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There is an active discussion in the public health community on how to assess and incorporate, in addition to safety and measures of protective efficacy, the full public health value of preventive vaccines into the evidence-based decision-making process of vaccine licensure and recommendations for public health use. The conference "Beyond efficacy: the full public health impact of vaccines in addition to efficacy measures in trials" held in Annecy, France (June 22-24, 2015) has addressed this issue and provided recommendations on how to better capture the whole public health impact of vaccines. Using key examples, the expert group stressed that we are in the midst of a new paradigm in vaccine evaluation, where all aspects of public health value of vaccines beyond efficacy should be evaluated. To yield a wider scope of vaccine benefits, additional measures such as vaccine preventable disease incidence, overall efficacy and other outcomes such as under-five mortality or non-etiologically confirmed clinical syndromes should be assessed in addition to traditional efficacy or effectiveness measurements. Dynamic modelling and the use of probe studies should also be considered to provide additional insight to the full public health value of a vaccine. The use of burden reduction and conditional licensure of vaccines based on collection of outcome results should be considered by regulatory agencies., (Copyright © 2016. Published by Elsevier Ltd.. All rights reserved.)

Objective: Employment is a vital part of the postdeployment return to civilian life. This study investigated factors associated with employment-related outcomes (employment status, self-reported work performance, and self-reported work satisfaction) among National Guard members returning from Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn deployments., Methods: The sample consisted of 1,151 National Guard service members who had returned from overseas deployments approximately six months earlier. Bivariate and multivariable analyses were performed to examine associations between predictors and employment-related outcome variables., Results: Higher-risk alcohol use was associated with reduced odds of being employed as well as with lower ratings of work satisfaction, whereas psychiatric symptom load was associated with lower self-reported work performance and work satisfaction ratings. Perceived social resources were associated with higher self-reported work performance and work satisfaction, whereas better physical functioning was associated with better self-reported work performance., Conclusions: Policy makers and clinicians may need to consider and assess alcohol use among unemployed National Guard members. They may also need to consider psychiatric symptom load and physical functioning among employed service members who perceive poor work performance and have low work satisfaction. Further research is needed on causal links between these predictors and employment outcomes.

Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks) and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template-mediated addition of telomeric repeats onto the ends of newly synthesized chromosomes. Loss of either end-capping function or telomere length maintenance has been associated with genomic instability or senescence in a variety of settings; therefore, telomeres and telomerase have well-established connections to cancer and aging. It has long been recognized that oxidative stress promotes shortening of telomeres, and that telomerase activity is a radiation-inducible function. However, the effects of ionizing radiation (IR) exposure on telomeres per se are much less well understood and appreciated. To gain a deeper understanding of the roles, telomeres and telomerase play in the response of human cells to IRs of different qualities, we tracked changes in telomeric end-capping function, telomere length, and telomerase activity in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET) gamma(γ)-rays or high LET, high charge, high energy (HZE) particles, delivered either acutely or at low dose rates. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, we reveal non-canonical roles for telomerase, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations, a finding also suggestive of cellular reprograming. Taken together, the results reported here establish the critical importance of telomeres and telomerase in the radiation response and, as such, have compelling implications not only for accelerated tumor repopulation following radiation therapy but also for carcinogenic potential following low dose exposures as well, including those of relevance to spaceflight-associated galactic cosmic radiations.

Aging results in a redistribution of polyunsaturated fatty acids (PUFAs) in myocardial phospholipids. In particular, a selective loss of linoleic acid (18:2n6) with reciprocal increases of long-chain PUFAs (eg, arachidonic and docosahexaenoic acids) in the mitochondrial phospholipid cardiolipin correlates with cardiac mitochondrial dysfunction and contractile impairment in aging and related pathologies. In this study, we demonstrate a reversal of this aged-related PUFA redistribution pattern in cardiac mitochondria from aged (25 months) C57Bl/6 mice by inhibition of delta-6 desaturase, the rate limiting enzyme in long-chain PUFA biosynthesis. Interestingly, delta-6 desaturase inhibition had no effect on age-related mitochondrial respiratory dysfunction, H2O2 release, or lipid peroxidation but markedly attenuated cardiac dilatation, hypertrophy, and contractile dysfunction in aged mice. Taken together, our studies indicate that PUFA metabolism strongly influences phospholipid remodeling and cardiac function but dissociates these processes from mitochondrial respiratory dysfunction and oxidant production in the aged mouse heart., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Emotional Processing Theory proposes that habituation to trauma-related stimuli is an essential component of PTSD treatment. However, the mechanisms underlying treatment-related habituation are not well understood. We examined one psychophysiological measure that holds potential for elucidating the biological processes involved in treatment response: trauma-potentiated startle response. Seventeen OEF/OIF combat Veterans participated in the study and completed three assessments using a trauma-potentiated startle paradigm over PTSD treatment. Results revealed different patterns of trauma-potentiated startle across treatment for responders and nonresponders, but no differences in within task habituation. Responders showed an increase followed by a decrease in trauma-potentiated startle, whereas nonresponders showed a relatively flat response profile. Results suggested that PTSD patients who engage with emotional content as demonstrated by greater startle reactivity may be more likely to respond to PTSD treatment. Furthermore, trauma-potentiated startle shows promise as an objective measure of psychophysiological responses involved in PTSD recovery., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To conduct an analysis of intrauterine device (IUD)-related outcomes including expulsion, contraceptive failure, and early discontinuation and to compare these outcomes in regard to age, parity, and IUD type., Methods: This was a multicenter retrospective chart review of adolescents and women aged 13-35 years who had an IUD inserted for contraception between June 2008 and June 2011., Results: A total of 2,523 patients' charts were reviewed. Of these, 2,138 patients were included in our analysis. After a mean follow-up of 37±11 months, the overall rates of IUD expulsion and pregnancy were 6% and 1%, respectively, and were not significantly different by age or parity. Intrauterine device discontinuation rates were 19% at 12 months and 41% after a mean follow-up of 37 months. Despite similar rates of IUD discontinuation between age groups at 12 months of use, teenagers and young women aged 13-19 years were more likely to request early discontinuation at the end of the total follow-up period. No significant difference was noted in pelvic inflammatory disease rates (2%) based on age. After adjusting for age and parity, we found that copper IUD users were more likely to experience expulsion and contraception failure compared with levonorgestrel intrauterine system users (hazard ratios 1.62, 95% confidence interval [CI] 1.06-2.50 and hazard ratios 4.89, 95% CI 2.02-11.80, respectively)., Conclusion: Similar to adults, IUD use in adolescents and nulliparous women is effective and associated with low rates of serious complications. Health practitioners should therefore consider IUDs for contraception in all females. Teenagers and young women are more likely to request premature discontinuation of their IUDs and may benefit from additional counseling.

Background: Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the "meningitis belt". Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135; and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococcal disease burden among children under 5 years of age., Methods: We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their "collective optimism" towards each criterion was documented on a scale from 0 to 100%., Results: For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health workers, end users and the effect on equity were all seen as highly likely (~ 90%). In terms of the maximum potential impact on meningitis disease burden, the median potential effectiveness of the vaccines in reduction of overall meningitis mortality was estimated to be 20%; (interquartile range 20-40% and min. 8%, max 50 %). For the multivalent meningococcal vaccines the experts had similar optimism for most of the 12 CHNRI criteria with slightly lower optimism in answerability and low development cost criteria. The main concern was expressed over the cost of product, its affordability and cost of implementation., Conclusions: With increasing recognition of the burden of meningococcal meningitis, especially during epidemics in Africa, it is vitally important that strategies are taken to reduce the morbidity and mortality attributable to this disease. Improved MC vaccines are a promising investment that could substantially contribute to reduction of child meningitis mortality world-wide.

Phase III studies of an oral, live, pentavalent, human-bovine reassortant rotavirus vaccine (RotaTeq; Merck) in developed countries have demonstrated that it is well tolerated with regard to intussusception and other adverse events and is efficacious in preventing rotavirus gastroenteritis and associated healthcare encounters. However, it cannot be assumed that rotavirus vaccines will be equally efficacious in infants and young children in the developing world. Differences in host populations, associated health conditions, and the epidemiology of rotavirus disease could affect vaccine performance. Concern about the potential for differences in efficacy stems from studies of previous candidate rotavirus vaccines, including bovine and rhesus rotaviruses, which showed no or variable efficacy in developing regions. Given this history, the World Health Organization (WHO) recommended that the efficacy of "new" rotavirus vaccines should be demonstrated in diverse geographic areas, including developing countries, before widespread implementation. Successful implementation of any rotavirus vaccine in the developing world requires additional clinical research and sharing of early introduction experiences. We discuss efforts to bring RotaTeq vaccine to the developing world. Critical steps to achieve this goal include the clinical evaluation of vaccine safety and efficacy in a multisite trial in Asia and Africa, evaluation of concomitant use with other pediatric vaccines routinely used, and vaccine assessment in special populations (premature, human immunodeficiency virus-infected, and malnourished infants). Completion of WHO prequalification of RotaTeq and affordability are also key requirements to routine vaccine introduction. The RotaTeq Partnership with the Nicaraguan Ministry of Health provides an example of the successful introduction of this vaccine into a developing world country.

During a mass campaign with a newly licensed meningococcal polysaccharide ACW135 vaccine in Burkina Faso, adverse events following immunization (AEFI) were monitored up to 4 weeks after the campaign. Eighty-six AEFI cases (5.9 cases per 100,000 vaccine doses distributed) were reported. Among 22 serious events, 4 severe local reactions were considered very likely and 4 severe allergic reactions were considered probably related to the vaccination. One fatal case in a child followed protracted seizures of undetermined cause. In a setting with no prior surveillance system, adverse events were reported at rates comparable to documented rates for meningococcal polysaccharide vaccines in other settings. The findings confirm the benefits of the vaccine in the control of meningococcal meningitis.

Following a large Neisseria meningitidis W135 (NmW135) epidemic in Burkina Faso (BF) during 2002, a newly licensed trivalent A/C/W135 meningococcal polysaccharide vaccine was introduced in 2003. We conducted a case-control study to assess the vaccine effectiveness (VE) against meningococcal disease. Thirty-two N. meningitidis A (NmA) and 3 NmW135 meningitis cases were enrolled and matched by age-neighborhood to 103 controls. After adjusting for confounding risk factors, VE against NmA or NmW135 was 83.6% (95% CI 31.8-97.0, p=0.01) for persons with verified vaccination. VE against probable/definite NmA alone was 94.0% (95% CI 58.7-99.0, p=0.0003). Low number of NmW135 cases did not allow estimation of VE against NmW135 alone. The vaccine was highly effective against the epidemic. Since 2003, the trivalent vaccine continues to be effectively used in Africa for the control of meningococcal disease epidemics.

A phase II open and parallel reactogenicity, immunogenicity and safety trivalent meningitis vaccine (Mencevax) trial was conducted on 413 volunteer 2-29-year-old rural residents in Ethiopia in November/December 2005. Adverse events (AE) were monitored at 1h, 1, 2, 3, 7 and 28 days after vaccination. No serious AE occurred except for burn injury (one) and severe malaria (one) after day 28. Irritability (45/411), loss of appetite (27/411), pain at injection site (26/412), dizziness (18/409), crying (14/411), insomnia, headache and diarrhoea (13/411) were the most frequent AEs. Overall, the vaccine is safe in the age groups studied.

The immunogenicity and safety of a meningococcal trivalent A/C/W135 polysaccharide vaccine was compared with that of a tetravalent A/C/Y/W135 polysaccharide vaccine in a randomised, double blind trial. The study included 360 adults, who received either a trivalent or tetravalent polysaccharide meningococcal vaccine. Antibody responses were determined by serum bactericidal antibody (rSBA) assays prior to vaccination and on day 28 and month 11 after vaccination. The percentage of participants in the trivalent vaccine group who had rSBA titres >or=8 on day 28 post-vaccination against serogroups A, C and W135 meningococci were 99, 98 and 91%, respectively. The corresponding figures in the tetravalent vaccine group were 99, 99 and 90%. The percentage of participants with various cut off levels of rSBA against serogroups A, W135 and C meningococci on day 28 and 11-month post-vaccination and the incidence of adverse events did not differ significantly between the two groups.

With the emergence of epidemic Neisseria meningitidis W135 meningitis in Burkina Faso during early 2002, the public health community was faced with the challenge of providing access to an appropriate and affordable vaccine in time for the upcoming 2003 epidemic season. Recognizing the implications of the emergent threat, the World Health Organization developed a strategy, established a public-private partnership to provide the needed vaccine, and then ensured that a stockpile was available for future use. The trivalent N meningitidis ACW135 polysaccharide vaccine that resulted is now one of the primary tools for epidemic response in African meningitis belt countries. It will remain so for the foreseeable future and until appropriate and affordable conjugate vaccines become part of national immunization programs in the region.

Malawi has extreme poverty and a high-human immunodeficiency virus (HIV) prevalence. Following Haemophilus influenzae type b (Hib) conjugate vaccine introduction during 2002, we evaluated vaccine impact by reviewing hospital surveillance data for acute bacterial meningitis in Blantyre district among children age 1-59 months admitted during 1997-2005. Documented annual Hib meningitis incidence rates decreased from 20-40/100,000 to near zero among both rural and urban residents despite no change in pneumococcal meningitis incidence rates. Before vaccine introduction, an average of 10 children/year had Hib meningitis and HIV infection compared to 2/year during 2003-2004 and none during 2005. Vaccine effectiveness was high following two or more doses of vaccine. The most urgent future need is for a sustainable routine infant immunization program, including a less expensive vaccine that preferably is delivered in a multivalent form.

Objectives: We sought to evaluate Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction (PROPELLER; BLADE) data acquisition in comparison with standard k-space sampling techniques for axial and sagittal brain imaging at 3 T regarding imaging artifacts., Material and Methods: Forty patients who gave consent were included in a prospective comparison of standard and PROPELLER (BLADE) k-space sampling techniques. All examinations were performed at 3 T with comparison of standard T2-weighted fluid-attenuated inversion recovery (FLAIR) to PROPELLER T2-weighted FLAIR in the axial image orientation and standard T1-weighted gradient echo to PROPELLER T1-weighted FLAIR in the sagittal image orientation. Imaging protocols were matched for spatial resolution, with data evaluation performed by 2 experienced neuroradiologists. Image data were compared regarding various image artifacts and overall image quality. Reader agreement was assessed by Cohen's kappa statistics., Results: PROPELLER T2-weighted axial data acquisition showed significantly less pulsation and Gibb's artifacts than the standard T2-weighted scan. Even without motion correction, the frequency of ghosting (motion) artifacts was substantially lower in the PROPELLER T2-weighted data and readers concordantly (kappa = 1) rated PROPELLER as better than or equal to the standard T2-weighted scan in the majority of cases (95%; P < 0.0001). In the comparison of sagittal T1-weighted data sets, readers showed only fair agreement (kappa = 0.24) and noted consistent wrap artifacts in PROPELLER T1-weighted FLAIR., Conclusion: PROPELLER (BLADE) brain magnetic resonance imaging is also applicable at 3 T. In addition to minimizing motion artifacts, the PROPELLER acquisition scheme reduces other magnetic resonance artifacts that would otherwise degrade scan quality.

Hepatitis B virus infection is a serious problem globally, and particularly in the Western Pacific Region where the population suffers disproportionately from the infection and its sequelae. By 2001, every immunization programme in the Region had included hepatitis B vaccine in their schedule. However, many challenges remain if every one of the 26 million children born in the 37 countries and areas of the Region each year is to be protected against hepatitis B infection. In 2003, the Regional Committee of the World Health Organization's Western Pacific Region resolved to improve hepatitis B control by making it one of two new pillars for strengthening the Expanded Programme on Immunization. The Committee endorsed the strategies of the Regional Plan to improve hepatitis B control through immunization, reducing chronic HBV infection (chronic carriage rate) to less than 1%, and aiming for coverage of at least 80% of the birth cohort in every district with three doses of hepatitis B vaccine by 2005. To help guide this process, an assessment was made of the progress to date, and is reported in this paper. Coverage data used in this evaluation were not independently verified, and could over-estimate progress made in some countries. Whilst there has indeed been great progress in the Region, a number of national programmes still lack the ability to reach all children with immunization services. Other major issues that need to be addressed are the challenges of delivering a timely birth dose, and for certain countries, the affordability of the vaccine over the short- and long-term.

Objective: The objective of this study was to compare the difference in lesion enhancement between 1.5 and 3 T using an extracellular gadolinium chelate in a rat brain glioma model., Methods: Five rats (CDF Fischer 344) with implanted C6/LacZ brain gliomas were evaluated using matched T1-weighted spin echo techniques and hardware configurations at 1.5 and 3 T. Serial imaging over 10 minutes after gadoteridol (ProHance) administration was performed. Contrast enhancement (CE), signal-to-noise ratios (SNR) for brain and tumor, as well as contrast-to-noise ratios (CNR) were evaluated using region-of-interest (ROI) analysis at both field strengths. All gliomas were also evaluated by histopathology., Results: CE at 3 T increased by 106% to 137% (all P<0.05) with maximum CE occurring at 5 minutes for both 1.5 and 3 T (9.8+/-2.2 vs 21.1+/-3.5; P=0.0004). At 3 T, SNR increased for normal brain by 66% to 76% (P<0.01) and SNR for tumor increased by 70% to 89% (P<0.01). CNR increased by 101% to 137% (P<0.05) depending on the time postcontrast. The highest CNR for both 1.5 T and 3 T occurred 5 minutes after contrast (1.5 T: 9.4+/-1.1 vs 3 T: 20.3+/-2.4; P<0.0004)., Conclusion: Using a standardized animal model and matched scan techniques, this study shows a significant benefit of 3 T compared with 1.5 T in contrast-enhanced brain tumor magnetic resonance imaging.

Haemophilus influenzae type b (Hib) still causes a substantial number of deaths among children in developing countries, despite the availability of effective conjugate vaccines. A major obstacle in developing a Hib vaccine has been limited awareness about the impact of Hib disease. A tool was developed to estimate the national rates of Hib meningitis and pneumonia by assessing retrospective local data over 7 to 10 days. Data from 11 countries in Africa, the Middle East, and Asia were studied and showed rates of Hib meningitis from >50 cases per 100,000 children >5 years in Ghana and Uganda to <15 per 100,000 in Iran, Jordan, and Uzbekistan. Results were affected by the quality of available data. The Hib rapid assessment tool can be useful to countries that desire a timely assessment of Hib disease rates.

PNQX (1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3, 4-f]quinoxaline-2,3-dione) is a potent AMPA (IC50 = 0.063 microM) and GlyN (IC50 = 0.37 microM) receptor antagonist that was developed in our laboratories. While possessing a desirable in vitro and in vivo activity profile, this compound suffers from low aqueous solubility. In an effort to improve its potency and physical properties, we have designed and synthesized novel ring-opened analogues 4, 6, 9, and 11. Modeling analyses demonstrated that, while the 5-substituent in these analogues was forced to adopt an out-of-plane conformation due to steric contacts with neighboring substituents, the overall structure retained a good fit to a previously described AMPA pharmacophore model. This nonplanar orientation may lessen efficient packing in the solid state, compared to PNQX, leading to increased water solubility. Indeed, several nonplanar analogues containing appropriate functionalities, for example, the sarcosine analogue 9, were found to retain AMPA (IC50 = 0.14 microM) and GlyN (IC50 = 0.47 microM) receptor affinity and possess improved aqueous solubility compared to PNQX. The synthesis and the SAR of these compounds are discussed.

Aims: The factor structure of DSM-IV substance disorder criteria is examined among alcohol, cannabis, cocaine and opiate users to determine the dimensionality of abuse and dependence criteria within each of these drug classes and whether a common construct can be generalized across drug classes., Design: 12-month criterion prevalence was assessed as part of the World Health Organization's Study on the Reliability and Validity of the Alcohol and Drug Use Disorder Instruments in various settings at eight sites around the world using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A majority of respondents were recruited from non-treatment settings. In addition to exploratory factor analysis, confirmatory factor analysis was used to analyse factor structures using weighted least square methods and tetrachoric correlation matrices. Multi-sample analysis techniques were used to model differences between drug-classes., Findings: In the full data analyses identified a single factor solution for each user population and across user populations. However, analyses of data from users reporting low to moderate symptomatology identified a two-dimensional construct among alcohol, cannabis and opiate users consisting of a major "dependence" factor and a lesser "abuse" factor. In addition, results showed that neither the abuse criterion "(A2) use in physical hazardous situations" or the dependence criterion "(D7) use despite knowledge of psychological/physical problems" were central to the latent construct in any of the user populations, except for D7 among alcohol users., Conclusions: The multi-dimensional results found among users with low to moderate symptomatology indicate that: (1) previous results from relatively homogeneous populations may have been biased towards lesser order solutions, and that (2) the DSM-IV substance disorder criteria describe at least two distinct phenomena, supporting the current DSM-IV organization of substance disorder criteria. Further work needs to evaluate whether prevalent symptoms are present in random or predictable combinations, whether combinations reflecting a specific hierarchy of severity can be identified, and whether incident symptoms are accumulated in a predictable pattern, within specific user populations and across user populations.

A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.

Our interest in the area of m4 muscarinic antagonists had led us to study a series of benzoxazine isoquinolines. One of the most potent and selective compounds of this series is example 1 with an IC50 value of 90.7 nM at m4 receptors, and 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82-fold (m5) more selective compared to the other receptors. The synthesis and receptor binding affinity of analogs of 1 are reported.

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

Unlabelled: AIMS/DESIGNS: As part of the Early Developmental Stages of Psychopathology (EDSP) study, results from the baseline cross-sectional assessment of DSM-IV alcohol disorders are presented for a sample of 14-24-year-olds residents in Munich, Germany (N = 3021; 71% response rate)., Findings: Life-time prevalence of DSM-IV alcohol abuse (men: 15.1%; women; 4.5%) was found to be considerably more prevalent than dependence (men: 10.0%; women 2.5%) with few cases among respondents younger than 16 years of age; 12-month prevalence of abuse was 8.4% among men and 2.7% among women and of dependence was 7.3% among men and 2.2% among women. Results show that peak incidence of alcohol disorders occurs at 16-17 years of age and that early initiation into alcohol use is associated with an increasing odds of disorder onset, especially for dependence among women. Exploratory analysis of retrospectively assessed diagnostic stability show: a temporal progression to abuse and then dependence, that nearly half of past abuse diagnoses are in remission, abuse remission is more common than progression to dependence, and dependence is highly persistent, especially among women., Conclusions: Alcohol disorders are frequent in adolescent and young adults being characterized by transient abuse and less prevalent but persistent dependence syndromes. The relatively high prevalence of dependence diagnoses in this young population wit few years of alcohol use is discussed with regard to the clinical validity of DSM-IV criteria in adolescents and young adults.

General population data are presented on patterns and predictors of temporal progression of alcohol dependence symptoms in the general population. The data come from the National Comorbidity Survey, a nationally representative general population survey of respondents ages 15-54. Lifetime symptom classes were estimated with latent class analysis (LCA). A 4-class LCA solution, including a 1st asymptomatic class and 3 progressively more serious symptomatic classes, was found to fit the data. Probability of initial symptom onset among drinkers was found to be highest in the 10-24 age range, to be higher among men than women, and to have increased dramatically in the past 4 decades. Age, gender, and cohort effects were less powerful in predicting symptom progression. A narrowing of the gender difference over time was due largely to a convergence in initial symptom onset among men and women ages 10-24. These results suggest that a rise in initial problems was more important than an increase in the transition from problems to dependence in accounting for the growing prevalence of alcohol dependence during the post-World War II years in the United States.

Ths paper describes the distribution of dependence criteria and diagnoses in a sample of 14- to 24-year-olds from Munich, Germany (n = 3,021; 71% response rate), evaluates differences between nondependent and dependent smokers and examines associations of smoking with other substances, affective and anxiety disorders. Assessment was made using the M-CIDI. The lifetime prevalence of DSM-IV nicotine dependence in the total sample is 19%, rising to 52% among regular smokers. No gender differences were seen in the progression from regular smoking to nicotine dependence, although men were more likely than women to initiate regular use. Analysis of daily cigarette use identified a significant dose-response relationship with the number of endorsed DSM-IV dependence criteria with unsuccessful cut-backs being the most prevalent criterion. As compared to nondependent smokers, dependent smokers were more likely to associate negative health effects with smoking and to have a desire to change and attempt a change in their pattern of use. Regular use of nicotine was found to be significantly associated with other substance and nonsubstance disorders, although dependent regular use was more strongly associated with these disorders than nondependent regular use. These results indicate that daily smoking is a behavior which is resistant to change despite an expressed desire and repeated cut-back attempts. Although initiation of regular smoking among nonsmokers does not occur frequently after the early twenties, the risk for dependent smoking among regular users persists into adulthood and is associated with a range of mental disorders.

The primary and secondary objectives of the Early Developmental Stages of Substance Abuse Study (EDSP) are described along with a detailed description of the overall design, special design features and instruments used. The EDSP is a 5-year prospective study with three waves of assessments. Special design features are the linkages with family genetic investigations as well as neuroendocrinological stress tests in high-risk subjects. Overall, 3,021 adolescents and young adults aged 14-24 years are included. The response rate for the baseline investigation was 71%. Diagnostic assessments were made by using a modified lifetime (baseline) and 12-month change version of the WHO-CIDI, adjusted for DSM-IV. Modifications refer to a more detailed quantitative assessment of symptoms and substance use variables as well as the inclusion of questions to assess course of disorders and subthreshold diagnostic conditions.

152255 (E-1,1'-(2-butene-1,4-diyl)bis[2-[4-[3-(1-piperidinyl)propoxy]-phe nyl]-1H-benzimidazole]) exhibited high affinity (Ki = 12.7 nM) for human dopamine (DA) D3 receptors expressed in CHO K1 cells but not for DA D2L receptors (Ki = 565 nM), DA D42 or DA D1 receptors (Ki > 3 microM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D3 receptors was demonstrated by blockade of quinpirole-stimulated [3H]-thymidine uptake in D3 transfected cells, an effect that was 28-fold more potent than in D2-transfected cells. Unlike classical DA D2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D3 antagonist that may have antipsychotic activity.

Background: As part of a longitudinal study, prevalence findings of DSM-IV disorders are presented for a random sample of 3021 respondents aged 14 to 24, with response rate 71%., Method: Assessment included various subtypes of disorders, subthreshold conditions and disorders that have only rarely been studied in other epidemiological surveys. The computer-assisted Munich-Composite International Diagnostic Interview (M-CIDI) was used to derive DSM-IV diagnoses., Results: Substance disorders were the most frequent (lifetime 17.7%; 12-month 11.4%), with abuse being considerably more frequent than dependence. Other mental disorders had a lifetime prevalence of 27.5% (12-month, 17.5%) with depressive disorders (16.8%) being more frequent than anxiety disorders (14.4%). Eating disorders (3.0%) and threshold somatoform disorders (1.2%) were rare disorders. Subthreshold anxiety and somatoform disorders, however, were more frequent than threshold disorders. Prevalence of disorders was equally high for males and females, although specific disorder prevalence varied significantly by gender. The co-occurrence of disorders (co-morbidity) was substantial and was significantly related to greater reductions in work productivity and increased rates of professional helpseeking behaviour., Conclusions: Findings underline that mental disorders in young adults are frequent and impairing, limiting work and education ability and social interaction. Given the fact that adolescents and young adults are in a key phase of socialization in terms of professional career and interpersonal relationships, our findings indicate a considerable risk potential for an accumulation of complicating factors and future chronicity. This paper is the first report of this ongoing longitudinal study about early developmental conditions of mental disorders.

Objective: To study patterns of co-occurrence of lifetime DSM-III-R alcohol disorders in a household sample., Methods: Data came from the National Comorbidity Survey (NCS), a nationally representative household survey. Diagnoses were based on a modified version of the Composite International Diagnostic Interview., Results: Respondents with lifetime NCS/DSM-III-R alcohol abuse or dependence had a high probability of carrying at least 1 other lifetime NCS/DSM-III-R diagnosis. Retrospective reports have suggested that most lifetime co-occurring alcohol disorders begin at a later age than at least 1 other NCS/DSM-III-R disorder. Earlier disorders are generally stronger predictors of alcohol dependence than alcohol abuse and stronger among women than men. Lifetime co-occurrence is positively, but weakly, associated with the persistence of alcohol abuse among men and of alcohol dependence among both men and women., Conclusions: Caution is needed in interpreting the results due to the fact that diagnoses were made by nonclinicians and results are based on retrospective reports of the age at onset. Within the context of these limitations, though, these results show that alcohol abuse and dependence are often associated with other lifetime DSM-III-R disorders and suggest that, at least in recent cohorts, the alcohol use disorders are usually temporally secondary. Prospective data and data based on clinically confirmed diagnoses are needed to verify these findings.

General population data are presented on the prevalence and correlates of comorbidity between DSM-III-R major depressive disorder (MDD) and other DSM-III-R disorders. The data come from the US National Comorbidity Survey, a large general population survey of persons aged 15-54 years in the non-institutionalised civilian population. Diagnoses are based on a modified version of the Composite International Diagnostic Interview (CIDI). The analysis shows that most cases of lifetime MDD are secondary. In the sense that they occur in people with a prior history of another DSM-III-R disorder. Anxiety disorders are the most common primary disorders. The time-lagged effects of most primary disorders on the risk of subsequent MDD continue for many years without change in magnitude. Secondary MDD is, in general, more persistent and severe than pure or primary MDD. This has special public health significance because lifetime prevalence of secondary MDD has increased in recent cohorts, while the prevalence of pure and primary depression has remained unchanged.

Age of onset reports obtained retrospectively for each symptom of DSM-III-R alcohol dependence (AD) are used to study patterns of lifetime symptom progression in a large general-population survey of people in the United States. It is shown that symptom progression among a substantial majority of respondents can be summarized as movement across three clusters. Cluster A is defined by symptoms of role impairment/hazardous use (A4), use despite social, psychological or physical problems (A6), and drinking larger amounts or over a longer period of time than intended (A1). Cluster B is defined by tolerance (A7) and impaired control (A2, A3). Cluster C is defined by withdrawal (A8, A9) and giving up activities in order to drink (A5). Clusters are shown to follow a time sequence, with at least one symptom in Cluster A usually occurring first, followed by symptoms in Clusters B and C. In all, 83.4% of the symptom cluster transitions estimated from retrospective age of onset reports are consistent with this progression. Progression to AD is differentially predicted by symptom profiles reported at the age of first symptom onset, with persons reporting Cluster C symptoms most likely to progress subsequently to AD. Furthermore, profiles of AD defined by the highest symptom cluster present at AD onset are differentially predicted by prior personal and parental histories of psychopathology and, among men, are predictive of diagnosis persistence.

General population data from the National Comorbidity Survey are presented on co-occurring DSM-III-R addictive and mental disorders. Co-occurrence is highly prevalent in the general population and usually due to the association of a primary mental disorder with a secondary addictive disorder. It is associated with a significantly increased probability of treatment, although the finding that fewer than half of cases with 12-month co-occurrence received any treatment in the year prior to interview suggests the need for greater outreach efforts.

Background: Data were obtained on the general population epidemiology of DSM-III-R posttraumatic stress disorder (PTSD), including information on estimated life-time prevalence, the kinds of traumas most often associated with PTSD, sociodemographic correlates, the comorbidity of PTSD with other lifetime psychiatric disorders, and the duration of an index episode., Methods: Modified versions of the DSM-III-R PTSD module from the Diagnostic Interview Schedule and of the Composite International Diagnostic Interview were administered to a representative national sample of 5877 persons aged 15 to 54 years in the part II subsample of the National Comorbidity Survey., Results: The estimated lifetime prevalence of PTSD is 7.8%. Prevalence is elevated among women and the previously married. The traumas most commonly associated with PTSD are combat exposure and witnessing among men and rape and sexual molestation among women. Posttraumatic stress disorder is strongly comorbid with other lifetime DSM-III-R disorders. Survival analysis shows that more than one third of people with an index episode of PTSD fail to recover even after many years., Conclusions: Posttraumatic stress disorder is more prevalent than previously believed, and is often persistent. Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumas.

Four related series of substituted quinoxalinediones containing angular fused-piperidine rings have been synthesized as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists with potential as neuroprotective agents, primarily for acute therapy immediately following a stroke. The compounds were tested for their affinity to the AMPA, kainate, and strychnine-insensitive glycine receptor sites. In AMPA binding, the most potent compound was 27a (PNQX, IC50 = 63 nM), with affinity comparable to the literature standard 1 (NBQX, IC50 = 52 nM). Other 6-nitro analogs from the 9-aza series had comparable affinity at the AMPA receptor, as did 6-nitro-8-aza derivatives such as 13a (iPNQX, IC50 = 290 nM). The receptor binding profile of 27a differed from that of 1 in that 27a possessed significant affinity at the glycine site of the N-methyl-D-aspartate (NMDA) receptor, whereas 1 was essentially inactive. Three compounds, 26c, 26d, and 26e, demonstrated moderate selectivity for kainate relative to AMPA receptors. Selected analogs reported herein as well as in the literature were superimposed to generate an AMPA pharmacophore model, and 6-substituted compounds from the PNQX and iPNQX series were combined and analyzed via quantitative structure-activity relationship techniques. Compounds with high affinity at non-NMDA receptors were further characterized in functional assays in neuronal cell culture and in a cortical wedge preparation. Both 1 and 27a showed comparable effectiveness in an AMPA- and kainate-induced excitoxicity assay. Both inhibited AMPA-induced depolarizations in the cortical wedge. However, 27a also inhibited spontaneous epileptiform discharges in the cortical wedge (reversed by glycine), while 1 was ineffective. The combination of AMPA and NMDA antagonist activity may contribute to the 30-fold difference in potency between 27a and 1 in the maximal electroshock convulsant assay in mice. The significant in vivo potency of 27a suggests that it has potential clinical utility.

A methodology recently developed by the U.S. EPA for estimating the carcinogenic risks from ionizing radiation is described. For most cancer sites, the risk model is one in which age-specific, relative risk coefficients are obtained by taking a geometric mean of the coefficients derived from the atomic bomb survivor data using two different methods for transporting risks from the Japanese to the U.S. population. The risk models are applied to estimate organ-specific risks per unit dose for a stationary population with mortality rates governed by 1980 U.S. vital statistics. With the exception of breast cancer, low-LET radiogenic cancer risk estimates are reduced by a factor of 2 at low doses and dose rates compared to acute high dose exposure conditions. For low dose (or dose rate) conditions, the risk of inducing a premature cancer death from uniform, whole body, low-LET irradiation is calculated to be 5.1 x 10(-2) Gy-1. Neglecting nonfatal skin cancers, the corresponding incidence risk is 7.6 x 10(-2) Gy-1. High-LET (alpha particle) risks are presumed to increase linearly with dose and to be independent of dose rate. High-LET risks are estimated to be 20 times the low-LET risks estimated under low dose rate conditions, except for leukemia and breast cancer where RBEs of 1 and 10 are adopted, respectively.

Objectives: To analyze nationally representative data on the lifetime and 12-month prevalences of use of and dependence on illegal drugs (marijuana/hashish, cocaine/crack, heroin, hallucinogens), nonmedical prescription psychotropic drugs (sedatives, tranquilizers, stimulants, analgesics), and inhalants; and to examine data on the sociodemographic correlates of use and dependence., Methods: The data come from the National Comorbidity Survey, a structured diagnostic interview administered to persons aged 15 to 54 years that generates reliable diagnoses according to the definitions and criteria of DSM-III-R., Results: Of the respondents, 51.0% used one of the above drugs at some time in their lives, and 15.4% did so in the past 12 months. These estimates are similar to those obtained in the 1991 National Household Survey of Drug Abuse, where lifetime prevalence was 45.2% and 12-month prevalence was 16.7% among respondents in the age range 15 to 54 years. Of National Comorbidity Survey respondents, 7.5% (14.7% of lifetime users) were dependent at some time in their lives and 1.8% were dependent in the past 12 months. The prevalence estimate for lifetime dependence was reduced to 5.3% when calculated the percentage of respondents in the age range of 28 to 54 years who reported an onset of dependence as of 10 years earlier (ie, when they were 18 to 44 years old) was computed. This is similar to the Epidemiologic Catchment Area Study estimate of 5.1% among respondents in the age range 18 to 44 years, a comparison that matches the two studies on year of assessment, age of risk, and cohort. Males were significantly more likely to report both lifetime and 12-month use and dependence. Use and dependence were found to be more common in cohorts born after World War II than those born before the end of the war. The demographic predictors of lifetime use differed from the predictors of lifetime dependence among users, and these, in turn, differed from the predictors of recent dependence among people with a lifetime history of dependence., Conclusions: Drug use and dependence are highly prevalent in the general population. The fact that there are differences in the correlates of first use, dependence among users, and persistence of dependence means that future research aimed at pinpointing modifiable risk factors must be based on disaggregated analyses of separate stages of progression.

Higher rates of withdrawal from dialysis have been shown among young diabetic patients. This study examined the hypothesis that diabetic status has a joint effect with age as the result of an age-related increase in co-morbid conditions among nondiabetic ESRD patients. Using data collected during the 1980s by the Michigan Kidney Registry, the experience of 4,753 white and 2,988 black Michigan dialysis patients (13,863 patient years) is analyzed. During follow-up, 364 white and 80 black patients withdrew from dialysis. By use of a Cox analysis, adjusted rates of withdrawal were shown to be higher among white than black patients (rate ratio (RR) = 3.34; P < 0.001), without significant differences by diabetic status. Rates increased with age (RR = 7.9 for 80+ versus 20 to 35 yr; P < 0.001), without significantly different patterns by race. Adjusted withdrawal rates among diabetics were 2.3 times that of nondiabetics overall (P < 0.001), with a statistically significant joint effect with age, the RR being highest among young patients. Among white patients, nondiabetics using continuous ambulatory peritoneal dialysis had a lower relative withdrawal rate than those using hemodialysis (RR = 0.73; P = 0.07), whereas diabetics using continuous ambulatory peritoneal dialysis showed slightly higher although statistically insignificant rates than their counterparts using hemodialysis (RR = 1.21; P = 0.50). Between 1980 and 1989, withdrawal rates for white patients aged 20 to 34 yr tended to decrease by 20% per year (P = 0.05), whereas they increased by 11% per year for patients aged 50 to 69 yr (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Data from a nationally representative sample of the general population are used to study cohort differences in the prevalence of DSM-III-R Major Depressive Episode (MDE). We document increasing lifetime prevalence of MDE among both men and women in more recent cohorts, but no major change in the sex ratio over the 40-year period retrospectively covered in the survey. We find a cohort difference in 12-month MDE, with older women much more likely than older men to have recurrent episodes. This sex difference in recurrence plays an important part in the elevated 12-month prevalence of depression among women compared to men in the 45-54 age range.

Background: This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States., Methods: The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview., Results: Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status., Conclusions: The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.

Basic epidemiologic prevalence data are presented on sex differences in DSM-III-R major depressive episodes (MDE). The data come from the National Comorbidity Survey (NCS), the first survey in the U.S. to administer a structured psychiatric interview to a nationally representative sample of the general population. Consistent with previous research, women are approximately 1.7 times as likely as men to report a lifetime history of MDE. Age of onset analysis shows that this sex difference begins in early adolescence and persists through the mid-50s. Women also have a much higher rate of 12-month depression than men. However, women with a history of depression do not differ from men with a history of depression in either the probability of being chronically depressed in the past year or in the probability of having an acute recurrence in the past year. This means that the higher prevalence of 12-month depression among women than men is largely due to women having a higher risk of first onset. The implications of these results for future research are discussed in a closing section of the paper.

To evaluate the mortality of continuous ambulatory peritoneal dialysis (CAPD) patients relative to hemodialysis (HD) patients, all Michigan residents 20 to 59 yr of age who initiated therapy for ESRD during the 1980s (N = 4,288) were studied. The study population was stratified by primary renal diagnosis (glomerulonephritis, hypertension, diabetes, other), and analyses were conducted within each group by Cox proportional hazards methods controlling for age, race, sex, and year in which chronic dialysis was initiated. Intent-to-treat (ITT) and treatment history (RxHx) censoring criteria were used. For patients with hypertension or other reported causes of ESRD, there was no significant difference in CAPD and HD patient mortality (relative risk (RR) = 0.99 and 1.05, respectively). In the ITT analysis, both glomerulonephritic (RR = 0.73; P = 0.10) and diabetic patients using CAPD experienced mortality rates lower than their HD counterparts. Among diabetics, this difference ranged from a RR of 0.40 to 0.70, being lowest for younger diabetics and statistically significant (P < or = 0.05) for ages 20 to 52 yr. Evaluation of mortality trends showed a significant (P < 0.01) decrease in diabetic CAPD mortality rates during the decade, whereas diabetic HD mortality rates increased (P = 0.06). Among diabetics, men had higher mortality rates than women (ITT--RxHx; RR = 1.22 to 1.27; P < 0.001) and white patients had higher mortality rates than black patients (ITT--RxHx, RR = 1.34 to 1.44; P < 0.001). Differences in mortality by sex and race were not found among nondiabetics, but mortality did increase significantly with age in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

For risk assessments, the average current residence time (time since moving into current residence) has often been used as a surrogate for the average total residence time (time between moving into and out of a residence). Since the distributions of the two quantities are not necessarily the same, neither are their averages. Housing surveys provide current residence time data; total residence times must, therefore, be inferred. By modeling the moving process, the total residence time distribution can be estimated from current residence time data. Using 1985 and 1987 U.S. housing survey data, distributions and averages for both current and total residence times were calculated for several housing categories. The average total residence time calculated for all U.S. households, 4.6 (se= 0.6) years, is less than half the average current residence time, 10.6 (se= 0.1) years.