Objective. To examine whether baseline obesity severity modifies the effects of two different, primary care-based, technology-enhanced lifestyle interventions among overweight or obese adults with prediabetes and/or metabolic syndrome. Patients and Methods. We compared mean differences in changes from baseline to 15 months in clinical measures of general and central obesity among participants randomized to usual care alone (n = 81) or usual care plus a coach-led group (n = 79) or self-directed individual (n = 81) intervention, stratified by baseline body mass index (BMI) category. Results. Participants with baseline BMI 35+ had greater reductions in mean BMI, body weight (as percentage change), and waist circumference in the coach-led group intervention, compared to usual care and the self-directed individual intervention . In contrast, the self-directed intervention was more effective than usual care only among participants with baseline BMIs between 25 ≤ 35. Mean weight loss exceeded 5% in the coach-led intervention regardless of baseline BMI category, but this was achieved only among self-directed intervention participants with baseline BMIs <35. Conclusions. Baseline BMI may influence behavioral weight-loss treatment effectiveness. Researchers and clinicians should take an individual's baseline BMI into account when developing or recommending lifestyle focused treatment strategy. This trial is registered with ClinicalTrials.gov NCT00842426. Nearly 70% of US adults are overweight  study was one of few pragmatic randomized controlled trials that successfully translated the Diabetes Prevention Program (DPP) lifestyle intervention into a primary care setting in the US. Published E-LITE data have demonstrated that two adapted, technology-enhanced DPP interventions  or usual care plus a coach-led (n = 79) or self-directed (n = 81) behavioral weight-loss intervention. Height was measured at baseline only, and weight and waist circumference were measured at baseline and at 3, 6, and 15 months. Measurements were taken in duplicate per standardized protocols [Participants were recruited (July 2009–June 2010) from a single primary care clinic that is part of a large multispecialty group practice in the San Francisco Bay Area. All data collection and intervention visits occurred at the clinic. Inclusion criteria included an age of at least 18 years, a BMI of at least 25, and the presence of prediabetes (defined by impaired fasting plasma glucose level of 100 to 125 mg/dL) or metabolic syndrome. Major exclusion criteria included serious medical or psychiatric conditions  or special life circumstances . Eligible and consenting overweight or obese adults with prediabetes and/or metabolic syndrome seen in primary care were randomized to receive usual care alone  core curriculum , which hP < 0.001). As in the main study [Baseline characteristics of each study group by baseline BMI category  were examined using analysis of variance (ANOVA) for continuous variables and Chi-square test for categorical variables. Between-group differences by baseline BMI category at 15 months were evaluated by intention-to-treat using all available data and tests of group by baseline BMI category interactions in repeated-measures mixed models. A separate model examined change in each of the 3 obesity outcome variables: BMI and percent body weight change for general obesity and waist circumference for abdominal obesity. The group by baseline BMI category interaction terms were significant for all three outcomes  and percent body weight change  for all three baseline BMI categories, and in waist circumference for the BMI 25 ≤ 30  and 35+  categories  only for the BMI 25 ≤ 30 category , in percentage weight loss for the BMI 25 ≤ 30  and 30 ≤ 35  categories, and in waist circumference for the BMI 30 ≤ 35 category . In the self-directed group mean weight loss reached 5% only among those with a baseline BMI of <35. Moreover, reductions in BMI (P = 0.01), weight as percentage change (P = 0.04), and waist circumference (P = 0.04) were significantly greater in the coach-led versus self-directed intervention within the BMI 35+ category, whereas the two interventions did not differ significantly for any of the three obesity measures in the two lower BMI categories.The self-directed intervention led to greater improvements in BMI  had greater reductions in all three obesity measures  in the coach-led intervention, but not in the self-directed intervention, compared with usual care. They also responded more favorably to the coach-led intervention compared to the self-directed intervention. In contrast, overweight participants (baseline BMI 25 ≤ 30) had similar mean BMI and percent body weight reductions in the two active interventions, both of which were more effective than usual care. Similarly, the coach-led intervention had no apparent incremental benefit over the self-directed intervention for participants with a baseline BMI of 30 ≤ 35, although they led greater reductions in percentage weight loss and BMI (coach-led) or waist circumference (self-directed) compared with usual care. These results imply that the self-directed intervention can be an effective and efficient alternative to the coach-led intervention for overweight individuals with prediabetes and/or metabolic syndrome but that individuals with the same cardiometabolic risk factors who are moderately or severely obese may only benefit from the latter, more structured approach. These findings add to recent evidence that suggests a structured, intensive—and yet practical—lifestyle intervention is indicated for increased degree of obesity , 21, as Previously, in the absence of empirical evidence, lifestyle intervention was thought to be ineffective in severely obese individuals  but has This is the first study, to our knowledge, that suggests the potential effectiveness of a coach-led, technology-enhanced DPP translation intervention in reducing obesity among adults at high risk of Type 2 diabetes and CVD with a BMI of 35 or above. This is a growing segment of the overall population for which surgery is currently recommended; however, surgery cannot be the only solution to an epidemic. It is imperative that alternative strategies are developed that are effective, accessible, and affordable with potential for broad reach and impact. Equally important, our study suggests that the low cost, self-directed intervention can be a viable alternative to the coach-led intervention for high-risk adults with a BMI less than 35. The increased efficiency and reach of the self-directed intervention makes it an appealing public health intervention strategy.Future studies are needed to explore factors that may modify or mediate the effectiveness of lifestyle interventions among persons with moderate or severe obesity. Potential effect modifiers include sociodemographic characteristics , comorbidity , and community/societal resources . Possible effect mediators include outcome expectancy, self-efficacy, social support, and self-monitoring, which are theory-based variables that have been shown to predict weight loss in diverse populations , 26.The present findings should be interpreted with consideration of several study limitations. This was a secondary data analysis, and all findings warrant replication in future confirmatory research. The sample size for each BMI-by-treatment subgroup was small, and the trial duration was only 15 months. However, the effect size confidence intervals and data consistency across the three obesity outcome measures suggest that the E-LITE coach-led intervention may have clinically significant benefits beyond usual care for moderately and severely obese adults at high cardiometabolic risk that are worth further investigation in fully-powered, longer-term studies. Also, the generalizability of the current findings may be limited by a rather homogenous study sample in terms of race/ethnicity and socioeconomic status, and participants were recruited from a single primary care clinic. Future research is needed to confirm the generalizability of our findings to more ethnically and socioeconomically diverse populations.In conclusion, baseline obesity status may influence behavioral weight loss treatment effectiveness. Less resource intensive approaches are perhaps adequate for individuals with lower baseline BMI in the overweight and obesity continuum, whereas the incremental benefit of more intensive, structured lifestyle change programs may not be evident except for those with higher BMI indicative of moderate or severe obesity. If confirmed in future definitive study, these findings would suggest that researchers and clinicians should take an individual's baseline BMI into account when developing or recommending a weight-loss treatment strategy. Understanding how to best allocate healthcare resources in weight-loss treatment may ultimately result in improved quality and affordability of obesity care.


Fibroblast growth factor 21 (FGF-21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and lipid metabolism in animal models. The relationship between plasma levels of FGF-21 and coronary heart disease (CHD) in unknown.This study aimed to investigate the correlation of serum FGF-21 levels and lipid metabolism in the patients with coronary heart disease. We performed a logistic regression analysis of the relation between serum levels of FGF-21 and CHD patients with and without diabetes and hypertension. This study was conducted in the Departments of Endocrinology and Cardiovascular Diseases at two University Hospitals. Participants consisted of one hundred and thirty-five patients who have been diagnosed to have CHD and sixty-one control subjects. Serum FGF-21 level and levels of fasting blood glucose; triglyceride; apolipoprotein B100; HOMA-IR; insulin; total cholesterol; HDL-cholesterol; LDL-cholesterol; and C-reactive protein were measured. We found that median serum FGF-21 levels were significantly higher in CHD than that of control subjects (P<0.0001). Serum FGF-21 levels in CHD patients with diabetes, hypertension, or both were higher than that of patients without these comorbidities. Serum FGF-21 levels correlated positively with triglycerides, fasting blood glucose, apolipoprotein B100, insulin and HOMA-IR but negatively with HDL-C and apolipoprotein A1 after adjusting for BMI, diabetes and hypertension. Logistic regression analysis demonstrated that FGF-21 showed an independent association with triglyceride and apolipoprotein A1.High levels of FGF-21 are associated with adverse lipid profiles in CHD patients. The paradoxical increase of serum FGF-21 in CHD patients may indicate a compensatory response or resistance to FGF-21. The fibroblast growth factor (FGF) family is composed of 22 members with a wide range of biological functions, including cell growth, development, angiogenesis, and wound healing Recent human studies indicate that increased circulating levels of FGF-21 are found in obese individuals and subjects with metabolic syndrome or type 2 diabetes To explore the physiological and pathological characteristics of FGF-21 in patients with CHD, we measured the serum concentrations of FGF-21 in 196 Chinese subjects and analyzed its association with a cluster of metabolic parameters. Unexpectedly, our data demonstrated that serum FGF-21 levels are significantly increased in CHD individuals and are independently associated with adverse lipid metabolism.Based on the clinical diagnostic criteria shown as following, individuals suffered from angina pectoris or myocardial infarctions were enrolled into this study as CHD subjects. Myocardial infarction was diagnosed on the basis of electrocardiogram findings, elevation of serum enzymes, and chest discomfort consistent with myocardial infarction. Angina pectoris was defined as recurrent chest discomfort related to exercise or excitement that lasted up to 15 minutes that was responsive to rest or nitroglycerin and together with objective evidence of myocardial ischemia (≥1 mm of ST-segment depression or ≥2 mm of T-wave inversion on an electrocardiogram at rest or inducible ischemia on exertion or pharmacologic stress testing). 135 CHD patients  were recruited in this study. 61 subjects  served as controls. All control subjects were selected based on the results of physician's questionnaire and clinical biochemical examination. The CHD patients who received medication within at least one year for lipid lowering, anti-hypertension and diabetic treatment were excluded. Written informed consent was given to all patients and control individuals, and all the procedures were approved by the Ethics Committee of Wenzhou Medical College.All subjects were assessed after overnight fasting for at least 10 h. The details of anthropometric measurements  and the methods for assay of biochemical variables  (Lp(a)) were obtained as reported previously After an overnight fasting, blood samples were taken. Serum insulin was measured with a two-site chemiluminescent enzyme immunometric assay using Immulite automated analyzer . Fasting blood glucose, total cholesterol, HDL-c, apolipoprotein A1 (ApoA1), apolipoprotein B100 (ApoB100), LDL-c, and triglycerides were measured by standard laboratory methods in a certified clinical examination laboratory.All analyses were performed with Statistical Package for Social Sciences version 13.0  similarly as described by Zhang et alBiochemical and clinical characteristics of the CHD patient and healthy groups are summarized in As shown in To determine whether serum FGF-21 was independently associated with anthropometric parameters and cardiovascular risk factors, stepwise logistic regression analysis involving all the parameters with significant correlations with serum FGF-21 was performed . StepwisOur primary aim was to observe the clinical manifestation of FGF-21 in conjunction with physiological and pathological aspects in CHD patients. Our results suggest that FGF-21 is correlated with CHD as supported by two novel findings. First, we demonstrate that in addition to fasting glucose, both apolipoprotein A1 and triglyceride are significantly associated with circulating FGF-21 in our research subjects independent of BMI, HDL cholesterol and insulin in multivariate analysis. Furthermore, we show that FGF-21 levels are 3-fold higher in CHD individuals with severely impaired cardiovascular systems.While numerous data have been published in animal model, little is known about FGF-21 in human subjects, particularly for patients with heart diseases. Previous studies indicated that circulating FGF-21 is significantly higher in obese populations with increased cardiovascular risk Serum FGF-21 levels were found to closely related to lipid metabolism. A recent study has already demonstrated that serum triglycerides and total cholesterol were independently associated with FGF-21 We have also showed that diabetes and hypertension have additional effects on FGF-21 levels in CHD patients, which is supported by the fact that serum FGF-21 levels in CHD individuals with diabetes, hypertension, or both were higher than in the CHD individuals without these complications. However, diabetes and hypertension are unlikely to be a primary factor for the increment of FGF-21 in CHD patients, since CHD patients without diabetes and hypertension had significantly higher FGF-21 levels than normal controls.The physiological and pathological significance of increasing serum FGF-21 levels in cardiovascular disease remains to be elucidated. As shown in previous studies There are several limitations in this study. Rather small collective of patients enrolled in this study is a major limitation of the study. A large sample size may be needed for more comprehensive investigation. In addition, our study did not address the cause-effect relationship between FGF-21 and the onset and development of CHD. Further studies are warranted to determine whether elevated serum FGF-21 is causally related to dyslipidemia or is a compensatory response to CHD.In summary, this study provides clinical evidence revealing that serum concentrations of FGF-21 are increased in CHD subjects. Together with previous findings


Methamphetamine use is associated with HIV acquisition and transmission among men who have sex with men (MSM). Contingency management (CM), providing positive reinforcement for drug abstinence and withholding reinforcement when abstinence is not demonstrated, may facilitate reduced methamphetamine use and sexual risk. We compared CM as a stand-alone intervention to a minimal intervention control to assess the feasibility of conducting a larger, more definitive trial of CM; to define the frequency of behavioral outcomes to power such a trial; and, to compute preliminary estimates of CM's effectiveness.We randomly assigned 127 MSM from Seattle, WA who use methamphetamine to receive a 12-week CM intervention (n = 70) or referral to community resources (n = 57).P = 0.11). Compared to control participants, CM participants were significantly more likely to report weekly or more frequent methamphetamine use and use of more than eight quarters of methamphetamine during the intervention and post-intervention periods.Retention at 24 weeks was 84%. Comparing consecutive study visits, non-concordant UAI declined significantly in both study arms. During the intervention, CM and control participants were comparably likely to provide urine samples containing methamphetamine  and to report non-concordant UAI . However, during post-intervention follow-up, CM participants were somewhat more likely to provide urine samples containing methamphetamine than control participants (aRR = 1.21; 95%CI: 0.95, 1.54, While it is possible to enroll and retain MSM who use methamphetamine in a trial of CM conducted outside drug treatment, our data suggest that CM is not likely to have a large, sustained effect on methamphetamine use.NCT01174654ClinicalTrials.gov Identifier  Men who have sex with men (MSM) who report using methamphetamine are 1.5 to 2.9 times more likely to acquire HIV than men who do not . MSM desReductions in sexual risk accompany participation in substance abuse treatment and peer-support programs ,11. In pDespite evidence supporting the potential effectiveness of CM, the intervention's effects on methamphetamine use and sexual risk have not been tested using a minimal intervention control. We conducted a randomized controlled trial of CM to reduce methamphetamine use and sexual risk among MSM outside of drug treatment. The goals of the study were to assess the feasibility of conducting a larger, more definitive trial of CM; to define the frequency of behavioral outcomes to power such a trial; and, to compute preliminary estimates of CM's effectiveness.We enrolled MSM from Seattle, WA. Between June 2007 and August 2008, participants were recruited through referrals from an STI clinic; an HIV clinic; community-based organizations (CBOs); printed media; radio; community outreach; and, referral by peers participating in the study.This study was initially designed to inform the design of a trial to test whether CM could prevent HIV acquisition among HIV-negative men who use methamphetamine. Therefore, from June 2007 to November 2007, we enrolled only HIV-negative men. Because of slow enrollment of HIV-negative men, in November 2007, we opened the study to HIV-positive men and revised the study objective to test whether a CM intervention could reduce HIV acquisition and transmission risk. Several studies illustrate that a considerable proportion of HIV-positive men use methamphetamine and that methamphetamine facilitates HIV transmission behaviors . AdditioThe study intervention was a 12-week CM program, adapted from previous studies, in which vouchers of escalating value were offered for consecutive urine samples that did not contain methamphetamine or crack or cocaine (herein referred to as cocaine) metabolites . InitialAll seven participants enrolled in the study while the above procedures were in place reported difficulty adhering to the intervention schedule, and only two attended ≥12 of their 36 visits. In response, in September 2007, we reduced the number of weekly urine testing visits to two (24 visits over the 12-week intervention) and increased the value of vouchers for the first stimulant-free urine sample to $7.50; other studies have employed a similar schedule . As befoUnder the initial CM intervention schedule, drop-in urine-testing visits were available from 10:00 am to 6:00 pm on Tuesdays, Thursdays, and Saturdays; we offered extended hours for working participants. After the enrollment visit, we sent postcards or e-mails to all participants encouraging participation in the intervention. We reminded participants who did not attend urine-testing visits for the first week by phone or e-mail. We sent postcards, phoned, or e-mailed all CM participants again at the midpoint of the intervention period. Under the revised CM intervention schedule, drop-in urine testing visits were available from 10:00 am to 6:00 pm on Tuesdays and Saturdays with flexible hours for working participants. Postcard, phone, and e-mail reminder strategies remained the same.We tested urine samples with the QuickScreen Pro Multi-Drug Screening Test , a point-of-care test used to qualitatively detect stimulant metabolites. For this assay, the estimated mean detection time in urine ranges from 43.6 to 66.9 hours for methamphetamine  and is 8Participants randomized to both control and CM arms received a printed list of local counseling, treatment, and outreach services at baseline and at each study visit. Study staff offered all participants assistance accessing services. Control participants did not submit twice-weekly urine samples and did not receive vouchers during the first 12 weeks of the study.The study randomized participants using block sizes of two, four, and eight varied randomly with a pseudo-random number generator, a deterministic process use to generate an effectively unpredictable sequence of numbers . The ranThe same study personnel administered the CM intervention and conducted the study visits. These personnel also performed data entry of the results of the urine testing and HIV/STI testing. The behavioral endpoints were automatically transferred from the ACASI to a database without the potential for modification. It was not possible to blind those administering the CM intervention to a participant's study arm.The University of Washington institutional review board approved the study protocol. All participants provided written informed consent.All study procedures took place at a large, public-transport accessible, community-based AIDS service organization. We screened participants for eligibility by phone and in person. All participants attended scheduled study visits every six weeks for six months. At each study visit, participants completed an audio computer-assisted self-interview (ACASI) that used a 6-week recall period and included questions about sexual behavior and substance use at the respondent- and partnership-level. Participants submitted urine samples for methamphetamine and cocaine metabolite testing at each of these visits.At enrollment, 12 weeks, and 24 weeks, participants were tested for HIV/STI after completing the ACASI . ParticiThe primary outcome was report of unprotected anal intercourse with a partner of unknown or discordant HIV status (non-concordant UAI) in the prior six weeks. The study included four secondary endpoints: the number of non-concordant UAI partners; results of methamphetamine urine testing; self-reported weekly or more frequent use of methamphetamine; and, self-reported use of >8 quarters (two grams) of methamphetamine. We chose non-concordant UAI as the primary outcome because this study was designed as a preliminary test of whether CM can be ultimately employed as an HIV prevention tool. We have previously shown this metric to be associated with HIV acquisition . The secWe conducted a test-retest reliability study of the behavioral endpoints assessed in this trial . From DeThe primary purpose of this trial was to gather data for the design of a phase IIb or III clinical trial. The study was originally designed to follow 60 individuals. Assuming that 14% of participants would report non-concordant UAI at baseline, this sample size was chosen to provide estimates of the proportion of men who report non-concordant UAI in the prior six weeks with an expected width of the 95% confidence interval (CI) of 0.085. We expected to lose 25% of our study population to follow-up and aimed to enroll 80 participants. Additional resources, however, allowed us to enroll 127 participants.t-tests to compare retention at the 24-week study visit and CM intervention adherence, respectively, between groups of participants defined by selected characteristics. We used generalized estimating equations (GEE) to estimate the proportion of participants reporting non-concordant UAI in the prior six weeks at each study visit. Analyses estimating the effectiveness of CM were intention to treat, on the basis of a binomial regression models with log links, to calculate relative risks comparing the proportion of men reporting non-concordant UAI between the study groups at study visits during the 12-week intervention and 12-week follow-up periods [P < 0.05 level.We used chi-squared tests and  periods . Our anaWe pre-selected baseline covariates that we thought would most strongly predict our outcomes of interest for adjusted analyses, including predictors of retention at the 24-week study visit. Of these covariates, we adjusted for variables that resulted in at least a 10% change in the adjusted RR (aRR) compared to the unadjusted RR . We chosWe assessed participants' stage of change for methamphetamine use by a single question ,33: "HavP < 0.01) and men who reported methamphetamine use for ≥10 years were less likely to attend the 24-week study visit than men who reported methamphetamine use for <10 years .Over our 15-month enrollment period, we screened 222 men for eligibility (14.8/month) and enrolled and randomized 127 men (8.5/month). Of these randomized participants, 107 (84%) attended the 24-week study visit; retention at 6-week assessments was similar for both groups . Of the 22 CM participants loss-to-follow-up at this visit, one was incarcerated, one was in a drug rehabilitation program, three withdrew from the study, and 17 could not be located for study visit attendance. Among the 13 control group participants who did not complete the first follow-up visit, one had died, two withdrew from the study, and 10 could not be located for study visit attendance.P = 0.03).Table P = 0.04). Participants who reported using methamphetamine weekly or daily at baseline attended fewer visits than participants who reported less frequent use  and participants whose urine contained methamphetamine at baseline attended fewer urine testing visits than participants whose urine did not contain methamphetamine . Since the mean detection time of the methamphetamine assay is shorter than the interval between urine testing visits, the proportion of metabolite-free urine samples provided by CM participants during the intervention visits may be over-estimated.Table At baseline, 6-weeks, 12-weeks, 18-weeks, and 24-weeks, the adjusted probabilities of reporting non-concordant UAI in the prior six weeks were 31.0% , 19.7% , 12.1% , 9.1%  and 10.2% , respectively. Figure CM and control participants were similarly likely to report non-concordant UAI during the 12-week intervention period. CM participants were less likely than control participants to report non-concordant UAI during the subsequent 12-week follow-up period, and also reported fewer non-concordant UAI partners than control participants during both the intervention and follow-up periods. None of these differences were statistically significant Table .P = 0.43). There were no incident syphilis, rectal gonococcal, or rectal chlamydial infections. Among the HIV-negative participants, one man in the CM arm and no men in the control arm acquired HIV .One man in CM arm and one man in the control arm acquired pharyngeal gonoccocal infection  control participants and 44 (63%) CM participants submitted ≥1 sample containing methamphetamine metabolites; 26 (46%) control participants and 23 (33%) CM participants submitted ≥1 sample containing cocaine metabolites; and, 43 (75%) control participants and 55 (79%) CM participants submitted ≥1 sample containing methamphetamine or cocaine metabolites.P = 0.11).CM and control participants were comparably likely to submit urine samples positive for methamphetamine at study visits during the intervention period Table ; howeverComparing participants at study visits six weeks apart, control participants at the later study visit were less likely to report either weekly or daily methamphetamine use or using >8 quarters of methamphetamine in the prior six weeks than participants at the earlier study visit ; although the frequency and quantity of methamphetamine use declined over time among men in the CM arm, these changes were not as large with respect to frequency  and not statistically significant with respect to quantity . CM participants were significantly more likely than control participants to report weekly or daily methamphetamine use and to report using >8 quarters of methamphetamine at each study visit; these differences were statistically significant during the 12-week follow-up period Table .P = 0.57) and follow-up periods ; however, these differences were not statistically significant. In the 6 weeks prior to baseline, 19% of control participants and 14% of CM participants participated in a substance abuse treatment program or peer support group (P = 0.45). After baseline, 26% of control participants and 21% of CM participants reported participating in such interventions (P = 0.38).Accounting for baseline stage of change, control group participants were more likely than CM participants to report being in the action or maintenance stage of change for methamphetamine use during the intervention  from December 2003 to December 2005. Our screening (14.8/month in the current study and 10.3/month in PROP) and enrollment rates (8.4/month and 7.4/month), attendance at CM visits (37% and 41%), and incentives earned  were similar . CompareOur study has several important limitations. First, we did not power the current study to detect differences between study groups based on methamphetamine use or sexual risk. Instead, this study was powered to provide precise estimates of the proportion of methamphetamine-using MSM who report non-concordant UAI. Despite this limitation, the precision of our post-intervention period aRR rules out the potential of CM to effect a large, sustained reduction in methamphetamine use as a stand-alone intervention, at least in the population we followed. Second, randomization did not provide us with study arms balanced with respect several pertinent variables. In particular, persons assigned to the CM arm were more likely to use methamphetamine at baseline, and higher levels of drug use have been associated with inferior responses to CM in prior studies . It is pIn summary, our small, randomized trial found that a 12-week CM intervention was associated with a potential increase in methamphetamine use, but decreases in sexual risk that were not statistically significant. While our experience suggests that a larger, more definitive controlled trial of CM to decrease methamphetamine use and sexual risk may be feasible, our findings suggest that CM would be unlikely to effect large, sustained reductions in methamphetamine use among MSM.The authors declare that they have no competing interests.TWM participated in study design and coordination, performed the statistical analyses, and drafted the manuscript. DRJ participated in study coordination. JPH participated in the design of the study and provided statistical expertise. GNC and SS participated in the conception and design of the study. MRG conceived of the study and its design and helped draft the manuscript. All authors contributed to the interpretation of the study data, revised it critically for important intellectual content, and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/774/prepub


Published human papillomavirus (HPV) vaccine trials indicate efficacy is strongest for those naive to the vaccine-types. However, few high-risk young women have been followed and cervical HPV has been the predominant outcome measure.We collected cervical and anal swabs, as well as oral rinse specimens from 645 sexually active inner-city young females attending a large adolescent health-clinic in New York City that offers free care and HPV vaccination. Specimens were tested for HPV-DNA using a MY09/MY11-PCR system. Type-specific prevalence of HPV at each anatomic site was compared for individuals by vaccination dose using generalized estimating equation logistic regression models.The majority of subjects reported being of non-Caucasian (92%) and/or Hispanic ethnicity (61%). Median age was 18 years (range:14–20). All had practiced vaginal sex, a third (33%) practiced anal sex, and most (77%) had also engaged in oral sex. At enrollment, 21% had not received the vaccine and 51% had received three doses. Prevalent HPV infection at enrollment was detected in 54% of cervical, 42% of anal and 20% of oral specimens, with vaccine types present in 7%, 6% and 1% of specimens, respectively. Comparing prevalence for vaccine types, the detection of HPV in the cervix of vaccinated compared to unvaccinated adolescents was significantly reduced: HPV6/11 , HPV16  and HPV18 . For anal HPV, the risk of detecting vaccine types HPV6/11  and HPV18 were significantly reduced for vaccinated adolescents however, the risk for HPV16 was not significantly decreased .HPV Prevalence is extremely high in inner-city female adolescents. Administration of the HPV vaccine reduced the risk for cervical HPV; however continued follow-up is required to assess the protection for HPV at all sites in young women with high exposure. Cervical human papillomavirus (HPV) infection is the most common sexually transmitted viral infection (STI). Adolescents and young women have the highest rates of cervical HPV. The FDA-approved quadrivalent vaccine, GARDASIL® , targets HPV16 and 18 , as well as HPV6 and 11 , and has the potential to reduce the burden of genital HPV and disease. The HPV vaccine clinical trials, however, focused almost exclusively on low-risk, primarily non-Hispanic Caucasian women with few sexual partners who were highly compliant with the vaccine schedule. When women who had a current infection  with an HPV vaccine type were assessed, the vaccine was shown to provide no benefit for preventing future infections by that type The association of HPV with anal and oropharyngeal papillomas and neoplasia is an important public health concern. Yet few clinical trials have reported on the effectiveness of the vaccine against anal or oral HPV Subsequent to the approval and release of GARDASIL, we initiated a cohort study of sexually active inner-city, mostly minority, adolescent females attending the largest adolescent-specific primary care facility in the U.S. – the Mount Sinai Adolescent Health Center in New York City; that provides free health services, including HPV vaccination. The data obtained from this study will be essential to understanding the real-world impact of HPV vaccination in high-risk adolescents, and for determining future cervical cancer prevention and screening practices in cohorts of women with different HPV vaccine coverage.In this report, we present data on the prevalence of HPV in this high-risk population and describe the cross-sectional association between the detection of cervical, anal and oral HPV with vaccine exposure.The Mount Sinai Adolescent Health Center (MSAHC) uses a unique model that integrates medical, dental, sexual/reproductive, mental health and health education services. All services are confidential and free to patients. It is located on the border of East Harlem and supports an underserved population of children, adolescents, and young adults (ages 10–24); ∼80% of who are females, come from all five Boroughs of New York City: 50% from Central and East Harlem, and other parts of Manhattan, 29% from the Bronx, and 20% from other Boroughs.Women are eligible to participate if they: 1) are between 12 and 19 years of age at time of consent, 2) have ever engaged in vaginal or anal intercourse, and 3) intend to get or have already received the FDA approved HPV vaccine (GARDASIL®). Women pregnant at time of recruitment or who have terminated a pregnancy within the last 4 weeks are excluded.www.myspace.com/hpvinfo; www.facebook.com/MSAHC).Adolescent women presenting to the MSAHC are informed about the study by research staff. Study flyers are also handed out instructing women attending the adolescent-health clinic to contact research staff if they are interested in participating. In addition, MySpace® and Facebook® social-networking pages were created as health education tools to explain facts related to HPV in more detail , and anticipatory guidance and age-specific health education. Screening for Chlamydia, gonorrhea and Syphilis is done routinely, and Herpes if symptoms are present.A self-administered questionnaire consisting of items to assess risk behaviors for HPV acquisition includes questions on: sexual behaviors, history of STIs and warts, characteristics of sexual partners, condom use, use of alcohol and illicit substances for participants and their sexual partners. The questionnaire is reviewed by a study coordinator at the time of the visit and any items not completed are queried. The enrollment clinical interview and questionnaire data were combined to describe the population and risk factor profiles for this analysis.Specimen collection is performed by MSAHC clinicians. Cervical cells are collected using an endocervical Cytobrush® placed in PreservCyt transport medium  medium. Anal cells are also collected in PreservCyt using a Dacron swab moistened in tap water. Oral cell samples are collected by oral rinse and gargle using a Scope® mouthwash . Specimens are stored at −20°C immediately following collection. Additional cervical and anal specimens are collected for Pap cytology at enrollment.The polymerase chain reaction (PCR) detection and typing of HPV-DNA has been described in detail elsewhere Samples hybridizing to the β-globin probe but negative for the generic probe are considered HPV negative. PCR products positive by Southern blot and any sample having a specific DNA fragment migrating at ∼450 bp are analyzed for HPV-DNA type. Filters are individually hybridized using biotinylated type-specific oligonucleotide probes for multiple HPV including vaccine types HPV 6, 11, 16 and 18. Samples that test positive by the generic probe mix but negative by all type-specific probes are considered to represent “uncharacterized” HPV types. Hybridization signals of the HPV type-specific probes are recorded using a 1–5+ validated scale for signal intensity alpha PV genus and uncharacterized HPV types. Related HR-HPV for vaccine type 16 included HPV31, 33, 35, 52, and 58  and HPV18-related types 39, 45 and 59 . No HPV6/11-related HPV types  were specifically identified. Statistical analyses were conducted with the STATA 12.0 and SAS 9.2 statistical software packages.Clinical and demographic characteristics of the study cohort were examined using frequency distributions. Associations between risk factors and HPV detection, including vaccine and related HPV types, were estimated by odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression. In addition, to examine the vaccine effect over multiple HPV types, we fit two models using a previously described generalized estimating equation (GEE) approach The cohort consisted of a predominantly minority population with a median age of 18 years who had not completed high-school at the time of enrollment Table 1.History of STIs in the population was high including Chlamydia (36.0%), trichomoniasis (7.6%), gonorrhea (5.7%), and genital warts (5.3%). Almost half (47.3%) of adolescents reported using condoms ‘never’, ‘rarely’ or only ‘sometimes’ when practicing vaginal sex, and many (55.2%) also reported using the withdrawal or rhythm method for contraception. The majority of adolescents, however, used some form of recurrent prescription-based contraception including oral contraceptive pills (52.7%), vaginal rings (25.4%) or Depo-Provera injections (23.1%). More than a quarter (31.3%) of subjects reported having been pregnant.Overall HPV-DNA detection at enrollment was 53.5% in the cervix, 41.5% in the anal canal, and 19.6% in the oral cavity. The prevalence of at least one vaccine type  was 6.6%, 6.2% and 1.3% in the cervical, anal and/or oral specimens, respectively. Among the most commonly detected cervical HPV types  were HR-HPV types HPV51 and 58, as well as low-risk types 53, 66, 84 and 90/106 Figure 1We examined the risk factors for HPV-vaccine, vaccine-related HR-types and all HPV types in the cervix or anal canal, using logistic regression adjusting only for vaccine dose Table 2.alpha-9 and -7) types. Whereas vaccine types were significantly less likely to be detected in the cervix and anal canal with any vaccine exposure, this was not observed for other related HR-HPV types or all types combined. Subjects who had engaged in vaginal sex more than two years prior to vaccination were also more likely to present with an HPV infection independent of vaccine dose.Except for vaccine exposure, similar risk factor associations were observed for detection of vaccine types alone and related HR-HPV , anal canal , and oral cavity  and anal canal , as well for HPV18 in the anal canal .alpha-9 and -7 genera by vaccine exposure . In addition, we assessed cross-sectional associations between HPV-DNA infection, vaccine exposure and risk factors. As such, the history of HPV exposure prior to vaccination is not known for those individuals enrolled after vaccine initiation. Furthermore, it is impossible to ascertain via HPV-DNA detection alone if test positivity is equated with true  viral infection that may cause neoplastic disease. With longitudinal follow-up, we will be able to assess the HPV incidence and risk factors for “breakthrough” persistent infections  The reported study has strengths and limitations. The current study evaluated HPV at multiple anatomical sites associated with sexual exposure. While it is generally understood that acquisition and prevalence of cervical HPV is at its highest in adolescent women, how this relates to the prevalence and acquisition of HPV in other tissues susceptible to HR-HPV associated tumorigenesis , is not currently known. Among the limitations, it should be noted that because we are specifically targeting sexually active adolescent females, either at the time they receive the HPV vaccine or soon thereafter, our population is older than the targeted age for vaccination, but covers the age range recommended for catch-up vaccination , the study cohort is younger (mean patient age in 2010 was 18.6 vs. 17.7 in this study) but comparable in terms of prior STIs. The high-risk nature of the population is also evident in the observed prevalent HPV detection. Among the strongest risk factors for detection of cervical and anal HPV (independent of vaccination) were number of sexual partners, anal intercourse, oral-to-anal sex, receipt of a Depo-Provera injection, and history of Chlamydia. Vaccination was significantly associated with cervical and anal HPV detection only after the vaccine types were assessed separately.Recent evidence suggests the HPV vaccines will impact both cervical and anal HPV co-incidence rates, although efficacy against anal HPV depends on cervical HPV positivity Finally, whereas the odds of detecting HPV vaccine types in the cervix decreased significantly among vaccinated adolescents, the odds of detecting other vaccine related and un-related HR-HPV types did not show consistent decreases with vaccination. We observed significant univariate declines in detection only for HPV16 and 18-related HR-HPV types 31 and 45 in the cervix and anal canal, respectively, as did other studies. While history of previous infection with a vaccine type could not be controlled for in the analyses, it is unlikely the result is solely due to prior exposure given the observed prevalence among unvaccinated individuals. Vaccine efficacy has been shown against persistent infection in the trial cohorts for HPV33, 31, 45 and 51 (with or without HPV16/18 co-infection) In summary, our data to date suggest continued detection of cervical and extra-cervical infection with HPV vaccine types after vaccination, in addition to other HR-HPV types. This study provides the ‘real-world’ impact of vaccinating high-risk adolescent populations  with potentially frequent prior exposures to HPV vaccine types, as well as to related HR-HPV types. Findings from studies such as this are therefore critical to document the continued burden of HPV and to properly design future multi-type prophylactic HPV vaccines and continued screening strategies to prevent HPV-related disease.


Antibodies against citrullinated proteins/peptides (ACPAs), and especially antibodies targeting mutated citrullinated vimentin (anti-MCVs), are novel biomarkers of rheumatoid arthritis (RA). Whereas ACPAs are specific and sensitive markers for RA, there have hardly been any reports relating to ACPAs in psoriatic arthritis (PsA) or in psoriasis without joint symptoms (PsO). The aim of the present study was to investigate the prevalence of anti-MCVs in PsA and PsO. Serum anti-MCV titers were measured in 46 PsA and 42 PsO patients and in 40 healthy controls by means of a commercial enzyme-linked immunosorbent assay. The potential correlations of the serum autoantibody levels with several clinical and laboratory parameters were examined. The anti-MCV levels in the PsA patients were significantly higher than those in the PsO group. Among the clinical variables, the presence of tender knee joints and nail psoriasis was significantly associated with anti-MCV positivity in the PsA patients. Higher anti-MCV titers in the PsO patients were associated with a more severe disease course and with the early onset of psoriatic skin symptoms. Our results suggest that anti-MCVs can be used as novel markers in the diagnosis of PsA and in a subset of PsO patients. Antibodies targeting mutated citrullinated vimentin (anti-MCVs) belong in the group of anti-citrullinated protein/peptide antibodies (ACPAs). Antibodies against citrullinated cyclic peptides (anti-CCPs) are the most widely used members of the ACPA group –3. The dhttp://www.psoriasis.org/). PsA occurs more frequently in subject with the HLA-B27 haplotype [Psoriatic arthritis (PsA) is a seronegative spondyloarthropathy that develops in up to 30 per cent of patients with psoriasis  who fulfilled the CASPAR classification criteria for PsA and who had been treated in the absence of any information as to their serologic status regarding antibody reactivities against citrullinated proteins. The basic demographic, clinical and laboratory characteristics on the PsA group are to be seen in Tables The basic characteristics on the 42 PsO patients are similarly given in Tables N = 40) served as controls (none of them had ever exhibited psoriatic skin or joint symptoms). Their mean age was 45.05 ± 19.56 years (range: 16–82 years) and the female : male ratio was 20 : 20.A randomly selected, self-stated healthy group of volunteers , with recombinant MCV as antigen. The analyses were conducted in accordance with the manufacturer's instructions. As recommended by the manufacturer, patients with anti-MCV titers higher than the 20 U/mL cut-off value were regarded as positive.U tests) and Spearman's rank correlation coefficient. All statistical analyses were performed with the statistical program SPSS Windows (v15.0). P  values <0.05 were considered significant.The data on the anti-MCV-positive and negative patient groups were compared by means of the Fisher exact test. Since the data were not normally distributed, the correlations between anti-MCV positivity and the clinical features were determined through the use of nonparametric methods. Nonparametric methods were applied to assess overall group differences via pairwise comparisons  but that between the PsO and control groups was not statistically significant (P = 0.0848).With the recommended cut-off value of 20 U/mL, 11 PsA patients (24%) and 3 PsO patients (8%) were found to be positive for anti-MCVs, whereas all of the controls were anti-MCV-negative. The differences between the PsA and PsO groups and between the PsA and control groups were statistically significant (P = 0.033) (P < 0.01) (both means were below the proposed cut-off level). On the other hand, the anti-MCV titers did not correlate significantly with the current disease activity (as determined by the PASI and DAS28 scores) at the time of serum sampling (data not shown). It seems, therefore, that the current psoriasis activity is not a critical determinant of the anti-MCV level in PsO. Rather, the PsO patients with the most severe disease course  display the highest anti-MCV levels. A similar analysis was not feasible in the PsA group, which consisted almost entirely of severe cases who were receiving systemic DMARD or biological therapy. Similarly as in the PsO group, the current disease activity, as demonstrated by the DAS28 level, was not associated with higher anti-MCV levels in the PsA group either .Significantly higher anti-MCV titers were found in the PsO subgroup with a more severe disease course  , althoug= 0.033)  demonstrP = 0.019; patients who exhibited the early appearance of psoriatic skin symptoms usually presented with higher anti-MCV levels than those of the patients with a late disease onset). In the PsA group, however, no correlation was found between the age at PsA onset and the serum anti-MCV level .As demonstrated in N = 3) did not allow a meaningful statistical analysis in this group. In order to identify clinical or laboratory features associated with high anti-MCV levels, we examined various parameters , PsA patP = 0.032), and a significantly higher mean anti-MCV titer was detected in the PsA subgroup with painful knees   . HoweverP = 0.006). However, when the PsA and PsO patients were subdivided on the basis of the presence of nail symptoms, although a clear tendency was observed toward a higher anti-MCV level in those with nail symptoms, the difference was not statistically significant (P = 0.305)  . This study has demonstrated significantly higher anti-MCV titers in PsA patients than in PsO patients or in healthy controls. The mean autoantibody level in the PsA group was 30.3 U/mL, as compared with 8.7 U/mL in the PsO group and 9.5 U/mL in the control group. The serum anti-MCV concentrations, although clearly higher in a subset of PsA patients, were markedly lower than the values of several hundred-to-thousand U/mL reported previously in RA patients . SimilarNail psoriasis and tender knee joints were observed significantly more frequently in the anti-MCV-positive PsA patients than in the anti-MCV seronegatives (64% versus 17%). It has recently been recognized that distal DIP joint disease in PsA is associated with diffuse inflammation that envelops the nail root and adjacent bone . Thus, nAlthough the mean anti-MCV titer of the PsO patients did not differ from that for the healthy controls, when the PsO patients were divided into moderate-to-severe and mild groups, higher anti-MCV antibody titers proved to be significantly associated with a more severe disease course. Furthermore, those treated with biological therapy had significantly higher anti-MCV levels than the moderate-to-severe psoriasis patients who did not require biological therapy. Although the mean anti-MCV titers were below the proposed cut-off level, these findings imply that, within the group of PsO patients, higher anti-MCV levels may distinguish those patients with a more severe disease course. Whether these patients have significant subclinical joint involvement potentially detectable with highly sensitive imaging methods is unclear. Furthermore, we cannot exclude the possibility that these patients will eventually develop clinically evident PsA. α therapy and are a relatively stable hallmark of RA. In view of the generally low  anti-MCV titers in our PsO population, it seems unlikely that biological treatment would significantly modify the anti-MCV levels. If therapy had an effect on anti-MCV levels, this would result in decreasing titers in patients on biological therapy. In our opinion, therefore, the higher antibody titers in the group of PsO patients treated with anti-TNF therapy are not directly related to the treatment, but rather to the underlying severe disease course leading to the use of biologicals. Indeed, anti-MCV positivity is associated with a more severe disease course and a poor radiographic prognosis in patients with early RA [As regards the role of  therapy in ACPA levels, some studies have reported significantly decreased serum RF and anti-CCP levels in RA patients in response to 6–12 months of TNF inhibitor therapy –47. Nicaearly RA . The idea that a more severe disease course in PsO is associated with higher anti-MCV level was supported by the finding that the anti-MCV levels displayed a significant inverse correlation with the age at the onset of psoriatic skin symptoms. It is well known that patients with early-onset PsO usually have a more significant genetic background (HLA-cw6) and, among others, develop PsA more frequently , 53. EarIn conclusion, our study suggests that anti-MCVs, apart from being biomarkers of early RA, can also be used to differentiate a subset of PsO patients. As the differentiation of early and mild forms of PsA can pose a significant challenge in some cases, the detection of anti-MCV positivity can aid the diagnosis of PsA, especially in patients with psoriatic nail symptoms and tender knee joints. Furthermore, high levels of anti-MCVs in PsO patients without clinically manifest arthritis may distinguish patients who are more likely to experience a severe disease course and potentially require biological therapy. However, this study needs to be extended to large groups of both PsA and PsO patients in order to confirm these associations.


The efficiency with which the brain resolves conflict in information processing is determined by contextual factors that modulate internal control states, such as the recent  and longer-term  occurrence of conflict. Local “control context” effects can be observed in trial-by-trial adjustments to conflict , whereas global control context effects are reflected in adjustments to the frequency of conflict encountered over longer sequences of trials . Previous neuroimaging and lesion studies suggest that the modulation of conflict-control processes by local control context relies on partly dissociable neural circuits for cognitive  vs. emotional conflicts. By contrast, emotional and non-emotional conflict-control processes have not been contrasted with respect to their modulation by global control context. We addressed this aim in a functional magnetic resonance imaging (fMRI) study that varied the proportion of congruent trials in emotional vs. non-emotional conflict tasks across blocks. We observed domain-general conflict-related signals in the dorsal anterior cingulate cortex (dACC) and pre-supplementary motor area and, more importantly, task-domain also interacted with global control context effects: specifically, the dorsal striatum and anterior insula tracked control-modulated conflict effects exclusively in the emotional domain. These results suggest that, similar to the neural mechanisms of local control context effects, there are both overlapping as well as distinct neural substrates involved in the modulation of emotional and non-emotional conflict-control by global control context. Cognitive control refers to processes that guide perceptual and motor selection in line with task goals, especially in the face of distraction from irrelevant stimuli or task-inappropriate response tendencies  and global (longer-term) “control context,” as defined by the incidence of congruent vs. incongruent stimuli, is known to affect the size of the congruency effect. Local control context effects are reflected in the modulation of congruency effects by (first-order) trial-by-trial congruency transitions  effects are defined by conflict effects that are smaller on a current trial when preceded by an incongruent trial than by a congruent trial  effects have been studied less extensively , but at the cost of foregoing a “hybrid” blocked/event-related analysis that could, in theory, gauge independent phasic and sustained neural responses.We chose this approach for two main reasons: first, a frequency-based design like the proportion congruent manipulation inherently entails a strong dependence between block and event types ; this non-orthogonality is obviously suboptimal for assessing putatively independent contributions of sustained and phasic fMRI responses, which can be easily misattributed in hybrid analyses even when the underlying blocked- and event-based factors are orthogonal by design , regions involved in conflict processing as modulated by global control context (by assessing congruency effects as a function of the proportion congruent manipulation), and regions involved in conflict processing as modulated by local control context . Most importantly, we searched for brain areas that displayed these effects in a domain-specific fashion, by analyzing the interaction between the above contrasts with the factor of task-domain . Behaviorally, we expected to observe comparable congruency, proportion congruent, and congruency sequence effects in both task-domains. At the neural level, we expected to replicate the previous findings on basic conflict and local control context effects (and their interaction with task-domain) that were described above   or high error percentage (one participant with >30% errors). The remaining twenty-one participants were 10 females and 11 males .Stimuli were displayed on a back-projection screen that was viewed by participants via a mirror attached to the head-coil. This set-up simulated a viewing distance of approximately 80 cm, resulting in individual stimuli extending ~9° horizontally and ~11° vertically for the face-word task and ~10° horizontally and ~12° vertically for the localizer. For the face-word task, stimuli were presented using E-prime software , and consisted of photographic gray-scale images displayed on a black background, depicting male or female faces posing either happy, fearful, or neutral emotional expressions , which was performed first, and a subsequent standard localizer task to provide independent functional definitions of the FFA and the amygdala as ROIs. The face-word task consisted of two blocks of 16 practice trials each , followed by 4 runs of the experimental task . The first two runs were of one block type  and the other two runs were of the other type , and this order was counterbalanced across participants.For the emotional blocks, 12 emotional faces were presented, 6 of them showing happy faces  and the other 6 showing fearful faces . For the non-emotional blocks, all the faces  had neutral facial expressions. Thus, each task involved 12 unique facial identities, such that the number of exposures (and familiarity) with the face stimuli was equated across the two task-domains. Like the faces, distracters were grouped by blocks: in emotional block, only happy and fear words were displayed, while in non-emotional blocks, only female and male words were presented. Stimuli were presented in a random order within each block, with the constraint that a given face image was never repeated across consecutive trials, in order to avoid potential confounds from repetition priming or low-level feature integration effects  the trial is incongruent. Besides this congruency factor, the proportion of congruent and incongruent trials within block was manipulated, presenting 75% of congruent trials and 25% of incongruent for the high proportion congruent condition , and 75% of incongruent trials and 25% of congruent for the low proportion congruent condition . Moreover, proportion of congruency alternated across the 8 blocks, starting with the low proportion congruent condition ; this order of blocks was found to be most effective in producing robust proportion congruent effects in behavioral pilot work, as has been recently reported  were also counterbalanced across participants.Stimuli were presented for 750 ms, followed by a jittered inter-trial interval (ITI) during which a fixation cross was displayed centrally on the screen. To facilitate optimal statistical segregation of blood-oxygenation-level-dependent (BOLD) signals across successive trials, the ITI was randomly drawn from a pseudo-exponential distribution, where 50% of interval lasted 2.5 s, 25% lasted 3 s, 16% lasted 3.5 s, and 9% lasted 4 s . At the beginning of each block, instructions indicating whether the subjects had to respond to the gender or to the expression of the faces were displayed for 7 s, and there were 3 s intervals between blocks within each run.The face-network localizer task consisted of a 1-back task, where participants were required to push the right hand index finger response button whenever two identical stimuli were presented in a row. Twelve blocks of 15 stimuli each were presented, alternating between blocks where only faces were displayed and blocks where only houses were presented. Each stimulus appeared on the screen for 750 ms, separated by a 250 ms ITI, and a 10 s fixation period between blocks. The purpose of this standard localizer scan is to define face-sensitive regions of the FFA and amygdala (via a face-blocks > house-blocks contrast) that could then be employed as independently defined ROIs to supplement the whole-brain analyses of the main task.previous trial congruency, representing the level of congruency encountered on the previous trial . The factorial combination of these 4 factors formed our 16 experimental conditions.As outlined above, there were two types of task-domains used in the main experiment , a congruency factor with two levels (congruent vs. incongruent), and two proportion congruent conditions . In addition to these variables, we coded sequential effects offline by creating one additional within-subjects variable, *-weighted single-shot gradient EPI sequence of 30 contiguous axial slices  with 3.5 mm thickness and 3 × 3 mm in plane-resolution. Structural images were acquired with a T1-weighted SPGR sequence using a 3D inversion recovery prepared sequence, recording 180 slices of 1 mm thickness in plane-resolution of 1 × 1 mm .Images were recorded on a 3T GE Signa EXCITE HD system using a standard 8-channel birdcage head coil. Functional images were acquired parallel to the anterior-posterior commissure line with a T2http://www.fil.ion.ucl.ac.uk/spm/software/spm8/). Functional data were slice-time corrected and spatially realigned to the first volume of the first run. The structural scan was co-registered to the functional images, and served to calculate transformation parameters for spatially warping functional images to the Montreal Neurological Institute (MNI) template brain (resampled voxel size: 2 mm3). Finally, normalized functional images were spatially smoothed with an 8 mm3 full-width-half-maximum Gaussian kernel. The first 5 volumes of each run were discarded prior to building and estimating the statistical models. In order to remove low-frequency confounds, data were high-pass filtered (128 s). Temporal autocorrelations were estimated using restricted maximum likelihood estimates of variance components using a first-order autoregressive model (AR-1), and the resulting non-sphericity was used to form maximum likelihood estimates of the activations.All preprocessing and statistical analyses were carried out using SPM8 , the interaction between congruency and proportion congruency , the interaction between previous trial and current trial congruency , as well as the interactions between these contrasts and the task-domain factor . Group effects were assessed by submitting the individual SPMs for the above contrasts to voxel-wise t-tests at the group level, where subjects were treated as random effects.Regressors for stimulus events  were created for each of the combinations of task-domain , proportion congruent (low proportion vs. high proportion), previous trial congruency (incongruent vs. congruent) and current trial congruency (congruent vs. incongruent) factors, resulting in a total of 16 different trial types/regressors. Additionally, we modeled error trials, the first trial of each block, and instruction screens as nuisance regressors. This model was applied to each subject's data, followed by linear contrasts between events of interest. Specifically, we computed the main effect of congruency . By contrast, we did not pursue an analysis of 4-way interaction effects between congruency, global control context, local control context, and task domain, because this analysis would involve some cell sizes of only 16 trials, which may render unreliable results. Moreover, it should be emphasized that our models assess exclusively event-related activity rather than pursuing a hybrid blocked/event-related approach, where sustained (block-wise) activation is modeled in addition to event-related responses . Specifically, the program was used to run 10,000 Monte Carlo simulation taking into account the whole-brain search volume and the estimated smoothness of the residuals of the respective group SPMs to generate probability estimates of a random field of noise producing a cluster of voxels of a given extent for a set of voxels passing a specific voxel-wise p-value threshold, which we set at p < 0.005 for all analyses. Given this voxel-wise threshold, the simulations determined that cluster sizes ranging between 162 and 261 voxels, depending on the specific group contrast, corresponded to a combined threshold of p < 0.05 (whole-brain corrected). Following identification of activations that passed the whole-brain corrected thresholds for interaction effects, we followed up these analyses by extracting mean cluster activation values using Marsbar software (http://marsbar.sourceforge.net/) in order to determine the likely causes for each interaction effect . All reported t-tests are 2-tailed.To control for false-positive rates in analyzing the main task data, combined voxel activation intensity and cluster extent thresholds corrected for multiple comparisons were determined by using 3dClustSim of the AFNI software suite  in defining activations in these regions .Finally, we also created functionally defined FFA and amygdala ROIs from the independent localizer task and used these to extract activation estimates for these regions during the main task. Given that the localizer data were independent of the main task and only served to define face-sensitive voxels in the FFA and amygdala, we employed a more lenient, arbitrary statistical threshold (voxel-wise a priori fixed cut-offs aimed at excluding fast guesses (RT < 150 ms) and very slow (presumably inattentive) responses (RT > 1500 ms), resulting in an exclusion of 9.4% of all trials. While these trimming values are arbitrary, they lie within the conventional range of cut-offs used in RT distributions of comparable 2-alternative forced-choice tasks, where fixed cut-offs have been shown to be an effective (and simple) methods for increasing power  = 24.29, p < 0.001, with slower RTs for incongruent trials (573 ms) compared to congruent ones (551 ms). The effect of congruency was furthermore modulated by local control context, F = 12.67, p < 0.005, showing the typical congruency sequence effect, that is, larger congruency effects when the previous trial was congruent  than when the previous trial was incongruent . This interaction was not modulated by task . We also detected a marginal interaction between task-domain, global control context, and congruency, F = 3.28, p = 0.085, due to a numerically larger global control context effect for the non-emotional task  than for the emotional task where no global control context effect on RT was detected . The interaction between proportion congruent, previous congruency and congruency factors was not significant (F < 1), and neither was the 4-way interaction involving task-domain   = 25.34, p < 0.001, with higher error rates for incongruent (10%) than for congruent trials (4%). The congruency effect was modulated both by local  and global control context , showing the typical pattern of congruency sequence and proportion congruent effects  = 30.13, p > 0.001] than those following an incongruent trial . Similarly, for global control context effects, smaller congruency effects were found in the low proportion congruent condition  than in the high proportion congruent condition . Task-domain did not interact with either of these effects . Akin to the reaction time data, the interaction between global and local control context effects  was not significant (F < 1), and neither was the 4-way interaction involving task domain .For error rates, we also observed a main effect of congruency, s Figure . For locAs noted in the Methods section, we avoided repetition of face stimuli over successive trial in order to preclude low-level feature priming effects from obscuring the assessment of local control context effects  effects in both the RT and accuracy data across task domains. Moreover, we observed proportion congruent  effects in the accuracy data, but not in RT data, for both task domains. Global and local control context effects did not interact with each other  via a combined voxel-height and cluster-extent threshold (see Methods) and are listed in Table The aim of the fMRI analyses was to reveal brain regions involved in either domain-general or domain-specific conflict-control processes. Specifically, we sought to identify regions involved in conflict processing , and regions where these responses were modulated by global control context (where congruency effects are modulated by the proportion congruent manipulation) and local control context . Most importantly, we additionally searched for brain areas that displayed these activation profiles in a domain-specific fashion, by analyzing interactions of the above contrasts with task-domain . All reported activations passed whole-brain correction (p > 0.1), thus indicating a domain-general role in conflict-control processes for these regions.To identify neural substrates of general conflict-related processing, we conducted a main effect contrast of the congruency factor , collapsed across all other factors. We observed conflict-related activation in a large voxel-cluster covering bilateral dACC and stretching into the right pre-supplementary motor area (preSMA), as well as in additional clusters in the right inferior frontal gyrus and in right middle temporal gyrus Figure . In ordeF = 4.86, p < 0.05] than for the emotional one, where congruent trials evoked descriptively greater activity than incongruent ones  , as well as a 3-way congruency × proportion congruent × task-domain interaction analysis. We obtained no activation clusters passing whole-brain correction criteria in the congruency × proportion congruent analysis. However, a number of brain regions displayed differential modulation of conflict processing by global control context across task-domains. Specifically, 3-way interaction effects were observed in the dorsal striatum (DS), specifically the bilateral putamen and globus pallidus, with the left cluster stretching into the thalamus, and the right cluster extending into the caudate Figure . In addiF = 6.06, p < 0.05, non-emotional task, F = 2.33, p > 0.1; right DS: congruency × proportion congruency interaction for the emotional task, F = 4.3, p = 0.051, non-emotional task, F = 2.8, p > 0.1; left insula: congruency × proportion congruency interaction for the emotional task, F = 8.23, p < 0.01], non-emotional task ; left middle occipital gyrus: congruency × proportion congruency interaction for the emotional task, F = 16.26, p < 0.001, non-emotional task, . As can be seen in Figure Follow-up analyses showed that in each of these regions, the 3-way interaction effect was driven by the fact that global control context modulated the congruency effects to a larger degree in the emotional than in the non-emotional task-domain . For both tasks, this local control context effect in the high proportion congruent condition reflected a relative increase in incongruent > congruent trial activity following an incongruent compared to a congruent trial, an activation signature that tracks the assumed level of local conflict-control  condition. Here, we observed (under whole-brain correction) an interaction between previous and current trial congruency in a region of the ACC/dmPFC  = 5.69, p < 0.05, with significant incongruent > congruent activation differences for the non-emotional task , but not for the emotional task   and therefore collapsed the analysis across this factor. However, for the amygdala, we did not detect any main effect of congruency or interactions between congruency and any of the other factors.The localizer task also fashioned us with functional amygdala ROIs. Since these face-sensitive activation clusters extended beyond the anatomical confines of the amygdala proper, we masked the functional ROIs with an anatomically defined amygdala ROI (see Methods). Mean activation estimates of the resultant clusters were submitted to the same analyses as the FFA ROIs. Once more, we did not find any interaction with laterality . In addition, we also explored the impact of local control context (by assessing congruency sequence effects) as a function of global context. At the behavioral level, we observed effects of global control context, with larger congruency effects when the proportion of congruent trials was high than when it was low. Similarly, we also observed effects of local control context, as reflected in congruency sequence effects. Neither of these effects was reliably modulated by task-domain, and global and local control context effects had additive (non-interactive) effects on behavior. The latter finding suggests that global and local control effects may rely on distinct mechanisms, an idea that finds support in previous behavioral studies  of conflict. Moreover, recall that when we discuss effects of global control context, we are not referring to sustained (block-wise) activations, but rather to transient (event-related) signals whose amplitudes were modulated as a function of control context .As noted above, we observed generic  and domain-general conflict-related activation in a large voxel-cluster covering dACC and stretching into the right preSMA, as well as in additional clusters in the right inferior frontal gyrus and in right middle temporal gyrus. Especially the former three are areas that have been extensively reported in the conflict-control literature  response with a less habitual  one. Intuitively, it is not obvious though why these requirements would be more pronounced in the emotional than in the non-emotional task version, but there is actually prior evidence suggesting that the resolution of emotional conflict may be more reliant on inhibitory mechanisms than the resolution of non-emotional conflict, at least in the context of the present tasks. Specifically, while local control context effects in the non-emotional version of this task have been shown to involve excitatory biasing in favor of processing task-relevant face stimuli  as a function of time within each block  and task. While we did not obtain a significant 4-way interaction effect indicative of differential learning between tasks (P > 0.1), the numerical values are suggestive of the possibility that learning within blocks of trials was more pronounced in the emotional task  than in the non-emotional task . Thus, it is possible that learning mechanisms involving the DS may be preferentially engaged by emotional stimuli, perhaps due to their intrinsic value or affective salience. In line with this possibility, namely that the DS may display some selective susceptibility to emotionally salient stimuli, some recent studies have indeed observed dorsal striatal responses specific to emotional distracters and clinical status, distinguishing between bipolar and unipolar depressed individuals  insula, a paralimbic cortical region that is considered to be a core component of affective processing systems in the human brain  rACC focus displaying local control effects (akin to prior studies), and this was the case for the high proportion congruent  condition only. However, these effects were also domain-general. Overall, the present data cast doubt on whether the rACC plays its well-established role in emotional conflict adaptation in the context of a simultaneous manipulation of global control context.Finally, it is important to note that the analysis of local control context (congruency sequence) effects in the emotional domain did not replicate previous findings in the amygdala (Etkin et al., The general lack of any task-domain effects in the amygdala represents a second unexpected null-finding, given the well-established specialization of this region for detecting emotionally salient stimuli (e.g., LeDoux, Previous imaging studies in the clinical domain that investigated emotional conflict processing have focused in particular on the modulation of conflict by local control context in patients with mood disorders. For instance, Etkin and colleagues observed diminished behavioral effects and neural engagement of control-related rACC-amygdala circuitry (cf. Etkin et al., In summary, we present a novel finding of a partial dissociation between neural conflict processing, as modulated by global control context, in the emotional as compared to the non-emotional domain. This partial dissociation mirrors that previously observed for mechanisms mediating local control context effects in the emotional vs. non-emotional tasks (Etkin et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Due to geographic overlap of malaria and visceral leishmaniasis (VL), co-infections may exist but have been poorly investigated. To describe prevalence, features and risk factors for VL-malaria co-infections, a case-control analysis was conducted on data collected at Amudat Hospital, Uganda (2000–2006) by Médecins sans Frontières. Cases were identified as patients with laboratory-confirmed VL and malaria at hospital admission or during hospitalization; controls were VL patients with negative malaria smears. A logistic regression analysis was performed to study the association between patients' characteristics and the occurrence of the co-infection.Of 2414 patients with confirmed VL, 450 (19%) were positively diagnosed with concomitant malaria. Most co-infected patients were males, residing in Kenya (69%). While young age was identified by multivariate analysis as a risk factor for concurrent VL and malaria, particularly the age groups 0–4 (odds ratio (OR): 2.44; 95% confidence interval (CI): 1.52–3.92) and 5–9 years , mild  and moderate  anemia negatively correlated with the co-morbidity. VL patients harboring skin infections were nearly three times less likely to have the co-infection , as highlighted by the multivariate model. Anorexia was slightly more frequent among co-infected patients . The in-hospital case-fatality rate did not significantly differ between cases and controls, being 2.7% and 3.1% respectively .Concurrent malaria represents a common condition among young VL patients living in the Pokot region of Kenya and Uganda. Although these co-morbidities did not result in a poorer prognosis, possibly due to early detection of malaria, a positive trend towards more severe symptoms was identified, indicating that routine screening of VL patients living in malaria endemic-areas and close monitoring of co-infected patients should be implemented. Visceral leishmaniasis (VL) and malaria are two major parasitic diseases sharing a similar demographic and geographical distribution. In areas where both diseases are endemic, such as Sudan, Uganda, India and Bangladesh, co-infection cases have been reported, but features and risk factors associated with these co-morbidities remain poorly characterized. In the present study, routinely collected data of VL patients admitted to Amudat Hospital, Uganda, were used to investigate the magnitude of VL-malaria co-infections and identify possible risk factors. Nearly 20% of the patients included in this study were found to be co-infected with VL and malaria, indicating that this is a common condition among VL patients living in malaria endemic areas. Young age (≤9 years) was identified as an important risk factor for contracting the VL-malaria co-infection, while being anemic or carrying a skin infection appeared to negatively correlate with the co-morbidity. Co-infected patients presented with slightly more severe symptoms compared to mono-infected patients, but had a similar prognosis, possibly due to early diagnosis of malaria as a result of systematic testing. In conclusion, these results emphasize the importance of performing malaria screening amongst VL patients living in malaria-endemic areas and suggest that close monitoring of co-infected patients should be implemented. Plasmodium-helminth co-infections Due to extensive overlap in the geographical distribution of many infectious diseases, multiple infections appear to be the rule rather than the exception in many tropical and subtropical regions Leishmania donovani complex. Most cases occur in East Africa, South-East Asia and Brazil, where nearly 0.5 million people get infected each year Visceral leishmaniasis (VL) is a life-threatening syndrome caused by protozoan parasites of the Leishmania donovani and transmitted by the sandfly Phlebotomus martiniTo gather evidence on the occurrence of such co-morbidities, a systematic review of the present literature was first conducted . This reThe main goal of the present study was to describe the prevalence of VL and malaria co-infections amongst VL patients attending Amudat hospital and identify risk factors associated with this condition. Recognition of the burden posed by these co-morbidities among different patient groups may contribute to improve the clinical management of VL in malaria-endemic areas.th April 2011).The analysis was conducted on anonymized data, collected as part of routine patient care; no additional investigations were performed. Therefore, no prior informed consent from the patients was required. Ethical approval for the study was obtained from the MSF Ethics Review Board . MSF support to Amudat Hospital medical activities included the establishment of a VL control program, in which patients were provided with free diagnosis and treatment. Clinically suspected VL patients, defined as individuals with a history of prolonged fever (≥14 days) associated with either splenomegaly or wasting, were included in MSF's program and further examined for VL. According to the diagnostic algorithm implemented 2; moderate-mild malnutrition: WHZ and BMIZ<−2SD, BMI 16.0–18.4 kg/m2; no malnutrition: WHZ and BMIZ>−2SD, BMI≥18.5 kg/m2) P-value<0.10 in the univariate analyses were entered stepwise in the multivariate models. If an additional variable significantly increased the model fit (as assessed by the −2 Log Likelihood test) the variable was retained in the multivariate analysis (P<0.05).A retrospective case-control analysis was performed. Cases were identified as patients with a laboratory-confirmed diagnosis of both VL and malaria at hospital admission or during hospitalization; controls were patients similarly diagnosed with VL, whose blood smears tested negative for malaria. Descriptive analyses were conducted to feature the overall study population and the co-infected patients and to assess prevalence and mortality rates of the co-infection. Statistical analysis was performed using SPSS 15.0 software . Univariate analyses exploring the association between the explanatory variables and the outcome were performed, using the Pearson Chi-square test. Specifically, risk factors, symptoms and the in-hospital death were examined for their association with the co-infection. Associations are shown as odds ratios (OR) with 95% confidence intervals (CI). Denominators can vary for each variable because of incomplete data in the database. Continuous variables were categorized into predefined groups: age  based on malaria risk, anemia on hemoglobin level  and spleen size beneath the costal margin by tertiles . Seasonality of the co-infection was examined by categorizing hospital admissions during wet season  and dry season , which reflects the climate in Uganda. Anthropometric indices –WHZ, weight-for-height Z-score for children ≤5 years, BMIZ, body mass index Z-score for children 6–19 years and BMI for patients >19 years– were used to categorize nutritional status, according to the WHO standards  were confirmed with VL. The diagnosis was confirmed by DAT in 1160 patients (46.2%), by DiaMed IT-Leish in 1115 patients (44.4%) and by parasitological evidence in a spleen or lymph node aspirate in 236 patients (9.4%). Of the 2511 VL-confirmed cases, 2461 (98%) were primary-VL infections, while the remaining 50 were relapsing-cases. 547 (22%) of the VL-confirmed patients were co-diagnosed with malaria at hospital admission or during hospitalization. Clinically-based diagnosis with negative or no microscopy confirmation occurred for 97 patients, who were excluded from the analysis. Only microscopy-confirmed cases of concomitant malaria were retained for analysis in the co-infected group, resulting in 19% of VL-confirmed patients (n = 450 out of 2414) co-infected with positively diagnosed malaria. Among the non-VL cases, 1107 patients (25%) were clinically diagnosed with probable hyper-reactive malarial splenomegaly, a severe syndrome frequently observed among patients exposed to persistent malarial antigenic stimulation. Most co-infected patients were males residing in Kenya (69%), with a median age of 10 years (inter quartile range 6–16) (n = 82/316) and a progressive decrease with age   . With th0 years) , the oddNearly all co- and mono-infected patients were diagnosed with a degree of anemia (hemoglobin level <11 g/dl) on hospital admission, with a median hemoglobin level of 7.3 g/dl (inter quartile range 6.7–9.7 for cases and 6.7–8.7 for controls) . Splenomn = 12) died while hospitalized. A similar in-hospital mortality rate was found in the control group   (data not shown).Of the 450 co-infected patients, 2.7% . However, the variable was kept in the final model as it was found to be a confounder for age. After adjusting for the other variables included in the model, age ≤9 years remained significantly associated with the co-infection. When compared to adults ≥30 years, the risk of being diagnosed with the co-morbidity was highest among children aged 0–4 years  and progressively decreased with age . Moderate  and mild anemia  negatively correlated with the co-infection. Finally, the model highlighted a negative association between being co-infected with VL and malaria and carrying a skin infection  and, to a lesser extent, intestinal parasites . Patients suspected to harbor such pathogens, in fact, were three times less likely to be diagnosed with the co-infection.All 9 variables associated with the co-infection in the univariate analyses were included in the multivariate logistic regression models. Two separate models were created, due to the high number of missing data in reporting the symptoms: model A, based on 2306 patients, which includes all variables except the symptoms and model B, based on 929 patients, which combines symptoms and all other variables. Model A  shows thIn model B , logistiNineteen percent of the VL-confirmed patients admitted to Amudat Hospital between 2000 and 2006 were co-diagnosed with malaria. Young age (≤9 years) was identified as a risk factor for concomitant VL and malaria, while being anemic or having a skin infection appeared to negatively correlate with the co-infection. Anorexia was slightly more frequent among co-infected patients compared to the mono-infected ones. The in-hospital case-fatality rate did not significantly differ between cases and controls, indicating that VL-malaria co-infections did not result in a poorer prognosis.et al. who investigated the in-hospital mortality of VL within the same study population et al.Plasmodium falciparum-specific Paracheck test in Kolaczinski's study), the role played by the use of such diagnostic tools is likely to be marginal, considering the high performance of the Paracheck test in Uganda P. falciparum causes most of malaria infections et al. (16%), emphasizing the importance of recruiting large numbers of participants.Affecting nearly one out of five VL patients, VL and malaria co-infections appeared to be a common condition among VL patients living in the Pokot Region of Kenya and Uganda. Though in agreement with the findings of Mueller The co-infected population described by the present study mainly consisted of male Kenyans (69%), with a median age of 10 years. Despite the similar demographic pattern found among the controls, young age appeared to be positively associated with the co-infection; children ≤9 years, in fact, were found to be more than two times more likely to be co-infected with malaria, compared to adults ≥30 years, reflecting the well-known age patterns of malaria a priori whether such correlation might reflect the reduced susceptibility of VL anemic patients to the malarial infection or simply result from the interaction of the two diseases upon each another. Splenic-associated hemolysis and reduced hematopoiesis, as a result of abnormal iron retention by macrophages, have been implicated in the multifactorial origin of VL-induced anemia, where both hemoglobin and plasma iron levels are affected in vitro intraerythrocytic growth of Plasmodium parasites in vivoLeishmania infections appeared to be unaffected or exacerbated by the concomitant presence of Plasmodium parasites Anemia, a hallmark of both VL and malaria, negatively correlated with the co-occurrence of malaria in VL patients. Given the bi-directional nature of such association, it is not possible to determine Unlike what may be observed in other co-morbidities Leishmania and Plasmodium spp) may be able to cross-regulate their host susceptibility. It should be noted, however, that diagnosis of intestinal parasitic infections for some patients might have been based on clinical suspicion only, with no laboratory-confirmation, and that testing for these parasites might have not been performed systematically, as suggested by the very low prevalence of positive patients (1.5%). A dedicated study recruiting larger patient cohorts diagnosed with intestinal parasitic infections and performing systematic testing of all study subject would be required to confirm this finding.More than half of the patients among both cases and controls were co-diagnosed with one or more infections beyond VL and malaria. If this figure reflects the high infectious disease burdens found in the study area, we cannot exclude the development of co-morbidities to be related to the VL infection. Importantly, if VL might have favored the superimposing of other infections, malaria neither exacerbated the susceptibility of co-infected patients nor influenced the concomitant disease-pattern, with the exception of skin infections and, to a lesser extent, intestinal parasites. VL patients diagnosed with bacterial and fungal skin infections, in fact, appeared to be more than two times less likely to be co-diagnosed with malaria, although no evident explanation could be found. Similarly, a negative, but not significant association between co-infected patients and VL patients suspected to harbor intestinal parasites was identified, suggesting that the parasites involved Click here for additional data file.