

  4. Abnormal Default-Mode Network Homogeneity in First-Episode, Drug-Naive Major Depressive Disorder

    PubMed Central

    Guo, Wenbin; Liu, Feng; Zhang, Jian; Zhang, Zhikun; Yu, Liuyu; Liu, Jianrong; Chen, Huafu; Xiao, Changqing

    2014-01-01

    Background Default mode network (DMN) is one of the most commonly recognized resting-state networks in major depressive disorder (MDD). However, the homogeneity of this network in MDD is poorly understood. As such, this study was conducted to determine whether or not an abnormal network homogeneity (NH) of DMN is observed in patients with first-episode and drug-naive MDD. Methods Twenty-four first-episode drug-naive patients with MDD and twenty-four healthy control subjects participated in the study. NH and independent component analysis (ICA) methods were used to analyze data. Results Depressed patients exhibited a significantly increased NH in the left dorsal medial prefrontal cortex (MPFC) and decreased NH in the right inferior temporal gyrus (ITG) compared with the healthy control subjects. Receiver operating characteristic curves (ROC) were analyzed and results revealed that the NH values of MPFC and ITG could be applied as candidate markers with relatively high sensitivity and specificity to distinguish patients from healthy control subjects. No correlation was observed between the NH values of the two regions and clinical variables. Conclusions Our findings suggested that an abnormal DMN homogeneity could be observed in MDD, which highlight the importance of the DMN in the pathophysiology of MDD. PMID:24609111

  5. Abnormal default-mode network homogeneity in first-episode, drug-naive schizophrenia at rest.

    PubMed

    Guo, Wenbin; Yao, Dapeng; Jiang, Jiajing; Su, Qinji; Zhang, Zhikun; Zhang, Jian; Yu, Liuyu; Xiao, Changqing

    2014-03-03

    Dysconnectivity hypothesis posits that schizophrenia relates to abnormal resting-state connectivity within the default-mode network (DMN) and this aberrant connectivity is considered as contribution of difficulties in self-referential and introspective processing. However, little is known about the alterations of the network homogeneity (NH) of the DMN in schizophrenia. In the present study, we used an automatic NH method to investigate the NH of the DMN in schizophrenia patients at rest. Forty-nine first-episode, drug-naive schizophrenia patients and 50 age-, gender-, and education-matched healthy controls underwent a resting-state functional magnetic resonance imaging (fMRI). An automated NH approach was used to analyze the data. Patients exhibited lower NH than controls in the left medial prefrontal cortex (MPFC) and the right middle temporal gyrus (MTG). Significantly higher NH values in the left posterior cingulate cortex (PCC) and the right cerebellum Crus I were found in the patient group than in the control group. No significant correlation was found between abnormal NH values and Positive and Negative Symptom Scale (PANSS) scores, duration of untreated psychosis (DUP), age or years of education in the patient group. Our findings suggest that abnormal NH of the DMN exists in first-episode, drug-naive schizophrenia and further highlight the importance of the DMN in the pathophysiology of schizophrenia. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study.

    PubMed

    Massard, Christophe; Penttinen, Heidi M; Vjaters, Egils; Bono, Petri; Lietuvietis, Vilnis; Tammela, Teuvo L; Vuorela, Annamari; Nykänen, Pirjo; Pohjanjousi, Pasi; Snapir, Amir; Fizazi, Karim

    2016-05-01

    ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600mg twice daily ODM-201 taken with food in capsules. We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. The capsule:TabA ratio of area under the concentration-time curve from time zero to the last sample at 48h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule:TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (≥50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n=4 [13%]) and nausea (n=4 [13%]). The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600mg twice daily in patients with non-mCRPC is ongoing. Copyright © 2015 European Association

  7. Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis.

    PubMed

    Singh, Jasvinder A; Hossain, Alomgir; Mudano, Amy S; Tanjong Ghogomu, Elizabeth; Suarez-Almazor, Maria E; Buchbinder, Rachelle; Maxwell, Lara J; Tugwell, Peter; Wells, George A

    2017-05-08

    Biologic disease-modifying anti-rheumatic drugs (biologics) are highly effective in treating rheumatoid arthritis (RA), however there are few head-to-head biologic comparison studies. We performed a systematic review, a standard meta-analysis and a network meta-analysis (NMA) to update the 2009 Cochrane Overview. This review is focused on the adults with RA who are naive to methotrexate (MTX) that is, receiving their first disease-modifying agent. To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (methotrexate (MTX)/other DMARDs) in people with RA who are naive to methotrexate. In June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE and Embase; and trials registers. We used standard Cochrane methods. We calculated odds ratios (OR) and mean differences (MD) along with 95% confidence intervals (CI) for traditional meta-analyses and 95% credible intervals (CrI) using a Bayesian mixed treatment comparisons approach for network meta-analysis (NMA). We converted OR to risk ratios (RR) for ease of interpretation. We also present results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial or harmful outcome (NNTB/H). Nineteen RCTs with 6485 participants met inclusion criteria (including five studies from the original 2009 review), and data were available for four TNF biologics (adalimumab (six studies; 1851 participants), etanercept (three studies; 678 participants), golimumab (one study; 637 participants) and infliximab (seven studies; 1363 participants)) and two non-TNF biologics (abatacept (one study; 509 participants) and rituximab (one study; 748 participants)).Less than 50% of the studies were judged to be at low risk of bias for allocation sequence generation, allocation concealment and blinding, 21% were at low risk for selective

  8. Prevalence and response to antiretroviral therapy of non-B subtypes of HIV in antiretroviral-naive individuals in British Columbia.

    PubMed

    Alexander, Christopher S; Montessori, Valentina; Wynhoven, Brian; Dong, Winnie; Chan, Keith; O'Shaughnessy, Michael V; Mo, Theresa; Piaseczny, Magda; Montaner, Julio S G; Harrigan, P Richard

    2002-03-01

    In North America, the B subtype of the major group (M) of HIV-1 predominates. Phylogenetic analysis of HIV reverse transcriptase and protease sequences isolated from 479 therapy-naive patients, first seeking treatment in British Columbia between June 1997 and August 1998, revealed a prevalence of 4.4% non-B virus. A range of different subtypes was identified, including one subtype A, 11 C, two D, five CRF01_AE, and one sample that could not be reliably subtyped. Baseline CD4 courts were significantly lower in individuals harbouring the non-B subtypes (P = 0.02), but baseline viral loads were similar (P = 0.80). In this study, individuals infected with non-B variants did not have a significantly different virological response to therapy after up to 18 months.

  9. Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes.

    PubMed

    Panagoulias, Ioannis; Georgakopoulos, Tassos; Aggeletopoulou, Ioanna; Agelopoulos, Marios; Thanos, Dimitris; Mouzaki, Athanasia

    2016-12-23

    IL-2 is the first cytokine produced when naive T helper (Th) cells are activated and differentiate into dividing pre-Th0 proliferating precursors. IL-2 expression is blocked in naive, but not activated or memory, Th cells by the transcription factor Ets-2 that binds to the antigen receptor response element (ARRE)-2 of the proximal IL-2 promoter. Ets-2 acts as an independent preinduction repressor in naive Th cells and does not interact physically with the transcription factor NFAT (nuclear factor of activated T-cells) that binds to the ARRE-2 in activated Th cells. In naive Th cells, Ets-2 mRNA expression, Ets-2 protein levels, and Ets-2 binding to ARRE-2 decrease upon cell activation followed by the concomitant expression of IL-2. Cyclosporine A stabilizes Ets-2 mRNA and protein when the cells are activated. Ets-2 silences directly constitutive or induced IL-2 expression through the ARRE-2. Conversely, Ets-2 silencing allows for constitutive IL-2 expression in unstimulated cells. Ets-2 binding to ARRE-2 in chromatin is stronger in naive compared with activated or memory Th cells; in the latter, Ets-2 participates in a change of the IL-2 promoter architecture, possibly to facilitate a quick response when the cells re-encounter antigen. We propose that Ets-2 expression and protein binding to the ARRE-2 of the IL-2 promoter are part of a strictly regulated process that results in a physiological transition of naive Th cells to Th0 cells upon antigenic stimulation. Malfunction of such a repression mechanism at the molecular level could lead to a disturbance of later events in Th cell plasticity, leading to autoimmune diseases or other pathological conditions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. First-line non-cytotoxic therapy in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of 10 randomised clinical trials.

    PubMed

    Poorthuis, Michiel H F; Vernooij, Robin W M; van Moorselaar, R Jeroen A; de Reijke, Theo M

    2017-01-06

    The aim of this study is to systematically evaluate all available treatment options in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, EMBASE, and the Cochrane libraries up to 1 March 2016 for peer-reviewed publications on randomised clinical trials (RCTs). RCTs were included if progression-free survival (PFS), overall survival (OS), quality of life (QoL), or adverse events (AEs) were quantitatively evaluated. We assessed the risk of bias with the Cochrane Collaboration's tool and graded the evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group's approach. We included 25 articles, reporting on 10 unique RCTs describing seven different comparisons. In one RCT, a prolonged OS and PFS (high quality) were found with abiraterone and prednisone compared to placebo plus prednisone. In one RCT, a prolonged OS and PFS (high quality) were found with enzalutamide compared to placebo. In two RCTs, a prolonged OS (high and moderate quality) was found with (223) radium compared to placebo, but its effect on PFS is unknown. In three RCTs, a prolonged OS (moderate quality) was found with sipuleucel-T compared to placebo, but no prolonged PFS (low quality). In one RCT a prolonged PFS (high quality) was found with orteronel compared to placebo, but no prolonged OS (moderate quality). In one RCT, a prolonged OS (moderate quality) was found with bicalutamide compared to placebo, but its effect on PFS is unknown. In one RCT, a prolonged PFS (high quality) was found with enzalutamide compared to bicalutamide, but its effect on OS is unknown. The best evidence was found for abiraterone and enzalutamide for effective prolongation of OS and PFS to treat chemotherapy-naive patients with mCRPC. However, taking both QoL and AEs into consideration, other treatment modalities could be considered for individual patients.

  11. Genetic background for development of resistance mutations within the HCV NS3 protease-helicase in direct acting antiviral naive patients.

    PubMed

    Grammatikos, Georgios; Jabara, Cassandra B; Ahmad, Monazza Q; Herrmann, Eva; Zeuzem, Stefan; Welsch, Christoph

    2014-01-01

    Subtype-specific response to ketoamide NS3 protease inhibitors is observed in patients with genotype 1 HCV infection. Whether the genetic diversity in the molecular target site of ketoamide compounds prior to treatment plays a role for resistance development and lower treatment response in subtype 1a is poorly understood. Using a public database, we retrieved worldwide NS3-sequence information of 581 dominant HCV variants from patients chronically infected with genotype 1 that were naive to direct-acting antivirals. We applied measures from phylogeny to study the pretreatment genetic diversity and complexity in NS3 full-length as well as the protease-helicase interface for subtype 1a and 1b, respectively. We found polymorphic sites more frequently in variants of subtype 1b than subtype 1a. Moreover, a significantly higher number of synonymous and non-synonymous substitutions were found in subtype 1b (P<0.001). Transitions were more frequent than transversions, most notably in subtype 1a, whereas the higher average number of nucleotide differences per site was found in subtype 1b. A comparison of NS3 full-length versus domain interface residues for both subtypes revealed a significant difference only for synonymous substitutions (P<0.001). Our study suggests that the nature of a mismatch nucleotide exchange in NS3 may constitute an important viral genetic factor for response to ketoamide protease inhibitors. Our analysis further suggests that the subtype-specific pace of resistance development seen in clinical trials is not primarily related to differences in genetic diversity in the direct acting antiviral naive population, but rather appears to correlate with the natural frequency of transition mutations characteristic of each subtype.

  12. Impact of an educational module in antidepressant-naive patients prescribed antidepressants for depression: Pilot, proof-of-concept, randomized controlled trial

    PubMed Central

    John, Annie P.; Singh, Nagendra Madan; Nagarajaiah; Andrade, Chittaranjan

    2016-01-01

    Background: Patients are educated about their illness and its treatment at the time of diagnosis. However, little is known about how much of this education is retained and how it influences knowledge about, attitudes toward, and experiences with medication in antidepressant-naive patients with depression. Methods: Antidepressant-naive outpatients with International Classification of Diseases-10 dysthymia or mild to moderate depression, who were advised antidepressant monotherapy, were randomized to control (n = 22) or intervention (n = 17) groups. Control patients received treatment as usual, and intervention patients received, in addition, a face-to-face, individualized, 10-min education session about the nature of depression, antidepressant treatment, efficacy and adverse effects of the prescribed drug, and plan of management. Knowledge about the illness and its treatment were assessed at baseline (before the educational intervention) and 6 weeks later. At follow-up, experiences with treatment were also evaluated. The study was double-blind. Results: At baseline, patients had poor knowledge about their illness and its treatment (most patients could not even name their diagnosis); however, few held unfavorable attitudes toward their prescribed medicines. At follow-up, there were modest improvements in both sets of outcomes. There were no differences between intervention and control groups in knowledge and attitude outcomes at baseline and end-point. Drug compliance did not differ between groups. However, importantly, intervention patients experienced a significantly larger number of adverse events than controls (mean, 3.5 vs. 1.7, respectively). Conclusions: For ethical reasons, patients need to be educated about their illness and its treatment. However, such education may be a two-edged sword, with an increased nocebo effect as the most salient consequence. Failure to identify benefits in our study may have been the result of a Type 2 error. This study provides a

  13. Reduced error signalling in medication-naive children with ADHD: associations with behavioural variability and post-error adaptations

    PubMed Central

    Plessen, Kerstin J.; Allen, Elena A.; Eichele, Heike; van Wageningen, Heidi; Høvik, Marie Farstad; Sørensen, Lin; Worren, Marius Kalsås; Hugdahl, Kenneth; Eichele, Tom

    2016-01-01

    Background We examined the blood-oxygen level–dependent (BOLD) activation in brain regions that signal errors and their association with intraindividual behavioural variability and adaptation to errors in children with attention-deficit/hyperactivity disorder (ADHD). Methods We acquired functional MRI data during a Flanker task in medication-naive children with ADHD and healthy controls aged 8–12 years and analyzed the data using independent component analysis. For components corresponding to performance monitoring networks, we compared activations across groups and conditions and correlated them with reaction times (RT). Additionally, we analyzed post-error adaptations in behaviour and motor component activations. Results We included 25 children with ADHD and 29 controls in our analysis. Children with ADHD displayed reduced activation to errors in cingulo-opercular regions and higher RT variability, but no differences of interference control. Larger BOLD amplitude to error trials significantly predicted reduced RT variability across all participants. Neither group showed evidence of post-error response slowing; however, post-error adaptation in motor networks was significantly reduced in children with ADHD. This adaptation was inversely related to activation of the right-lateralized ventral attention network (VAN) on error trials and to task-driven connectivity between the cingulo-opercular system and the VAN. Limitations Our study was limited by the modest sample size and imperfect matching across groups. Conclusion Our findings show a deficit in cingulo-opercular activation in children with ADHD that could relate to reduced signalling for errors. Moreover, the reduced orienting of the VAN signal may mediate deficient post-error motor adaptions. Pinpointing general performance monitoring problems to specific brain regions and operations in error processing may help to guide the targets of future treatments for ADHD. PMID:26441332

  14. Neuroanatomical Maps of Psychosis Onset: Voxel-wise Meta-Analysis of Antipsychotic-Naive VBM Studies

    PubMed Central

    Fusar-Poli, Paolo; Radua, Joaquim; McGuire, Philip; Borgwardt, Stefan

    2012-01-01

    Background: Despite impressive advancements in early interventions in psychosis, there is an urgent need of robust neurobiological markers to improve the predictive value of psychosis transition. Available structural imaging literature in the field is undermined by several methodological caveats and a number of confounders such as exposure to antipsychotic treatment. Methods: Fourteen voxel-based morphometry studies of antipsychotic-naive subjects at enhanced clinical risk for psychosis (high risk [HR]) or experiencing a first-episode psychosis (FEP) were included. Formal meta-analysis of effect sizes and “signed differential mapping” voxel-based meta-analysis were combined to control the results for sample sizes, strength of individual findings, and confounding variables. Results: Formal effect size meta-analysis indicated consistent gray matter (GM) reductions both in subjects at enhanced clinical risk for psychosis and in first-episode subjects when compared with control groups. Voxel-based meta-analysis showed GM reductions in the temporal, limbic prefrontal cortex within the HR group and in the temporal insular cortex and cerebellum within the FEP group. Psychosis onset was characterized by GM decreases in temporal, anterior cingulate, cerebellar, and insular regions. GM alterations in the temporal regions directly related to severity of psychotic symptoms. There was no publication bias. Heterogeneity across studies was low. Sensitivity analyses confirmed robustness of the above results. Conclusions: Vulnerability to psychosis is associated with consistent GM decreases in prefrontal and temporolimbic areas. The onset of full disease is accompanied by temporoinsular, anterior cingulate, and cerebellar GM reductions. Neuroanatomical alterations in temporal regions may underlie the clinical onset of psychotic symptoms. PMID:22080494

  15. Neural Correlates of Aggression in Medication-Naive Children with ADHD: Multivariate Analysis of Morphometry and Tractography.

    PubMed

    Cha, Jiook; Fekete, Tomer; Siciliano, Francesco; Biezonski, Dominik; Greenhill, Laurence; Pliszka, Steven R; Blader, Joseph C; Roy, Amy Krain; Leibenluft, Ellen; Posner, Jonathan

    2015-06-01

    Aggression is widely observed in children with attention deficit/hyperactivity disorder (ADHD) and has been frequently linked to frustration or the unsatisfied anticipation of reward. Although animal studies and human functional neuroimaging implicate altered reward processing in aggressive behaviors, no previous studies have documented the relationship between fronto-accumbal circuitry-a critical cortical pathway to subcortical limbic regions-and aggression in medication-naive children with ADHD. To address this, we collected behavioral measures and parental reports of aggression and impulsivity, as well as structural and diffusion MRI, from 30 children with ADHD and 31 healthy controls (HC) (mean age, 10±2.1 SD). Using grey matter morphometry and probabilistic tractography combined with multivariate statistical modeling (partial least squares regression and support vector regression), we identified anomalies within the fronto-accumbal circuit in childhood ADHD, which were associated with increased aggression. More specifically, children with ADHD showed reduced right accumbal volumes and frontal-accumbal white matter connectivity compared with HC. The magnitude of the accumbal volume reductions within the ADHD group was significantly correlated with increased aggression, an effect mediated by the relationship between the accumbal volume and impulsivity. Furthermore, aggression, but not impulsivity, was significantly explained by multivariate measures of fronto-accumbal white matter connectivity and cortical thickness within the orbitofrontal cortex. Our multi-modal imaging, combined with multivariate statistical modeling, indicates that the fronto-accumbal circuit is an important substrate of aggression in children with ADHD. These findings suggest that strategies aimed at probing the fronto-accumbal circuit may be beneficial for the treatment of aggressive behaviors in childhood ADHD.

  16. Effects of phytase supplementation in broiler diets on a natural Eimeria challenge in naive and vaccinated birds.

    PubMed

    Shaw, A L; van Ginkel, F W; Macklin, K S; Blake, J P

    2011-04-01

    Our study was conducted to determine the effects of dietary phytase on a natural Eimeria challenge in naive and vaccinated broilers. Prior to the experiment the litter was seeded with Eimeria by orally infecting 10-d-old chicks with a cocktail containing 100,000 and 5,000 sporulated Eimeria acervulina and Eimeria tenella oocysts, respectively. Straight-run broiler chicks were placed across 48 floor pens on fresh or seeded litter. Eight treatment combinations were created to include 2 dietary Ca-nonphytate P (npP) levels [0.9% Ca, 0.45% npP; 0.7% Ca, 0.35% npP, 500 phytase units of Optiphos phytase (JBS United, Sheridan, IN)], unchallenged versus challenged, and unvaccinated versus vaccinated groups of chicks. Body weights and feed consumption (FC) were recorded on d 10, 18, and 21. A total of 10 birds/treatment were killed on d 10 and 18 to obtain tissue samples from the duodena and ceca for lesion scoring and cytokine response measurement. At 21 d of age, the left tibia was removed from 18 birds/treatment to assess bone strength. Body weight, FC, and bone strength were unaffected (P > 0.05) by diet or vaccination. By d 21, birds exposed to coccidia had lower FC (P < 0.01), higher feed conversion (P < 0.001), and decreased bone strength (P < 0.01) compared with those not challenged. Regardless of treatment, gross and microscopic scoring of the intestines showed few differences (P > 0.05). Expression of interferon-γ did not differ (P > 0.05) in the duodena or ceca at either time point. The IL-17 gene expression was increased (P < 0.05) in phytase-supplemented, vaccinated, or challenged birds by 18 d of age, with significant interactions (P < 0.05) occurring between birds challenged and fed the marginal diet or vaccinated. Phytase supplementation was unable to provide additional benefits to performance or P utilization in birds vaccinated, subjected to a coccidiosis infection, or both. Based on cytokine production in the intestinal tract on d 10 and 18 postchallenge

  17. Schistosoma mansoni: migration potential of normal and radiation attenuated parasites in naive guinea pigs

    SciTech Connect

    Kamiya, H.; McLaren, D.J.

    1987-02-01

    Compressed tissue autoradiography using (75Se)selenomethionine labelled parasites has been used to investigate the migration potential of normal and radiation attenuated cercariae of Schistosoma mansoni in naive guinea pigs. By Day 14 after infection. 44% of normal parasites were detected as reduced silver foci in the liver; this value corresponded well with the number of liver parasites recovered by retrograde perfusion of the hepatic portal system on Day 42 (42% of the challenge). In contrast, cercariae subjected to 50 krad of gamma irradiation failed to migrate out of the skin. The migration capacity of 20 krad irradiated parasites was less severely affected in that about half of the challenge parasites reached the lungs, but virtually none moved to the liver. These data are discussed in relation to the kinetics of immunity induced in guinea pigs by infection or vaccination with normal or radiation attenuated parasites.

  18. The influence of naive causal theories on lay concepts of mental illness.

    PubMed

    Kim, Nancy S; Ahn, Woo-Kyoung

    2002-01-01

    Two experiments, incorporating both real-life (Experiment 1) and artificial (Experiment 2) stimuli, demonstrated that lay concepts of mental disorders can be reliably predicted from subjects' naive causal theories about those disorders. Symptoms that are deeper causes (X, where X causes Y, which causes Z) are more important in lay concepts than intermediate causes (Y), which in turn are more important than terminal effects (Z). In addition, symptoms that cause or are caused by other symptoms are more important in lay concepts than symptoms not participating in any causal relationships. Implications of these results for current models of categorization and for research on lay theories of mental disorders are discussed, and future directions for research are suggested.

  19. Targeted Help for Spoken Dialogue Systems: Intelligent Feedback Improves Naive Users' Performance

    NASA Technical Reports Server (NTRS)

    Hockey, Beth Ann; Lemon, Oliver; Campana, Ellen; Hiatt, Laura; Aist, Gregory; Hieronymous, Jim; Gruenstein, Alexander; Dowding, John

    2003-01-01

    We present experimental evidence that providing naive users of a spoken dialogue system with immediate help messages related to their out-of-coverage utterances improves their success in using the system. A grammar-based recognizer and a Statistical Language Model (SLM) recognizer are run simultaneously. If the grammar-based recognizer suceeds, the less accurate SLM recognizer hypothesis is not used. When the grammar-based recognizer fails and the SLM recognizer produces a recognition hypothesis, this result is used by the Targeted Help agent to give the user feed-back on what was recognized, a diagnosis of what was problematic about the utterance, and a related in-coverage example. The in-coverage example is intended to encourage alignment between user inputs and the language model of the system. We report on controlled experiments on a spoken dialogue system for command and control of a simulated robotic helicopter.

  20. A Public Database of Memory and Naive B-Cell Receptor Sequences.

    PubMed

    DeWitt, William S; Lindau, Paul; Snyder, Thomas M; Sherwood, Anna M; Vignali, Marissa; Carlson, Christopher S; Greenberg, Philip D; Duerkopp, Natalie; Emerson, Ryan O; Robins, Harlan S

    2016-01-01

    The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics.

  1. A Public Database of Memory and Naive B-Cell Receptor Sequences

    PubMed Central

    Sherwood, Anna M.; Vignali, Marissa; Carlson, Christopher S.; Greenberg, Philip D.; Duerkopp, Natalie; Emerson, Ryan O.; Robins, Harlan S.

    2016-01-01

    The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics. PMID:27513338

  2. Elicitation from virus-naive individuals of cytotoxic T lymphocytes directed against conserved HIV-1 epitopes

    PubMed Central

    Reche, Pedro A; Keskin, Derin B; Hussey, Rebecca E; Ancuta, Petronela; Gabuzda, Dana; Reinherz, Ellis L

    2006-01-01

    Cytotoxic T lymphocytes (CTL) protect against viruses including HIV-1. To avoid viral escape mutants that thwart immunity, we chose 25 CTL epitopes defined in the context of natural infection with functional and/or structural constraints that maintain sequence conservation. By combining HLA binding predictions with knowledge concerning HLA allele frequencies, a metric estimating population protection coverage (PPC) was computed and epitope pools assembled. Strikingly, only a minority of immunocompetent HIV-1 infected individuals responds to pools with PPC >95%. In contrast, virus-naive individuals uniformly expand IFNγ producing cells and mount anti-HIV-1 cytolytic activity. This disparity suggests a vaccine design paradigm shift from infected to normal subjects. PMID:16674822

  3. Transmitted drug resistance to rilpivirine in newly diagnosed antiretroviral naive adults.

    PubMed

    Alvarez, M; Monge, S; Chueca, N; Guillot, V; Viciana, P; Anta, L; Rodriguez, C; Gomez-Sirvent, J L; Navarro, G; de los Santos, I; Moreno, S; García, F

    2015-01-01

    We characterized transmitted drug resistance to rilpivirine and the predicted efficacy of first-line rilpivirine-containing regimens in antiretroviral-naive Spanish patients. International Antiviral Society-USA mutations were detected in 138 of 2781 patients (4.9%), E138A (3.4%) being the most prevalent. Using the Stanford Algorithm, 121 patients (4.4%) showed low-level or intermediate resistance. No differences in the predicted efficacy of first-line non-nucleoside reverse transcriptase inhibitor-based regimens were observed. As rilpivirine becomes more widely used in clinical practice, the evolution of its transmitted drug resistance will need to be monitored. In addition, the exact role of E138A singletons on rilpivirine activity as part of first-line regimens merits further evaluation. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  4. [An accurate approach to hyperspectral mineral identification based on naive bayesian classification model].

    PubMed

    He, Jin-Xin; Chen, Sheng-Bo; Wang, Yang; Wu, Yan-Fan

    2014-02-01

    The spectral absorption features are very similar between some minerals, especially hydrothermal alteration minerals related to mineralization, and they are also influenced by other factors such as spectral mixture. As a result, many of the spectral identification approaches for the minerals with similar spectral absorption features are prone to confusion and misjudgment. Therefore, to solve the phenomenon of "same mineral has different spectrums, and same spectrum belongs to different minerals", this paper proposes an accurate approach to hyperspectral mineral identification based on naive bayesian classification model. By testing and analyzing muscovite and kaolinite, the two typical alteration minerals, and comparing this approach with spectral angle matching, binary encoding and spectral feature fitting, the three popular spectral identification approaches, the results show that this approach can make more obvious differences among different minerals having similar spectrums, and has higher classification accuracy, since it is based on the position of absorption feature, absorption depth and the slope of continuum.

  5. Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

    PubMed Central

    DeKosky, Brandon J.; Lungu, Oana I.; Park, Daechan; Johnson, Erik L.; Charab, Wissam; Chrysostomou, Constantine; Kuroda, Daisuke; Ellington, Andrew D.; Ippolito, Gregory C.; Gray, Jeffrey J.; Georgiou, George

    2016-01-01

    Elucidating how antigen exposure and selection shape the human antibody repertoire is fundamental to our understanding of B-cell immunity. We sequenced the paired heavy- and light-chain variable regions (VH and VL, respectively) from large populations of single B cells combined with computational modeling of antibody structures to evaluate sequence and structural features of human antibody repertoires at unprecedented depth. Analysis of a dataset comprising 55,000 antibody clusters from CD19+CD20+CD27− IgM-naive B cells, >120,000 antibody clusters from CD19+CD20+CD27+ antigen–experienced B cells, and >2,000 RosettaAntibody-predicted structural models across three healthy donors led to a number of key findings: (i) VH and VL gene sequences pair in a combinatorial fashion without detectable pairing restrictions at the population level; (ii) certain VH:VL gene pairs were significantly enriched or depleted in the antigen-experienced repertoire relative to the naive repertoire; (iii) antigen selection increased antibody paratope net charge and solvent-accessible surface area; and (iv) public heavy-chain third complementarity-determining region (CDR-H3) antibodies in the antigen-experienced repertoire showed signs of convergent paired light-chain genetic signatures, including shared light-chain third complementarity-determining region (CDR-L3) amino acid sequences and/or Vκ,λ–Jκ,λ genes. The data reported here address several longstanding questions regarding antibody repertoire selection and development and provide a benchmark for future repertoire-scale analyses of antibody responses to vaccination and disease. PMID:27114511

  6. Short communication: Transmitted HIV drug resistance in antiretroviral-naive pregnant women in north central Nigeria.

    PubMed

    Imade, Godwin E; Sagay, Atiene S; Chaplin, Beth; Chebu, Philippe; Musa, Jonah; Okpokwu, Jonathan; Hamel, Donald J; Pam, Ishaya C; Agbaji, Oche; Samuels, Jay; Meloni, Seema; Sankale, Jean-Louis; Okonkwo, Prosper; Kanki, Phyllis

    2014-02-01

    The World Health Organization (WHO) recommends periodic surveillance of transmitted drug resistance (TDR) in communities in which antiretroviral therapy (ART) has been scaled-up for greater than 3 years. We conducted a survey of TDR mutations among newly detected HIV-infected antiretroviral (ARV)-naive pregnant women. From May 2010 to March 2012, 38 ARV-naive pregnant women were recruited in three hospitals in Jos, Plateau state, north central Nigeria. Eligible subjects were recruited using a modified version of the binomial sequential sampling technique recommended by WHO. HIV-1 genotyping was performed and HIV-1 drug resistance mutations were characterized according to the WHO 2009 surveillance drug resistance mutation (SDRM) list. HIV subtypes were determined by phylogenetic analysis. The women's median age was 25.5 years; the median CD4(+) cell count was 317 cells/μl and the median viral load of 16 was 261 copies/ml. Of the 38 samples tested, 34 (89%) were successfully genotyped. The SDRM rate was <5% for all ART drug classes, with 1/34 (2.9%) for NRTIs/NNRTIs and none for protease inhibitors 0/31 (0%). The specific SDRMs detected were M41L for nucleoside reverse transcriptase inhibitors (NRTIs) and G190A for nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIV-1 subtypes detected were CRF02_AG (38.2%), G' (41.2%), G (14.7%), CRF06-CPX (2.9%), and a unique AG recombinant form (2.9%). The single ARV-native pregnant woman with SDRMs was infected with HIV-1 subtype G'. Access to ART has been available in the Jos area for over 8 years. The prevalence of TDR lower than 5% suggests proper ART administration, although continued surveillance is warranted.

  7. Short Communication: Transmitted HIV Drug Resistance in Antiretroviral-Naive Pregnant Women in North Central Nigeria

    PubMed Central

    Sagay, Atiene S.; Chaplin, Beth; Chebu, Philippe; Musa, Jonah; Okpokwu, Jonathan; Hamel, Donald J.; Pam, Ishaya C.; Agbaji, Oche; Samuels, Jay; Meloni, Seema; Sankale, Jean-Louis; Okonkwo, Prosper; Kanki, Phyllis

    2014-01-01

    Abstract The World Health Organization (WHO) recommends periodic surveillance of transmitted drug resistance (TDR) in communities in which antiretroviral therapy (ART) has been scaled-up for greater than 3 years. We conducted a survey of TDR mutations among newly detected HIV-infected antiretroviral (ARV)-naive pregnant women. From May 2010 to March 2012, 38 ARV-naive pregnant women were recruited in three hospitals in Jos, Plateau state, north central Nigeria. Eligible subjects were recruited using a modified version of the binomial sequential sampling technique recommended by WHO. HIV-1 genotyping was performed and HIV-1 drug resistance mutations were characterized according to the WHO 2009 surveillance drug resistance mutation (SDRM) list. HIV subtypes were determined by phylogenetic analysis. The women's median age was 25.5 years; the median CD4+ cell count was 317 cells/μl and the median viral load of 16 was 261 copies/ml. Of the 38 samples tested, 34 (89%) were successfully genotyped. The SDRM rate was <5% for all ART drug classes, with 1/34 (2.9%) for NRTIs/NNRTIs and none for protease inhibitors 0/31 (0%). The specific SDRMs detected were M41L for nucleoside reverse transcriptase inhibitors (NRTIs) and G190A for nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIV-1 subtypes detected were CRF02_AG (38.2%), G′ (41.2%), G (14.7%), CRF06-CPX (2.9%), and a unique AG recombinant form (2.9%). The single ARV-native pregnant woman with SDRMs was infected with HIV-1 subtype G′. Access to ART has been available in the Jos area for over 8 years. The prevalence of TDR lower than 5% suggests proper ART administration, although continued surveillance is warranted. PMID:24164431

  8. Visualizing Non Infectious and Infectious Anopheles gambiae Blood Feedings in Naive and Saliva-Immunized Mice

    PubMed Central

    Choumet, Valerie; Attout, Tarik; Chartier, Loïc; Khun, Huot; Sautereau, Jean; Robbe-Vincent, Annie; Brey, Paul; Huerre, Michel; Bain, Odile

    2012-01-01

    Background Anopheles gambiae is a major vector of malaria and lymphatic filariasis. The arthropod-host interactions occurring at the skin interface are complex and dynamic. We used a global approach to describe the interaction between the mosquito (infected or uninfected) and the skin of mammals during blood feeding. Methods Intravital video microscopy was used to characterize several features during blood feeding. The deposition and movement of Plasmodium berghei sporozoites in the dermis were also observed. We also used histological techniques to analyze the impact of infected and uninfected feedings on the skin cell response in naive mice. Results The mouthparts were highly mobile within the skin during the probing phase. Probing time increased with mosquito age, with possible effects on pathogen transmission. Repletion was achieved by capillary feeding. The presence of sporozoites in the salivary glands modified the behavior of the mosquitoes, with infected females tending to probe more than uninfected females (86% versus 44%). A white area around the tip of the proboscis was observed when the mosquitoes fed on blood from the vessels of mice immunized with saliva. Mosquito feedings elicited an acute inflammatory response in naive mice that peaked three hours after the bite. Polynuclear and mast cells were associated with saliva deposits. We describe the first visualization of saliva in the skin by immunohistochemistry (IHC) with antibodies directed against saliva. Both saliva deposits and sporozoites were detected in the skin for up to 18 h after the bite. Conclusion This study, in which we visualized the probing and engorgement phases of Anopheles gambiae blood meals, provides precise information about the behavior of the insect as a function of its infection status and the presence or absence of anti-saliva antibodies. It also provides insight into the possible consequences of the inflammatory reaction for blood feeding and pathogen transmission. PMID

  9. Divergent responses of exposed and naive Pacific tree frog tadpoles to invasive predatory crayfish.

    PubMed

    Pease, Katherine M; Wayne, Robert K

    2014-01-01

    Invasive predators can devastate native species and ecosystems. However, native species may be able to coexist with invasive predators through a variety of mechanisms, such as changes in morphology or behavior due to a plastic response or selection on fixed anti-predator traits. We examined whether exposed and naive populations of Pacific tree frog tadpoles (Pseudacris regilla) display divergent morphological and behavioral traits in response to the invasive predatory red swamp crayfish (Procambarus clarkii). Tadpoles were collected from three study streams with and three without crayfish, in the Santa Monica Mountains of Southern California. We analyzed tadpole morphology and tested anti-predator behavior and survival in the laboratory. Tadpoles from streams with crayfish had shallower, narrower tails than tadpoles from streams without crayfish. Tadpoles from streams with and without crayfish were less active after exposure to crayfish chemical cues. The divergent morphology of naive and exposed tadpoles is consistent with tadpoles exhibiting a plastic response to crayfish or undergoing selection from crayfish predation. In laboratory predation experiments, we found no difference in survival between tadpoles from streams with and without crayfish but tadpoles that survived predation had deeper tail muscles than those that were killed or injured. Our results suggest that deeper tails are advantageous in the presence of crayfish, yet tadpoles from crayfish streams had shallower tails than those from crayfish-free streams. Shallower tails may have an alternative unmeasured advantage or there may be a physiological constraint to developing deeper tails in the wild. These results highlight the ability of a native frog to respond to an invasive predatory crayfish, potentially allowing for coexistence.

  10. Which thoughts can kill a boxer? naive theories about cognitive and emotional antecedents of suicide.

    PubMed

    Spörrle, Matthias; Försterling, Friedrich

    2007-12-01

    We investigated naive theories regarding the association among beliefs, emotions and behaviours to test Rational Emotive Behaviour Therapy's (REBT) assumption that rational cognitions and adaptive emotions lead to functional behaviours whereas irrational cognitions and maladaptive emotions trigger dysfunctional reactions. We applied an experimental between-subjects design. Participants read newspaper articles about the defeat of a boxer. In one condition, the authentic article informed participants that he committed suicide and in the other, a fictitious article about the same defeat described the athlete as successfully continuing his career. Different question formats were employed to assess participants' assumptions about the stimulus person's defeat-related cognitions and emotions: rating scales, sentence completion and free responses. Participants assumed significantly more irrational beliefs (e.g. I absolutely have to win) on the side of the boxer in the suicide scenario than in the non-suicide version. This finding was obtained by directive and non-directive assessment methods. Additionally, participants expected the suicidal stimulus person to be experiencing maladaptive emotions (e.g. depression, guilt) whereas a successful resumption of his career lead to expectations of adaptive affects (e.g. sadness, concern). Ratings of the functionality revealed that sadness, fear, annoyance and concern were expected to be more functional than depression, anxiety, rage and guilt. The results show that naive psychological theories about the antecedents of dysfunctional behaviour are in accordance with theoretical assumptions of REBT: Irrational beliefs are viewed to be connected with maladaptive emotions and to result in dysfunctional behaviour, and adaptive emotions are thought to be of higher functional value than their maladaptive counterparts. The use of different question formats and a between-subject design excluded that results are due to methodological

  11. Efficient Culture of Human Naive and Memory B Cells for Use as APCs.

    PubMed

    Su, Kuei-Ying; Watanabe, Akiko; Yeh, Chen-Hao; Kelsoe, Garnett; Kuraoka, Masayuki

    2016-11-15

    The ability to culture and expand B cells in vitro has become a useful tool for studying human immunity. A limitation of current methods for human B cell culture is the capacity to support mature B cell proliferation. We developed a culture method to support the efficient activation and proliferation of naive and memory human B cells. This culture supports extensive B cell proliferation, with ∼10(3)-fold increases following 8 d in culture and 10(6)-fold increases when cultures are split and cultured for 8 more days. In culture, a significant fraction of naive B cells undergo isotype switching and differentiate into plasmacytes. Culture-derived (CD) B cells are readily cryopreserved and, when recovered, retain their ability to proliferate and differentiate. Significantly, proliferating CD B cells express high levels of MHC class II, CD80, and CD86. CD B cells act as APCs and present alloantigens and microbial Ags to T cells. We are able to activate and expand Ag-specific memory B cells; these cultured cells are highly effective in presenting Ag to T cells. We characterized the TCR repertoire of rare Ag-specific CD4(+) T cells that proliferated in response to tetanus toxoid (TT) presented by autologous CD B cells. TCR Vβ usage by TT-activated CD4(+) T cells differs from resting and unspecifically activated CD4(+) T cells. Moreover, we found that TT-specific TCR Vβ usage by CD4(+) T cells was substantially different between donors. This culture method provides a platform for studying the BCR and TCR repertoires within a single individual. Copyright © 2016 by The American Association of Immunologists, Inc.

  12. Decreased insular connectivity in drug-naive major depressive disorder at rest.

    PubMed

    Guo, Wenbin; Liu, Feng; Xiao, Changqing; Zhang, Zhikun; Liu, Jianrong; Yu, Miaoyu; Zhang, Jian; Zhao, Jingping

    2015-07-01

    The insula has extensive links to the fronto-limbic circuit and associated regions, which is involved in the neurobiology of major depressive disorder (MDD). However, few studies are designed to examine the insular connectivity in MDD. This study was performed to examine the insular connectivity in drug-naive MDD directly by using the insular cortices as seeds. Functional magnetic resonance imaging data were obtained from 44 drug-naive MDD patients and 44 healthy controls at rest. The functional connectivity (FC) method was used to analyze the images. Significantly decreased FCs were found between the right insula and the left middle frontal gyrus (MFG, orbital part), left superior temporal gyrus (STG), right putamen, and right middle occipital gyrus (MOG), and between the left insula and the left superior temporal pole and right MOG in the patients compared with the controls. There were significantly negative correlations between the z values of the left insula-left superior temporal pole connectivity and the current episode duration (r=-0.332, p=0.028), between the z values of the right insula-left STG connectivity and the episode number (r=-0.343, p=0.023), and between the z values of the right insula-left MFG (orbital part) connectivity and the Automatic Thoughts Questionnaire scores (r=-0.359, p=0.017) in the patients. The findings reveal that depressed patients have decreased insular connectivity with the fronto-limbic circuit, hate circuit, and visual regions, and suggest that the insula may act as an integration center of emotional processing which is disrupted in the depressed patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Ethanol elimination kinetics following massive ingestion in an ethanol naive child.

    PubMed

    Wiener, Sage W; Olmedo, R; Howland, Ma; Nelson, Ls; Hoffman, Rs

    2013-07-01

    At low-to-moderate concentrations, ethanol elimination follows zero-order kinetics. It is unknown whether renal, pulmonary or other first-order processes become significant in patients with very high serum ethanol concentrations. Additionally, it is unclear whether ethanol naive subjects induce their metabolism during acute intoxication. We present the toxicokinetic analysis in a child with a massive ingestion of ethanol. A 15-year-old girl without significant medical history presented to the Emergency Department after drinking 24 ounces of tequila. She was found unresponsive at home with a Glasgow Coma Score of 3. Her presenting vitals were as follows: 118/69 mmHg blood pressure; pulse rate was 88 beats per minute; respiratory rate of 20 breaths per minute; pulse-oximetry is 96% on room air. Other than obtundation, her physical examination was normal. She was intubated for airway protection and admitted to the ICU. Her initial serum ethanol concentration was 543 mg/dL. A repeat level 3 h later was 722 mg/dL. Post-absorptive ethanol concentrations decreased from 693 mg/dL to 291 mg/dL over the following 15.5 h. The patient had spontaneous eye opening 24 h after presentation. Her projected serum ethanol concentration at that time was 215 mg/dL. She was extubated 2 h later and had an uneventful recovery. The elimination of ethanol in the post-absorptive phase remained zero-order at a rate of 26.3 mg/dL/h (5.7 mmol/L/h) with a Pearson's correlation coefficient (R (2)) of 0.9968 (p < 0.01). There was no evidence of acute induction in metabolism although pharmacodynamic tolerance likely occurred. Even at very high ethanol concentrations in ethanol naive subjects, elimination of ethanol follows a zero-order toxicokinetic model.

  14. Moderate prevalence of transmitted drug resistance mutations among antiretroviral-naive HIV-infected pregnant women in Rio de Janeiro, Brazil.

    PubMed

    Pilotto, José H; Grinsztejn, Beatriz; Veloso, Valdilea G; Velasque, Luciane S; Friedman, Ruth K; Moreira, Ronaldo I; Rodrigues-Pedro, Adriana; Oliveira, Sandra M; Currier, Judith S; Morgado, Mariza G

    2013-04-01

    Transmission of drug-resistant HIV-1 strains has been gaining attention and is becoming a growing problem throughout the world. The aim of this study was to determine the prevalence of transmitted drug resistance mutations (TDRM) among antiretroviral (ARV)-naive HIV-infected pregnant women in Rio de Janeiro, Brazil. ARV-naive pregnant women were recruited at Hospital Geral de Nova Iguacu (HGNI), Rio de Janeiro, from 2005 to 2008. HIV genotyping was carried out using ViroSeq (Abbott v. 2.0). TDRM were detected using the Calibrated Population Resistance Tool-CPR v. 6.0.The prevalence of mutations associated with resistance in the protease and reverse transcriptase regions of the HIV genome were assessed in samples collected prior to initiation of ARV prophylaxis or treatment. Among 238 eligible specimens that were collected, 197 samples were successfully amplified using reverse transcription polymerase chain reaction. Eighty-one percent of women were infected with HIV subtype B, 10% with subtype F1 viruses, 1.0% with subtype C virus, and 8.0% with recombinant forms of the virus. The prevalence of HIV TDRM was 5.6% for nucleoside reverse transcriptase inhibitors, 2.0% for nonnucleoside reverse transcriptase inhibitors, and 3.0% for protease inhibitors. The overall prevalence of any drug resistance was 10.7%. There were no multiclass resistant strains identified in the analyzed samples. The prevalence of HIV TDRM among the pregnant women in our cohort was moderate. Resistance testing should be encouraged in Rio de Janeiro, among other locations, for all HIV-infected pregnant women prior to prevention of mother-to-child transmission of HIV.

  15. Dacarbazine with or without oblimersen (a Bcl-2 antisense oligonucleotide) in chemotherapy-naive patients with advanced melanoma and low-normal serum lactate dehydrogenase: 'The AGENDA trial'.

    PubMed

    Bedikian, Agop Y; Garbe, Claus; Conry, Robert; Lebbe, Celeste; Grob, Jean J

    2014-06-01

    In a previous large randomized, open-label study, retrospective subset analysis revealed that the addition of the Bcl-2 antisense oligonucleotide oblimersen to dacarbazine (Dac) significantly improved overall survival, progression-free survival, and the response rate in chemotherapy-naive patients with advanced melanoma and normal baseline serum lactate dehydrogenase (LDH) levels. To confirm and expand on this observation, we conducted a prospective double-blind, placebo-controlled study to determine whether oblimersen augmented the efficacy of Dac in advanced melanoma patients with low-normal baseline LDH levels. A total of 314 chemotherapy-naive patients were randomly assigned to receive Dac (1000 mg/m(2)) preceded by a 5-day continuous intravenous infusion of either oblimersen sodium (7 mg/kg/day) or placebo every 21 days for less than eight cycles. Co-primary efficacy endpoints were overall survival and progression-free survival. Response and progression of the disease were assessed by independent blinded review of computed tomography scan images. No difference in overall nor progression-free survival was observed between the Dac-oblimersen and Dac-placebo groups. Although the overall (17.2 vs. 12.1%) and durable (10.8 vs. 7.6%) response rates numerically favored Dac-oblimersen over Dac-placebo, they did not differ significantly (P=0.19 and 0.32, respectively). The incidence of hematologic adverse events, particularly thrombocytopenia and neutropenia, was higher in the Dac-oblimersen group than in the Dac-placebo group. Withdrawals from the study because of treatment-related adverse events were low (i.e. <2.5%) in both groups. The addition of oblimersen to Dac did not significantly improve overall survival nor progression-free survival in patients with advanced melanoma and low-normal levels of LDH at baseline.

  16. Abnormal neural activity as a potential biomarker for drug-naive first-episode adolescent-onset schizophrenia with coherence regional homogeneity and support vector machine analyses.

    PubMed

    Liu, Yi; Zhang, Yan; Lv, Luxian; Wu, Renrong; Zhao, Jingping; Guo, Wenbin

    2017-05-02

    Patients with adolescent-onset schizophrenia (AOS) hold the same but severe form of symptoms with adult-onset schizophrenia, and with worse outcome and poor treatment response to antipsychotics. Several dominant brain regions of schizophrenia patients show significantly abnormal structural and functional connectivity during resting-state scans. However, coherence regional homogeneity (Cohe-ReHo) in drug-naive first-episode patients with AOS remains unclear. A total of 48 drug-naive first-episode AOS outpatients and 31 healthy controls underwent resting-state functional magnetic resonance scans. Cohe-ReHo and support vector machine analyses were used to analyze the data. Compared with the healthy controls, the AOS group showed significantly decreased Cohe-ReHo values distributed over brain regions, including the left postcentral gyrus, left superior temporal gyrus, left paracentral lobule, right precentral gyrus, right inferior parietal lobule (IPL), right middle frontal gyrus, and bilateral precuneus. No region with increased Cohe-ReHo values was observed in the AOS group compared with healthy controls. In addition, the right IPL was correlated with fluency (r=-0.324, p=0.030). However, the correlation was not significant after the Bonferroni correction at p<0.0083 (0.05/6). A combination of the Cohe-ReHo values in the bilateral precuneus and right IPL discriminated the patients from controls with the sensitivity, specificity, and accuracy of 91.67%, 87.10%, and 89.87%, respectively. Our findings suggested that the AOS patients exhibited diminished Cohe-ReHo values in some regions within the DMN network and sensorimotor network. The abnormalities in particular brain regions (bilateral precuneus and right IPL) may serve as potential biomarkers for AOS. Copyright © 2017. Published by Elsevier B.V.

  17. Negative selection and peptide chemistry determine the size of naive foreign peptide-MHC class II-specific CD4+ T cell populations.

    PubMed

    Chu, H Hamlet; Moon, James J; Kruse, Andrew C; Pepper, Marion; Jenkins, Marc K

    2010-10-15

    Naive CD4(+) T cell populations that express TCRs specific for different foreign peptide-MHC class II complex (pMHCII) ligands can vary in size over several orders of magnitude. This variation may explain why immune responses to some peptides are stronger than others. In this study, we used a sensitive pMHCII-tetramer-based cell enrichment method to study the derivation of two naive foreign pMHCII-specific naive CD4(+) T cell populations that differed in size by 8-fold in normal mice. Analysis of mice in which thymic negative selection was impaired revealed that the smaller population underwent more clonal deletion than the larger population. In addition, large naive cell populations tended to recognize peptides with tryptophan residues as TCR contacts. Thus, the foreign pMHCII that tend to be recognized by large naive populations induce minimal clonal deletion and contain certain amino acids with the capacity to interact favorably with TCRs.

  18. Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation

    PubMed Central

    Roberto, Alessandra; Castagna, Luca; Zanon, Veronica; Bramanti, Stefania; Crocchiolo, Roberto; McLaren, James E.; Gandolfi, Sara; Tentorio, Paolo; Sarina, Barbara; Timofeeva, Inna; Santoro, Armando; Carlo-Stella, Carmelo; Bruno, Benedetto; Carniti, Cristiana; Corradini, Paolo; Gostick, Emma; Ladell, Kristin; Price, David A.; Roederer, Mario; Mavilio, Domenico

    2015-01-01

    Early T-cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Posttransplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined. Here, we show that T memory stem cells (TSCM), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T-cell population in the early days following haploidentical transplantation combined with pt-Cy and precede the expansion of effector cells. Transferred naive, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant TSCM originate from naive precursors. Moreover, donor naive T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generate detectable recall responses, but only in the presence of the cognate antigen. We thus define the cellular basis of T-cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naive-derived TSCM in the clinical setting to overcome immunodeficiency. These trials were registered at www.clinicaltrials.gov as #NCT02049424 and #NCT02049580. PMID:25742699

  19. Predicting Ecstasy Use among Young People at Risk: A Prospective Study of Initially Ecstasy-Naive Subjects

    ERIC Educational Resources Information Center

    Vervaeke, Hylke K.E.; Benschop, Annemieke; Van Den Brink, Wim; Korf, Dirk J.

    2008-01-01

    Our aim is to identify predictors of first-time ecstasy use in a prospective study among young people at risk. As part of the multidisciplinary Netherlands XTC Toxicity Study (NeXT), we monitored 188 subjects aged up to 18 years who were ecstasy-naive at baseline but seemed likely to start taking ecstasy in the near future. After an 11- to…

  20. The Galileo Bias: A Naive Conceptual Belief That Influences People's Perceptions and Performance in a Ball-Dropping Task

    ERIC Educational Resources Information Center

    Oberle, Crystal D.; McBeath, Michael K.; Madigan, Sean C.; Sugar, Thomas G.

    2005-01-01

    This research introduces a new naive physics belief, the Galileo bias, whereby people ignore air resistance and falsely believe that all objects fall at the same rate. Survey results revealed that this bias is held by many and is surprisingly strongest for those with formal physics instruction. In 2 experiments, 98 participants dropped ball pairs…

  1. Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program

    PubMed Central

    Kime, Cody; Sakaki-Yumoto, Masayo; Goodrich, Leeanne; Hayashi, Yohei; Sami, Salma; Derynck, Rik; Asahi, Michio; Panning, Barbara; Yamanaka, Shinya; Tomoda, Kiichiro

    2016-01-01

    Developmental signaling molecules are used for cell fate determination, and understanding how their combinatorial effects produce the variety of cell types in multicellular organisms is a key problem in biology. Here, we demonstrate that the combination of leukemia inhibitory factor (LIF), bone morphogenetic protein 4 (BMP4), lysophosphatidic acid (LPA), and ascorbic acid (AA) efficiently converts mouse primed pluripotent stem cells (PSCs) into naive PSCs. Signaling by the lipid LPA through its receptor LPAR1 and downstream effector Rho-associated protein kinase (ROCK) cooperated with LIF signaling to promote this conversion. BMP4, which also stimulates conversion to naive pluripotency, bypassed the need for exogenous LPA by increasing the activity of the extracellular LPA-producing enzyme autotaxin (ATX). We found that LIF and LPA-LPAR1 signaling affect the abundance of signal transducer and activator of transcription 3 (STAT3), which induces a previously unappreciated Kruppel-like factor (KLF)2-KLF4-PR domain 14 (PRDM14) transcription factor circuit key to establish naive pluripotency. AA also affects this transcription factor circuit by controlling PRDM14 expression. Thus, our study reveals that ATX-mediated autocrine lipid signaling promotes naive pluripotency by intersecting with LIF and BMP4 signaling. PMID:27738243

  2. Predicting Ecstasy Use among Young People at Risk: A Prospective Study of Initially Ecstasy-Naive Subjects

    ERIC Educational Resources Information Center

    Vervaeke, Hylke K.E.; Benschop, Annemieke; Van Den Brink, Wim; Korf, Dirk J.

    2008-01-01

    Our aim is to identify predictors of first-time ecstasy use in a prospective study among young people at risk. As part of the multidisciplinary Netherlands XTC Toxicity Study (NeXT), we monitored 188 subjects aged up to 18 years who were ecstasy-naive at baseline but seemed likely to start taking ecstasy in the near future. After an 11- to…

  3. Early Understanding of Age- and Environment-Related Noxiousness in Biological Kinds: Evidence for a Naive Theory.

    ERIC Educational Resources Information Center

    Springer, Ken; And Others

    1996-01-01

    Evaluates whether children have a naive theory in which biological kinds, specifically food, are distinguished by potential for decomposition. Four experiments were conducted with subjects between the ages of four and six years. Claims that children seem to have a domain-specific theory of biological kinds, although they are unaware of the exact…

  4. The Galileo Bias: A Naive Conceptual Belief That Influences People's Perceptions and Performance in a Ball-Dropping Task

    ERIC Educational Resources Information Center

    Oberle, Crystal D.; McBeath, Michael K.; Madigan, Sean C.; Sugar, Thomas G.

    2005-01-01

    This research introduces a new naive physics belief, the Galileo bias, whereby people ignore air resistance and falsely believe that all objects fall at the same rate. Survey results revealed that this bias is held by many and is surprisingly strongest for those with formal physics instruction. In 2 experiments, 98 participants dropped ball pairs…

  5. Effects of Training on Naive Listeners' Judgments of the Speech Intelligibility of Children with Severe-to-Profound Hearing Loss

    ERIC Educational Resources Information Center

    Ellis, Lee W.; Beltyukova, Svetlana A.

    2008-01-01

    Purpose: This study examined the effects of feedback training, familiarization training, and no training on naive listeners' word identification (WI) and magnitude estimation scaling (MES) judgments of the speech intelligibility of children with severe-to-profound hearing impairments. Method: Depending on the training group, listeners received a…

  6. 1,25-dihydroxyvitamin D{sub 3} impairs NF-{kappa}B activation in human naive B cells

    SciTech Connect

    Geldmeyer-Hilt, Kerstin; Heine, Guido; Hartmann, Bjoern; Baumgrass, Ria; Radbruch, Andreas; Worm, Margitta

    2011-04-22

    Highlights: {yields} In naive B cells, VDR activation by calcitriol results in reduced NF-{kappa}B p105 and p50 protein expression. {yields} Ligating the VDR with calcitriol causes reduced nuclear translocation of NF-{kappa}B p65. {yields} Reduced nuclear amount of p65 after calcitriol incubation results in reduced binding of p65 on the p105 promoter. {yields} Thus, vitamin D receptor signaling may reduce or prevent activation of B cells and unwanted immune responses, e.g. in IgE dependent diseases such as allergic asthma. -- Abstract: 1{alpha},25-dihydroxyvitamin D{sub 3} (calcitriol), the bioactive metabolite of vitamin D, modulates the activation and inhibits IgE production of anti-CD40 and IL-4 stimulated human peripheral B cells. Engagement of CD40 results in NF-{kappa}B p50 activation, which is essential for the class switch to IgE. Herein, we investigated by which mechanism calcitriol modulates NF-{kappa}B mediated activation of human naive B cells. Naive B cells were predominantly targeted by calcitriol in comparison with memory B cells as shown by pronounced induction of the VDR target gene cyp24a1. Vitamin D receptor activation resulted in a strongly reduced p105/p50 protein and mRNA expression in human naive B cells. This effect is mediated by impaired nuclear translocation of p65 and consequently reduced binding of p65 to its binding site in the p105 promoter. Our data indicate that the vitamin D receptor reduces NF-{kappa}B activation by interference with NF-{kappa}B p65 and p105. Thus, the vitamin D receptor inhibits costimulatory signal transduction in naive B cells, namely by reducing CD40 signaling.

  7. HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK

    PubMed Central

    El Bouzidi, Kate; White, Ellen; Mbisa, Jean L.; Sabin, Caroline A.; Phillips, Andrew N.; Mackie, Nicola; Pozniak, Anton L.; Tostevin, Anna; Pillay, Deenan; Dunn, David T.

    2016-01-01

    Background Darunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings. Objectives We examined darunavir DRMs emerging in clinical practice in the UK. Patients and methods Baseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls. Results Of 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group. Conclusions Our findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility. PMID:27856703

  8. HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK.

    PubMed

    El Bouzidi, Kate; White, Ellen; Mbisa, Jean L; Sabin, Caroline A; Phillips, Andrew N; Mackie, Nicola; Pozniak, Anton L; Tostevin, Anna; Pillay, Deenan; Dunn, David T

    2016-12-01

    Darunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings. We examined darunavir DRMs emerging in clinical practice in the UK. Baseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls. Of 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group. Our findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

  9. Immunohistochemical Analysis of Lyme Disease in the Skin of Naive and Infection-Immune Rabbits following Challenge

    PubMed Central

    Chong-Cerrillo, Celeste; Shang, Ellen S.; Blanco, David R.; Lovett, Michael A.; Miller, James N.

    2001-01-01

    In this study, skin histopathology from naive and infection-derived immune rabbits was compared following intradermal challenge using Borrelia burgdorferi B31 strain. The presence or absence of spirochetes in relationship to host cellular immune responses was determined from the time of intradermal inoculation to the time of erythema migrans (EM) development (∼7 days in naive rabbits) and through development of challenge immunity (∼5 months in naive rabbits). Skin biopsies were obtained and analyzed for the presence of spirochetes, B cells, T cells, polymorphonuclear cells (PMNs), and macrophages by immunohistochemical techniques. In infected naive animals, morphologically identifiable spirochetes were detected at 2 h and up to 3 weeks postinfection. At 12 and 24 h postinfection there was a marked PMN response that decreased by 36 to 48 h; by 72 h the PMNs were replaced by a few infiltrating macrophages. At the time of EM development and 14 days postinfection, the PMNs and macrophages were replaced by a lymphocytic infiltrate. There was a greater number of spirochetes at 14 days, a time when EM had resolved, than at 7 days postinfection. By 3 weeks postinfection there were few organisms and lymphocytes detectable. In contrast to infected naive rabbits, intact spirochetes were never visualized in skin biopsies from infection-immune rabbits; only spirochetal antigen was detected at 2, 12, and 24 h in the presence of a numerous PMN infiltrate. By 36 h postchallenge, spirochetal antigen could not be detected and the PMN response was replaced by a few infiltrating macrophages. By 72 h postchallenge, PMNs and macrophages were absent from the skin; B and T cells were never detected at any time point in skin from infection-immune rabbits. The destruction of spirochetes in immune animals in the presence of PMNs and in the absence of a lymphocytic infiltrate suggests that infection-derived immunity is antibody mediated. PMID:11349081

  10. Using an Integrated Naive Bayes Calssifier for Crawling Relevent Data on the Web

    NASA Astrophysics Data System (ADS)

    Mihsra, A.

    2015-12-01

    In our experiments (at JPL, NASA) for DARPA Memex project, we wanted to crawl a large amount of data for various domains. A big challenge was data relevancy in the crawled data. More than 50% of the data was irrelevant to the domain at hand. One immediate solution was to use good seeds (seeds are the initial urls from where the program starts to crawl) and make sure that the crawl remains into the original host urls. This although a very efficient technique, fails under two conditions. One when you aim to reach deeper into the web; into new hosts (not in the seed list) and two when the website hosts myriad content types eg. a News website.The relevancy calculation used to be a post processing step i.e. once we had finished crawling, we trained a NaiveBayes Classifier and used it to find a rough relevancy of the web pages that we had. Integrating the relevancy into the crawling rather than after it was very important because crawling takes resources and time. To save both we needed to get an idea of relevancy of the whole crawl during run time and be able to steer its course accordingly. We use Apache Nutch as the crawler, which uses a plugin system to incorporate any new implementations and hence we built a plugin for Nutch.The Naive Bayes Parse Plugin works in the following way. It parses every page and decides, using a trained model (which is built in situ only once using the positive and negative examples given by the user in a very simple format), if it is relevant; If true, then it allows all the outlinks from that page to go to the next round of crawling; If not, then it gives the urls a second chance to prove themselves by checking some commonly expected words in the url relevant to that domain. This two tier system is very intuitive and efficient in focusing the crawl. In our initial test experiments over 100 seed urls, the results were astonishingly good with a recall of 98%.The same technique can be applied to geo-informatics. This will help scientists

  11. Early and late effects of highly active antiretroviral therapy: a 2 year follow-up of antiviral-treated and antiviral-naive chronically HIV-infected patients.

    PubMed

    Clerici, Mario; Seminari, Elena; Maggiolo, Franco; Pan, Angelo; Migliorino, Marco; Trabattoni, Daria; Castelli, Francesco; Suter, Fredy; Fusi, Maria Luisa; Minoli, Lorenzo; Carosi, Giampiero; Maserati, Renato

    2002-09-06

    Control of HIV replication can be observed in highly active antiretroviral therapy (HAART)-treated and, occasionally, in HAART-naive patients. The immunological correlates of these situations were examined in a longitudinal study. A prospective study. Immunovirological analyses in 16 chronically HIV-infected, HAART-naive patients (time 0) who started HAART. Fifteen patients (short-term HAART) were re-evaluated after 24 months (time 1). Results were compared with those of 30 patients who received HAART for more than 12 months before the study period (long-term HAART) and were analysed at the same timepoints. Fifteen patients who were antiviral therapy naive (naive) at both timepoints were also studied. Over a 24-month period CD4 and CD8 cell counts and viraemia remained unchanged in naive and long-term HAART patients; CD4 cell counts increased and viraemia diminished in short-term HAART individuals. Antigen-stimulated proliferation was unmodified in naive and short-term HAART patients, but improved in long-term HAART individuals. Gp160-stimulated IL-2 and IFN-gamma production was augmented in long-term HAART patients and marginally modified in other patients. IL-7 production was unmodified in naive individuals, augmented in short-term HAART patients, and diminished in long-term HAART patients. Chemokine production was similar in all patients. Naive patients showed the highest CD8 cell counts at both timepoints. HAART has a major impact on the outcome of HIV infection, even if functional immune modulation in HAART-treated patients is evident only after long periods of therapy. Low but detectable HIV replication in HAART-naive patients with preserved immune functions might not be associated with CD4 cell reduction, functional immune defects, or changes in viraemia. Copyright 2002 Lippincott Williams & Wilkins

  12. Human Neonatal Naive CD4+ T Cells Have Enhanced Activation-Dependent Signaling Regulated by the microRNA miR-181a

    PubMed Central

    Palin, Amy C.; Ramachandran, Vasavi; Acharya, Swati; Lewis, David B.

    2014-01-01

    Human neonates have reduced and delayed CD4+ T-cell immunity to certain pathogens compared to older children and adults, but the mechanisms for these developmental differences in immune function remain poorly understood. We investigated the hypothesis that impaired human neonatal CD4+ T-cell immunity was due to reduced signaling by naive CD4+ T cells following engagement of the αβ-TCR/CD3 complex and CD28. Surprisingly, calcium flux following engagement of CD3 was significantly higher in neonatal naive CD4+ T cells from umbilical cord blood compared to naive CD4+ T cells from adult peripheral blood. Enhanced calcium flux was also observed in adult CD4+ recent thymic emigrants. Neonatal naive CD4+ T cells als