Methods and strategies for gene structure curation in WormBase.

The Caenorhabditis elegans genome sequence was published over a decade ago; this was the first published genome of a multi-cellular organism and now the WormBase project has had a decade of experience in curating this genome's sequence and gene structures. In one of its roles as a central repository for nematode biology, WormBase continues to refine the gene structure annotations using sequence similarity and other computational methods, as well as information from the literature- and community-submitted annotations. We describe the various methods of gene structure curation that have been tried by WormBase and the problems associated with each of them. We also describe the current strategy for gene structure curation, and introduce the WormBase 'curation tool', which integrates different data sources in order to identify new and correct gene structures. Database URL: http://www.wormbase.org/.

Paclitaxel maintenance chemotherapy following intraperitoneal chemotherapy for ovarian cancer.

The aim of this study was to determine the feasibility of two treatment regimens for ovarian cancers: (1) combined intraperitoneal/intravenous (IP/IV) cisplatin/paclitaxel; or (2) IV only carboplatin/paclitaxel; both followed by 12 cycles of maintenance paclitaxel. A total of 102 subjects were identified who underwent surgery for stage III ovarian cancer. All subjects received either IV or IV/IP chemotherapy, and had a complete response. The subjects were then prescribed maintenance paclitaxel IV for an additional 12 months. Demographic and clinical data were analyzed. Forty-five subjects received combined IP/IV chemotherapy versus 57 who received IV therapy alone. IP/IV versus IV administration was not associated with differences in age, ethnicity, tumor histology, or incidence of intestinal surgery. Toxicities included fatigue, neuropathy, myelosuppression, and nausea/vomiting in both groups. In the IP/IV group, 29/47 subjects (61.7%) completed 12 cycles of maintenance paclitaxel versus 18/55 (32.7%) in the IV group (P = 0.006). The mean number completed by the IP/IV group was 8.6, while the IV group completed 5.8 cycles (P = 0.002). In subjects who received <12 cycles, the mean number of cycles completed by the IP/IV group was 3.1 versus 2.8 in the IV group. The reasons for stopping included neuropathy (33), fatigue (8), myelosuppression (7) and disease progression (6). Patients who received combined IP/IV chemotherapy were more likely to complete maintenance therapy than those who only received IV chemotherapy. Patients who stop maintenance therapy usually do so early in the course. Additional resources directed at physical and emotional support during early cycles of maintenance chemotherapy may allow more to complete the regimen.

A mutation in Drosophila simulans that lengthens the circadian period of locomotor activity.

The length of the Thr-Gly repeat within the period gene of Drosophilids, coevolves with its immediate flanking region to maintain the temperature compensation of the fly circadian clock. In Drosophila simulans, balancing selection appears to maintain a polymorphism in this region, with three repeat lengths carrying 23, 24 or 25 Thr-Gly pairs, each in complete linkage disequilibrium with a distinctive flanking region amino acid moiety. We wondered whether separating a specific length repeat from its associated flanking haplotype might have functional implications for the circadian clock. We fortuitously discovered a population of flies collected in Kenya, in which a chimeric Thr-Gly haplotype was segregating that carried the (Thr-Gly)24 repeat, but the flanking region of a (Thr-Gly)23 allele. One of the five isofemale lines that carried this 'mutant' Thr-Gly sequence showed a dramatically long and temperature-sensitive free-running circadian period. This phenotype was mapped to the X chromosome, close to the D. simulans per gene, but there was also a significant effect of a modifying autosomal locus or loci. It seems remarkable that such a mutant phenotype should be discovered in a screen of chimeric Thr-Gly regions.

Sexually transmitted infections among HIV infected and HIV uninfected high-risk youth in the REACH study. Reaching for Excellence in Adolescent Care and Health.

OVERVIEW: This review presents the findings of published research in the Reaching for Excellence in Adolescent Care and Health (REACH) Project on sexually transmitted infections (STIs) within the context of the project's scientific agenda. Methods employed in the study for specimen collection, management, and laboratory analysis are presented. This review presents published analyses of cross-sectional data; longitudinal analyses are underway. In addition, baseline prevalence data on selected STIs and sexual risk profiles of the subjects in REACH are presented. High STI rates were evident in both human immunodeficiency virus (HIV) infected and uninfected youth of both genders regardless of sexual orientation. High infection rates at baseline suggest that prevention-oriented programs for risk reduction among adolescents should focus on both HIV infected and at-risk, uninfected youth.

Contraceptive choices in HIV infected and HIV at-risk adolescent females.

PURPOSE: To describe reported contraception use in HIV infected and HIV uninfected but at-risk female adolescents, and determine associations with the reported consistent use of effective contraception methods, including its association with pregnancy. METHODS: HIV infected and at-risk female youth, aged 13-18 years, who were sexually active and reporting no intention to become pregnant, were included. Contraception use data from three consecutive visits (approximately 6 months apart) were used. RESULTS: Ninety-four percent of HIV infected and 89% of at-risk subjects reported choosing a main contraception method with demonstrated efficacy when used consistently. Approximately 50% chose partner condoms. HIV infected youth were more likely to report 100% partner condom use in the past 3 months (73% vs. 46%; OR 3.3; 95% CI: 1.7-5.6). At-risk youth were 2.5 times more likely than HIV infected subjects to report using nothing (95% CI: 1.1-5.8). Slightly more than half (56%) demonstrated the consistent reporting of effective methods (CREM) of contraception. In multivariate analysis, HIV infection (OR 4.0; 95% CI: 2.2-8.2) and African-American race (OR 2.7; 95% CI: 1.1-6.6) were significantly associated with CREM. Subjects reporting inconsistent or unreliable contraception use had higher 1-year pregnancy rates than CREM subjects (32% vs. 14%; p = .002). CONCLUSIONS: Only half of HIV infected and at-risk youth reported using effective contraception consistently, despite its availability. Additionally, regardless of reported contraceptive use, the rates of unplanned pregnancy were unacceptably high.

Incident pregnancy rates in HIV infected and HIV uninfected at-risk adolescents.

PURPOSE: To compare pregnancy incidence between HIV infected and HIV uninfected adolescents over a 3-year period and to characterize factors that differentiate pregnant from nonpregnant HIV infected females. METHODS: Female adolescents enrolled in Reaching for Excellence in Adolescent Care and Health (REACH), a national cohort study, and nonpregnant at baseline comprised the sample (n = 345). Subject information on pregnancy, risk behavior, and psychosocial characteristics was obtained through interview, chart review, physical examination and laboratory data collected every 3 months. Incident pregnancy rate was analyzed using Cox proportional hazards modeling; the predictors of incident pregnancy were evaluated using repeated measures analysis. RESULTS: Ninety-four pregnancies were identified over 3 years. No significant difference in pregnancy incidence was detected between HIV infected and uninfected females (20.6 and 28.4 per 100 person-years, respectively, p = .16). However, for adolescents with living children at entry, HIV infected females were significantly less likely to become pregnant than HIV uninfected (HR = .45; p = .03). Among HIV infected adolescents, significant predictors of incident pregnancy were older age (p = .01) and not using hormonal contraception (p = .00), whereas increased spiritual hope and passive problem-solving capacity were protective against pregnancy (p = .02, and.05, respectively). Multivariate analysis revealed pregnancy prior to study entry to be predictive for (OR = 3.0; 95% CI: 1.2-7.7), and increased spiritual hope to be protective (OR = .4; 95% CI: .2-.9) against incident pregnancy in HIV infected females without the hormonal contraceptive variable in the model. CONCLUSIONS: The pregnancy rate is high in this study population. Further research is needed into its determinants and attenuating factors, particularly the role of spiritual elements, to design better contraceptive services and reproduction-related education targeting high-risk youth.

HIV-1 RNA levels and development of clinical disease in two different adolescent populations.

HIV infection rates in American youth continue to increase unabated. As adolescent-specific therapeutic interventions are planned, information on HIV infection's course and its predictors becomes critically important for valid and precise study design. We report on age-specific disease rates stratified by estimated time since infected and predictors of HIV disease progression through four clinical categories in two distinct adolescent populations. Adolescents with hemophilia infected through contaminated blood products showed disease progression rates of 18 to 23 events per 100 person-years (PYs) by age and years infected. Predictors of first progression included HIV-1 RNA >30,000 copies/ml (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.5-3.9), antiretroviral monotherapy (RR, 2.4; 95% CI, 1.7-3.3); Latino/a ethnicity (RR, 2.2; 95% CI, 1.2-4.2) and initial intermediate clinical status (RR, 1.9; 95% CI, 1.3-2.9). Sexually-infected adolescents >18 years who had been infected >3 to 6 years had a disease progression rate of 16 events per 100 PY. For these youths, the sole predictor of first progression was viral load (VL) (RR for VL >30,000 copies per ml, 8.4; 95% CI, 2.8-25.1). This article examines the predictive capacity of viral load and evaluates other cofactors for disease progression in different adolescent populations. These data will be of value in clinical trial design.

Performance of antigens used in detecting delayed-type hypersensitivity in adolescents infected with the human immunodeficiency virus.

We examined the performance of delayed-type hypersensitivity (DTH) antigens employing a new Candida albicans product in a human immunodeficiency virus (HIV)-infected and nonanergic adolescent population. Diameters of induration (in millimeters) for three intradermally applied antigens (C. albicans, tetanus toxoid, and mumps) were compared in a population of HIV-infected 12 to 18 year olds at study entry in a national multicenter study of HIV disease progression. CD4+ T-cell counts were measured in quality-controlled laboratories. The influence of past immunization, gender, and clinical status on antigen reactivity was evaluated with contingency table comparisons and relative risk estimation. Nearly one-half of the 123 eligible subjects were untreated, and almost three-quarters were early in HIV disease by clinical indicators. There was no statistically significant difference in reactivity by past immunization status. Candida antigen (CASTA; Greer Laboratories) evoked DTH response in a significantly higher number of males and females at every level of induration (largest P value, 0.049 for male comparisons; all P values, <0.001 for females) and in subjects with early and intermediate HIV disease at every level of induration (all P values, <0.0001) than either tetanus or mumps antigens. No two-antigen combination was as useful as all three antigens across either gender or clinical categories, although candida and tetanus was the most useful two-antigen combination at indurations of <3 mm. The superior performance of a new C. albicans antigen may extend the utility of DTH assessment in monitoring immune function.

Serologic examination of hepatitis B infection and immunization in HIV-positive youth and associated risks. The Pediatric AIDS Clinical Trials Group Protocol 220 Team.

This seroprevalence report examines serologic evidence of hepatitis B immunization or infection and associated demographic/behavioral factors in adolescent (aged 12-20) subjects enrolled in a nontherapeutic clinical trial at 43 Pediatric AIDS Clinical Trials Group (PACTG) clinical centers. Subjects (n = 94) infected with the human immunodeficiency virus (HIV) through sexual activity were categorized as hepatitis B virus (HBV)-immunized, HBV-infected, or nonimmune by hepatitis B serology performed on specimens collected within the subject's first 48 weeks on study (1993-1995). Sixteen percent of the 94 serologically classified subjects were immunized; 19% HBV-infected; 65% nonimmune. Of the three risk factor scores examined (sociodemographic, sexual, and substance abuse), substance use alone demonstrated a significant difference among groups (despite virtually no reported injecting drug behavior), with the sexual risk score exhibiting marginally significant differences. Logistic regression analysis (restricted to nonimmunized subjects) showed that male-male sexual activity raised the odds of HBV infection by a factor of 5.14 (95% confidence interval [CI]: 1.45-18. 23) relative to heterosexual activity; and that for every one point increase on the substance abuse risk scale the odds of infection increased 5% (95% CI: 0.99-1.10). The HBV infection rate in PACTG 220 HIV-positive females is twice United States population-based rates; the rate in PACTG 220 HIV-positive males is nearly seven times higher. Past immunization efforts in this population appear to have been based on sexual activity volume without regard to injecting-drug use in sex partners.

The REACH Project of the Adolescent Medicine HIV/AIDS Research Network: design, methods, and selected characteristics of participants.

PURPOSE: To describe the Reaching for Excellence in Adolescent Care and Health (REACH) Project of the Adolescent Medicine Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) Research Network, a unique collaborative effort to conceive and implement a research design intended to examine HIV pathogenesis, pubertal hormonal variation, and the effects of sexually transmitted disease comorbidity in HIV-infected youth to improve their health care. METHODS: This multidisciplinary team has drawn on basic science and clinical experience to produce a study design with relevant and feasible study aims and testable hypotheses. Particular attention has been paid to centralized training and quality control practices. Standardized measurements include direct and computer interviews, physical examination, laboratory analysis, and medical chart abstraction. The protocol has been approved by local institutional review boards. RESULTS: A highly standardized and quality control monitored protocol has been implemented at 16 sites throughout the United States collecting historical, observational, and laboratory data in a group of HIV-infected adolescents and HIV-negative controls. Preliminary data collected on subjects are consistent with published reports of the sociodemographic and clinical characteristics of the HIV epidemic in sexually active youth, thus supporting the integrity of the protocol development process. The study population is, for the most part, in older adolescence, predominantly minority and female, and with publicly financed or no health insurance. CONCLUSIONS: The REACH Project is positioned to address questions about the clinical course, immunologic profile, and viral dynamics in HIV-positive youth, and thus is able to inform drug development and management strategies for this understudied population.

A profile of human immunodeficiency virus-infected adolescents receiving health care services at selected sites in the United States.

OBJECTIVE: To determine the demographic/clinical profile of human immunodeficiency virus (HIV)-infected adolescents in care at selected sites. METHODS: We mailed surveys requesting prevalence data from physicians in government-funded HIV research and care programs on HIV-infected youth (10-21 years) receiving care. RESULTS: A total of 49% responses yielded information on 978 subjects. Vertical, blood, and sexual were predominant transmission modes. Three-quarters were of an ethnic/racial minority; 50% were female. The earliest median CD4 count was 0.467 x 10(9)/liter (467/microliter). Percent asymptomatic varied by transmission: vertical (16%), blood products (40%), male-male sexual (67%) and female-male sexual (M:73%) (F:74%). Clinical indicated Pneumocystis carinii pneumonia prophylaxis was differentially prescribed: vertical (96%), blood (89%), and sexually (male-male-47%) (female-male: M: 36% and F: 56%). Of these youth 78% are not represented in national AIDS case data. CONCLUSIONS: Examination of numerator data from selected sites indicates three transmission-driven adolescent HIV epidemics with different characteristics. Minority youth are disproportionately represented; many vertically infected infants are surviving to adolescence; sexual activity is a significant transmission avenue. HIV-infected youth appear to enter care with considerable immunosuppression. Clinical profiles and treatment patterns appear to differ by transmission mode. Further study is needed on adolescent HIV disease progression and determinants of access to care and treatment.

Guidelines for adolescent health research: a position paper of the society for adolescent medicine.

Their ambiguous legal and ethical status has become a barrier to adolescents' appropriate involvement in research from which they may benefit and which is needed to improve adolescent health care and to inform health policy. Involvement of adolescents in research should be based on a scientific and empathetic understanding of their developing capabilities and a careful assessment of risks and benefits. The important role of parents and communities as protectors of adolescents should be respected and enhanced as we acknowledge and respect developing adolescent autonomy. These guidelines provide a framework to interpret the federal regulations for protection of human subjects in light of the unique legal, ethical, developmental, contextual, and racial issues that affect adolescents. The guidelines are designed to protect individual adolescent research subjects and to facilitate important youth research that would promote the health of adolescents.

The role of cytochrome P450 in developmental pharmacology.

Numerous sources of human heterogeneity affect biotransformation of compounds. Cytochrome P450, the primary oxidative pathway of drug metabolism, is the dominant phase I oxidative system metabolizing, to some degree, most of the drugs used clinically in humans. The P450 pathway is a major site of drug-drug, drug-diet, and drug-disease/condition interactions. Functional variability in this system can have pronounced consequences in suboptimal therapeutic response or enhanced toxicity. Methods for cataloguing specific P450 enzymes are being developed and their identification will promote rational drug development, more efficient clinical trial evaluation, and improved therapeutic approaches to patients requiring special consideration. These methods will facilitate the study of the impact of pubertal development on function in this system.

A research agenda for the study of therapeutic agents in adolescents.

Without an understanding of the developmental factors which initiate functional changes in the adolescent's capacity for drug disposition, the choice of any developmental measure (e.g., Tanner staging) to include in a focused research effort is premature. The role of growth and gender in pubertal functional change must be delineated. In addition, research must target clinically relevant pharmacokinetic changes resulting from this functional development and relate these to modifications of drug effect (i.e., using effect-controlled trials rather than concentration-controlled trials). Such studies could define population characteristics associated with pubertal development that produce pharmacodynamic changes. Drug effect in the adolescent, particularly at the receptor level, needs study. A strategy for the systematic evaluation of these issues is discussed.

Influence of polar route schedules on the duty and rest patterns of aircrew.

The duty and rest periods of aircrew operating the polar route from London via Anchorage were recorded during five schedules which involved 1-, 2- or 3-day sojourns in Japan. Sleep throughout each schedule was fragmented, with naps before duty and short sleeps after arrival at a new location. Sleep disturbance rather than cumulative sleep loss appeared to be the overriding problem, and the shorter schedules had the most marked disturbances in sleep during the trip and during the immediate recovery period. Electroencephalographic studies are necessary to confirm these observations, and information on circadian rhythmicity is needed to define the circumstances which lead to persistence of sleep disturbance on return to Europe.